%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 110 0 R 112 0 R 140 0 R 184 0 R 200 0 R 238 0 R 392 0 R 562 0 R 690 0 R 706 0 R 828 0 R 986 0 R 1080 0 R 1238 0 R 1324 0 R 1326 0 R 1328 0 R 1330 0 R 1332 0 R 1334 0 R 1336 0 R 1338 0 R 1340 0 R 1348 0 R 1350 0 R 1352 0 R 1354 0 R 1356 0 R 1358 0 R ] /Count 30 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 15 0 R /F3 22 0 R /F4 29 0 R /F5 1360 0 R >> /XObject << /I1 36 0 R /I2 37 0 R /I3 116 0 R /I4 117 0 R /I5 124 0 R /I6 125 0 R /I7 132 0 R /I8 133 0 R /I9 138 0 R /I10 139 0 R /I11 188 0 R /I12 189 0 R /I13 192 0 R /I14 193 0 R /I15 196 0 R /I16 197 0 R /I17 198 0 R /I18 199 0 R /I19 242 0 R /I20 243 0 R /I21 292 0 R /I22 293 0 R /I23 342 0 R /I24 343 0 R /I25 390 0 R /I26 391 0 R /I27 694 0 R /I28 695 0 R /I29 698 0 R /I30 699 0 R /I31 702 0 R /I32 703 0 R /I33 704 0 R /I34 705 0 R /I35 990 0 R /I36 991 0 R /I37 1020 0 R /I38 1021 0 R /I39 1050 0 R /I40 1051 0 R /I41 1078 0 R /I42 1079 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20131206223654+00'00') /ModDate (D:20131206223654+00'00') /Title (State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus \(MERS-CoV\) in Humans  PLOS Currents Outbreaks) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 56 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R 78 0 R 80 0 R 82 0 R 84 0 R 86 0 R 88 0 R 90 0 R 92 0 R 94 0 R 96 0 R 98 0 R 100 0 R 102 0 R 104 0 R 106 0 R 108 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 25469 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 636.553 577.500 101.447 re W n 0.267 0.267 0.267 rg BT 15.000 711.948 Td /F2 21.0 Tf [(State of Knowledge and Data Gaps of Middle )] TJ ET BT 15.000 679.382 Td /F2 21.0 Tf [(East Respiratory Syndrome Coronavirus \(MERS-)] TJ ET BT 15.000 646.816 Td /F2 21.0 Tf [(CoV\) in Humans)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 624.568 Td /F3 9.8 Tf [(November 12, 2013)] TJ ET BT 119.305 624.568 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 125.506 624.568 Td /F3 9.8 Tf [(Research)] TJ ET BT 26.250 609.217 Td /F1 9.8 Tf [(- The WHO MERS-CoV Research Group)] TJ ET 0.271 0.267 0.267 rg BT 26.250 586.273 Td /F1 9.8 Tf [(The WHO MERS-CoV Research Group -. State of Knowledge and Data Gaps of Middle East Respiratory )] TJ ET BT 525.255 586.273 Td /F1 9.8 Tf [(Syndrome )] TJ ET BT 26.250 570.829 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\) in Humans. PLOS Currents Outbreaks. 2013 Nov 12. Edition 1. doi: )] TJ ET BT 26.250 555.385 Td /F1 9.8 Tf [(10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8.)] TJ ET q 15.000 30.236 577.500 522.060 re W n 0.271 0.267 0.267 rg BT 26.250 522.089 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 498.433 Td /F1 9.8 Tf [(Background: Between September 2012 and 22 October 2013, 144 laboratory-confirmed and 17 probable MERS-)] TJ ET BT 26.250 482.989 Td /F1 9.8 Tf [(CoV cases from nine countries were notified to WHO.)] TJ ET BT 26.250 460.045 Td /F1 9.8 Tf [(Methods: We summarize what is known about the epidemiology, virology, phylogeny and emergence of MERS-)] TJ ET BT 26.250 444.601 Td /F1 9.8 Tf [(CoV to inform public health policies.)] TJ ET BT 26.250 421.657 Td /F1 9.8 Tf [(Results: The median age of patients \(n=161\) was 50 years \(range 14 months to 94 years\), 64.5% were male )] TJ ET BT 26.250 406.213 Td /F1 9.8 Tf [(and 63.4% experienced severe respiratory disease. 76.0% of patients were reported to have "e1 underlying )] TJ ET BT 26.250 390.769 Td /F1 9.8 Tf [(medical condition and fatal cases, compared to recovered or asymptomatic cases were more likely to have an )] TJ ET BT 26.250 375.325 Td /F1 9.8 Tf [(underlying condition \(86.8% vs. 42.4%, p0 is)] TJ ET BT 26.250 352.381 Td /F1 9.8 Tf [(Conclusions: Sustained human-to-human transmission of MERS-CoV has not been observed. Outbreaks have )] TJ ET BT 26.250 336.937 Td /F1 9.8 Tf [(been extinguished without overly aggressive isolation and quarantine suggesting that transmission of virus may )] TJ ET BT 26.250 321.493 Td /F1 9.8 Tf [(be stopped with implementation of appropriate infection control measures.)] TJ ET BT 26.250 280.697 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 257.041 Td /F1 9.8 Tf [(The first case of a novel coronavirus, now called Middle East respiratory syndrome coronavirus \(MERS-CoV\), was )] TJ ET BT 26.250 241.597 Td /F1 9.8 Tf [(identified in a patient with acute pneumonia and renal failure in Jeddah, Kingdom of Saudi Arabia \(KSA\) in June )] TJ ET BT 26.250 226.153 Td /F1 9.8 Tf [(2012 )] TJ ET 0.267 0.267 0.267 rg BT 54.154 228.108 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.187 226.153 Td /F1 9.8 Tf [(. Following identification of the virus a subsequent case from Qatar who was being treated in the UK was )] TJ ET BT 26.250 210.709 Td /F1 9.8 Tf [(identified )] TJ ET 0.267 0.267 0.267 rg BT 75.292 212.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 81.325 210.709 Td /F1 9.8 Tf [( and a hospital cluster of pneumonia among health care workers in Zarqa, Jordan in March/April of )] TJ ET BT 26.250 195.265 Td /F1 9.8 Tf [(2012 was retrospectively determined to have been caused by the same virus )] TJ ET 0.267 0.267 0.267 rg BT 408.226 197.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 414.258 195.265 Td /F1 9.8 Tf [(. Since then, as of 22 October )] TJ ET BT 26.250 179.821 Td /F1 9.8 Tf [(2013, 144 laboratory-confirmed and 17 probable MERS-CoV cases from nine countries \(Figure 1a\) have been )] TJ ET BT 26.250 164.377 Td /F1 9.8 Tf [(notified to the World Health Organization \(WHO\) )] TJ ET 0.267 0.267 0.267 rg BT 266.061 166.332 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 272.093 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.849 166.332 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 280.881 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 283.637 166.332 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 289.669 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 292.425 166.332 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 298.457 164.377 Td /F1 9.8 Tf [( in accordance with the provisions of the International )] TJ ET BT 26.250 148.933 Td /F1 9.8 Tf [(Health Regulations \(2005\).)] TJ ET BT 26.250 125.989 Td /F1 9.8 Tf [(WHO, in coordination and cooperation with its affected member states, and an informal network of academic )] TJ ET BT 26.250 110.545 Td /F1 9.8 Tf [(and public health researchers, has compiled available information on MERS-CoV. Here we summarize what is )] TJ ET BT 26.250 95.101 Td /F1 9.8 Tf [(currently known about the epidemiology of MERS-CoV, including the geographic spread and timeline of cases, )] TJ ET BT 26.250 79.657 Td /F1 9.8 Tf [(characteristics and severity of cases, clinical features and treatment strategies, description of clusters, and the )] TJ ET BT 26.250 64.213 Td /F1 9.8 Tf [(epidemic potential of MERS-CoV; and the virology, phylogeny and emergence of the MERS-CoV virus. In addition )] TJ ET BT 26.250 48.769 Td /F1 9.8 Tf [(to summarizing the published literature, we also present summary data on the known laboratory-confirmed and )] TJ ET Q q 15.000 636.553 577.500 101.447 re W n 0.267 0.267 0.267 rg BT 15.000 711.948 Td /F2 21.0 Tf [(State of Knowledge and Data Gaps of Middle )] TJ ET BT 15.000 679.382 Td /F2 21.0 Tf [(East Respiratory Syndrome Coronavirus \(MERS-)] TJ ET BT 15.000 646.816 Td /F2 21.0 Tf [(CoV\) in Humans)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 624.568 Td /F3 9.8 Tf [(November 12, 2013)] TJ ET BT 119.305 624.568 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 125.506 624.568 Td /F3 9.8 Tf [(Research)] TJ ET BT 26.250 609.217 Td /F1 9.8 Tf [(- The WHO MERS-CoV Research Group)] TJ ET 0.271 0.267 0.267 rg BT 26.250 586.273 Td /F1 9.8 Tf [(The WHO MERS-CoV Research Group -. State of Knowledge and Data Gaps of Middle East Respiratory )] TJ ET BT 525.255 586.273 Td /F1 9.8 Tf [(Syndrome )] TJ ET BT 26.250 570.829 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\) in Humans. PLOS Currents Outbreaks. 2013 Nov 12. Edition 1. doi: )] TJ ET BT 26.250 555.385 Td /F1 9.8 Tf [(10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8.)] TJ ET q 15.000 30.236 577.500 522.060 re W n 0.271 0.267 0.267 rg BT 26.250 522.089 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 498.433 Td /F1 9.8 Tf [(Background: Between September 2012 and 22 October 2013, 144 laboratory-confirmed and 17 probable MERS-)] TJ ET BT 26.250 482.989 Td /F1 9.8 Tf [(CoV cases from nine countries were notified to WHO.)] TJ ET BT 26.250 460.045 Td /F1 9.8 Tf [(Methods: We summarize what is known about the epidemiology, virology, phylogeny and emergence of MERS-)] TJ ET BT 26.250 444.601 Td /F1 9.8 Tf [(CoV to inform public health policies.)] TJ ET BT 26.250 421.657 Td /F1 9.8 Tf [(Results: The median age of patients \(n=161\) was 50 years \(range 14 months to 94 years\), 64.5% were male )] TJ ET BT 26.250 406.213 Td /F1 9.8 Tf [(and 63.4% experienced severe respiratory disease. 76.0% of patients were reported to have "e1 underlying )] TJ ET BT 26.250 390.769 Td /F1 9.8 Tf [(medical condition and fatal cases, compared to recovered or asymptomatic cases were more likely to have an )] TJ ET BT 26.250 375.325 Td /F1 9.8 Tf [(underlying condition \(86.8% vs. 42.4%, p0 is)] TJ ET BT 26.250 352.381 Td /F1 9.8 Tf [(Conclusions: Sustained human-to-human transmission of MERS-CoV has not been observed. Outbreaks have )] TJ ET BT 26.250 336.937 Td /F1 9.8 Tf [(been extinguished without overly aggressive isolation and quarantine suggesting that transmission of virus may )] TJ ET BT 26.250 321.493 Td /F1 9.8 Tf [(be stopped with implementation of appropriate infection control measures.)] TJ ET BT 26.250 280.697 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 257.041 Td /F1 9.8 Tf [(The first case of a novel coronavirus, now called Middle East respiratory syndrome coronavirus \(MERS-CoV\), was )] TJ ET BT 26.250 241.597 Td /F1 9.8 Tf [(identified in a patient with acute pneumonia and renal failure in Jeddah, Kingdom of Saudi Arabia \(KSA\) in June )] TJ ET BT 26.250 226.153 Td /F1 9.8 Tf [(2012 )] TJ ET 0.267 0.267 0.267 rg BT 54.154 228.108 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.187 226.153 Td /F1 9.8 Tf [(. Following identification of the virus a subsequent case from Qatar who was being treated in the UK was )] TJ ET BT 26.250 210.709 Td /F1 9.8 Tf [(identified )] TJ ET 0.267 0.267 0.267 rg BT 75.292 212.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 81.325 210.709 Td /F1 9.8 Tf [( and a hospital cluster of pneumonia among health care workers in Zarqa, Jordan in March/April of )] TJ ET BT 26.250 195.265 Td /F1 9.8 Tf [(2012 was retrospectively determined to have been caused by the same virus )] TJ ET 0.267 0.267 0.267 rg BT 408.226 197.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 414.258 195.265 Td /F1 9.8 Tf [(. Since then, as of 22 October )] TJ ET BT 26.250 179.821 Td /F1 9.8 Tf [(2013, 144 laboratory-confirmed and 17 probable MERS-CoV cases from nine countries \(Figure 1a\) have been )] TJ ET BT 26.250 164.377 Td /F1 9.8 Tf [(notified to the World Health Organization \(WHO\) )] TJ ET 0.267 0.267 0.267 rg BT 266.061 166.332 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 272.093 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.849 166.332 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 280.881 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 283.637 166.332 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 289.669 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 292.425 166.332 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 298.457 164.377 Td /F1 9.8 Tf [( in accordance with the provisions of the International )] TJ ET BT 26.250 148.933 Td /F1 9.8 Tf [(Health Regulations \(2005\).)] TJ ET BT 26.250 125.989 Td /F1 9.8 Tf [(WHO, in coordination and cooperation with its affected member states, and an informal network of academic )] TJ ET BT 26.250 110.545 Td /F1 9.8 Tf [(and public health researchers, has compiled available information on MERS-CoV. Here we summarize what is )] TJ ET BT 26.250 95.101 Td /F1 9.8 Tf [(currently known about the epidemiology of MERS-CoV, including the geographic spread and timeline of cases, )] TJ ET BT 26.250 79.657 Td /F1 9.8 Tf [(characteristics and severity of cases, clinical features and treatment strategies, description of clusters, and the )] TJ ET BT 26.250 64.213 Td /F1 9.8 Tf [(epidemic potential of MERS-CoV; and the virology, phylogeny and emergence of the MERS-CoV virus. In addition )] TJ ET BT 26.250 48.769 Td /F1 9.8 Tf [(to summarizing the published literature, we also present summary data on the known laboratory-confirmed and )] TJ ET Q q 15.000 636.553 577.500 101.447 re W n 0.267 0.267 0.267 rg BT 15.000 711.948 Td /F2 21.0 Tf [(State of Knowledge and Data Gaps of Middle )] TJ ET BT 15.000 679.382 Td /F2 21.0 Tf [(East Respiratory Syndrome Coronavirus \(MERS-)] TJ ET BT 15.000 646.816 Td /F2 21.0 Tf [(CoV\) in Humans)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 624.568 Td /F3 9.8 Tf [(November 12, 2013)] TJ ET BT 119.305 624.568 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 125.506 624.568 Td /F3 9.8 Tf [(Research)] TJ ET BT 26.250 609.217 Td /F1 9.8 Tf [(- The WHO MERS-CoV Research Group)] TJ ET 0.271 0.267 0.267 rg BT 26.250 586.273 Td /F1 9.8 Tf [(The WHO MERS-CoV Research Group -. State of Knowledge and Data Gaps of Middle East Respiratory )] TJ ET BT 525.255 586.273 Td /F1 9.8 Tf [(Syndrome )] TJ ET BT 26.250 570.829 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\) in Humans. PLOS Currents Outbreaks. 2013 Nov 12. Edition 1. doi: )] TJ ET BT 26.250 555.385 Td /F1 9.8 Tf [(10.1371/currents.outbreaks.0bf719e352e7478f8ad85fa30127ddb8.)] TJ ET q 15.000 30.236 577.500 522.060 re W n 0.271 0.267 0.267 rg BT 26.250 522.089 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 498.433 Td /F1 9.8 Tf [(Background: Between September 2012 and 22 October 2013, 144 laboratory-confirmed and 17 probable MERS-)] TJ ET BT 26.250 482.989 Td /F1 9.8 Tf [(CoV cases from nine countries were notified to WHO.)] TJ ET BT 26.250 460.045 Td /F1 9.8 Tf [(Methods: We summarize what is known about the epidemiology, virology, phylogeny and emergence of MERS-)] TJ ET BT 26.250 444.601 Td /F1 9.8 Tf [(CoV to inform public health policies.)] TJ ET BT 26.250 421.657 Td /F1 9.8 Tf [(Results: The median age of patients \(n=161\) was 50 years \(range 14 months to 94 years\), 64.5% were male )] TJ ET BT 26.250 406.213 Td /F1 9.8 Tf [(and 63.4% experienced severe respiratory disease. 76.0% of patients were reported to have "e1 underlying )] TJ ET BT 26.250 390.769 Td /F1 9.8 Tf [(medical condition and fatal cases, compared to recovered or asymptomatic cases were more likely to have an )] TJ ET BT 26.250 375.325 Td /F1 9.8 Tf [(underlying condition \(86.8% vs. 42.4%, p0 is)] TJ ET BT 26.250 352.381 Td /F1 9.8 Tf [(Conclusions: Sustained human-to-human transmission of MERS-CoV has not been observed. Outbreaks have )] TJ ET BT 26.250 336.937 Td /F1 9.8 Tf [(been extinguished without overly aggressive isolation and quarantine suggesting that transmission of virus may )] TJ ET BT 26.250 321.493 Td /F1 9.8 Tf [(be stopped with implementation of appropriate infection control measures.)] TJ ET BT 26.250 280.697 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 257.041 Td /F1 9.8 Tf [(The first case of a novel coronavirus, now called Middle East respiratory syndrome coronavirus \(MERS-CoV\), was )] TJ ET BT 26.250 241.597 Td /F1 9.8 Tf [(identified in a patient with acute pneumonia and renal failure in Jeddah, Kingdom of Saudi Arabia \(KSA\) in June )] TJ ET BT 26.250 226.153 Td /F1 9.8 Tf [(2012 )] TJ ET 0.267 0.267 0.267 rg BT 54.154 228.108 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.187 226.153 Td /F1 9.8 Tf [(. Following identification of the virus a subsequent case from Qatar who was being treated in the UK was )] TJ ET BT 26.250 210.709 Td /F1 9.8 Tf [(identified )] TJ ET 0.267 0.267 0.267 rg BT 75.292 212.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 81.325 210.709 Td /F1 9.8 Tf [( and a hospital cluster of pneumonia among health care workers in Zarqa, Jordan in March/April of )] TJ ET BT 26.250 195.265 Td /F1 9.8 Tf [(2012 was retrospectively determined to have been caused by the same virus )] TJ ET 0.267 0.267 0.267 rg BT 408.226 197.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 414.258 195.265 Td /F1 9.8 Tf [(. Since then, as of 22 October )] TJ ET BT 26.250 179.821 Td /F1 9.8 Tf [(2013, 144 laboratory-confirmed and 17 probable MERS-CoV cases from nine countries \(Figure 1a\) have been )] TJ ET BT 26.250 164.377 Td /F1 9.8 Tf [(notified to the World Health Organization \(WHO\) )] TJ ET 0.267 0.267 0.267 rg BT 266.061 166.332 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 272.093 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.849 166.332 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 280.881 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 283.637 166.332 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 289.669 169.421 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 292.425 166.332 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 298.457 164.377 Td /F1 9.8 Tf [( in accordance with the provisions of the International )] TJ ET BT 26.250 148.933 Td /F1 9.8 Tf [(Health Regulations \(2005\).)] TJ ET BT 26.250 125.989 Td /F1 9.8 Tf [(WHO, in coordination and cooperation with its affected member states, and an informal network of academic )] TJ ET BT 26.250 110.545 Td /F1 9.8 Tf [(and public health researchers, has compiled available information on MERS-CoV. Here we summarize what is )] TJ ET BT 26.250 95.101 Td /F1 9.8 Tf [(currently known about the epidemiology of MERS-CoV, including the geographic spread and timeline of cases, )] TJ ET BT 26.250 79.657 Td /F1 9.8 Tf [(characteristics and severity of cases, clinical features and treatment strategies, description of clusters, and the )] TJ ET BT 26.250 64.213 Td /F1 9.8 Tf [(epidemic potential of MERS-CoV; and the virology, phylogeny and emergence of the MERS-CoV virus. 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utuuuvvlvvww`wwxLxxy@yzz{{H{|,|}8~~x8t,D\8H \xx,@\x,@\x,Hl 8l@l Lx<`<h0l@l Lx<`<h0l Lx(\,P|<p @|(l@l Lx<`<h0l Lx(\,P|<p @|(l Lx(\,P|<p @|(lH|L,h @|(l\ lL\$4p<p d$lTàĤ8`tȀ@PɌ $<T$@̐TtTdPѴҀҼ(lӴL@l8|@ؔ`ڴ۔d4݀XޠDlߔ߼@lH 8` ,p$`X \D,d@h\  LPpxp<8d,8H$8|\( dt 0 @      4     0 @ X p     0H`x 8Ph(@Xp0H`x 8Ph(@P`p\ $<lT0tX XHX Hp(Lp  @ T  ! !<!!"\""###$,%%&@&'0'x'(P()D)))*(*P**+4+,p--p-.T./x/0<001h111242D2l233,3X3334D4p44445505D5X5l55555666,6@6T6x666669>?|@<@ABC(CDtE<ETEEFFpFFGGTGGHHHH`HxHHHHHII I8IPIhIIIIIIJJ(J@JXJpJJJJJKKK0KHKKKKKLLL0LHL`LxLLLLLMM M8MPMhMMMMMMNN(N@NXNpNNNNNOOO0OHO`OxOOOOOPP P8PPPhPPPPPPQQ(Q8QQRRR4RLRdR|RRRRRS S$S4SSSST TTTTTUU(U@UXUpUUUVVV0V0V0V0V0V0V0V0V0V0V0V0V0V0V0V0V0VXVVWW$W<WPWWWWWWXXX0XHX\XtXXXXXXYY,YDY\YtYYYYZZZ0ZHZ`ZxZZZZZ[[ [8[P[h[[[\<\](]@]X]p]]]^^,^<^^^^_`4``aaa4aDb bcPchccccdDde4eLede|eef,fgg,gDg\gtggggghhh4hDii|jjjjkkkl llllmm mnTnnoop<pTplppppppqq,qqqqqqqrtrrrsss8s`ssstt0tXttttu$uLutuuuvv@vhvvvww8w`wwwxx,xTxxxxy yHytyyyzz@zhzzz{ {4{`{{{||(|T|||||} }H}p}}}~~@~h~~~4\(tpxDtl@X4H(d<DD|dT(8HXhx(8HXhx(8HXhx(dD@|X$4DTdtd Xx4(HDxt0$@8̴hҜԜT`hx40lH<0hd   P D`T!$t%')+.P1 457:<?\BLE|EFlGGHIIIJJK8KdK|KKLL$L\LLLMNTNOOOOP P\P|PPPPQQQ4QLQdQ|QQQQQRR<R\RSLSSSST T(TDT`T|TTTTUU$U@U\UxUUUUVV8VPVVVVWW$WDW\WWWWXX4XXXXY8YTYlYYYYYYZZLZZ[T[\\]\]]^$^P^^_D__`$`a|b b|bc,cdhee`ef f|fg<gh@hiPijtjkDklLlmnnlno\op|pq,qqrxrstHtuTuv$vw`wxHxxydyzPz{\{|0||}0}}~T~4$8\4X<(@Xx 8Pp(@Xp8Xx 8Pl 8Ph(@Xp0H`x8PhT+h >2   : `   (Z4;b ;; 0    " F m " : %: h: ; ;Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. DejaVu changes are in public domain Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. DejaVu changes are in public domain DejaVu SansDejaVu SansBookBookDejaVu SansDejaVu SansDejaVu SansDejaVu SansVersion 2.32Version 2.32DejaVuSansDejaVuSansDejaVu fonts teamDejaVu fonts teamhttp://dejavu.sourceforge.nethttp://dejavu.sourceforge.netFonts are (c) Bitstream (see below). DejaVu changes are in public domain. Glyphs imported from Arev fonts are (c) Tavmjung Bah (see below) Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Arev Fonts Copyright ------------------------------ Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the modifications to the Bitstream Vera Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Tavmjong Bah" or the word "Arev". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Tavmjong Bah Arev" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL TAVMJONG BAH BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the name of Tavmjong Bah shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from Tavmjong Bah. For further information, contact: tavmjong @ free . fr.Fonts are (c) Bitstream (see below). DejaVu changes are in public domain. Glyphs imported from Arev fonts are (c) Tavmjung Bah (see below) Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Arev Fonts Copyright ------------------------------ Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the modifications to the Bitstream Vera Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Tavmjong Bah" or the word "Arev". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Tavmjong Bah Arev" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL TAVMJONG BAH BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the name of Tavmjong Bah shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from Tavmjong Bah. For further information, contact: tavmjong @ free . fr.http://dejavu.sourceforge.net/wiki/index.php/Licensehttp://dejavu.sourceforge.net/wiki/index.php/LicenseDejaVu SansDejaVu SansBookBook~Z  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghjikmlnoqprsutvwxzy{}|~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! 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All Rights Reserved. DejaVu changes are in public domain Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. DejaVu changes are in public domain DejaVu SerifDejaVu SerifBoldBoldDejaVu Serif BoldDejaVu Serif BoldDejaVu Serif BoldDejaVu Serif BoldVersion 2.32Version 2.32DejaVuSerif-BoldDejaVuSerif-BoldDejaVu fonts teamDejaVu fonts teamhttp://dejavu.sourceforge.nethttp://dejavu.sourceforge.netFonts are (c) Bitstream (see below). DejaVu changes are in public domain. Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Fonts are (c) Bitstream (see below). DejaVu changes are in public domain. Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. http://dejavu.sourceforge.net/wiki/index.php/Licensehttp://dejavu.sourceforge.net/wiki/index.php/LicenseDejaVu SerifDejaVu SerifBoldBold~Z '  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghjikmlnoqprsutvwxzy{}|~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! 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?X?t???@ @0@L@l@@A0ALAABB,BXBBBBBC$C\CCDDHDDEE$EHElEEEEFF@FdFFFFG G4G\GGGH H8H`HHHII0I`IIIJJ4J\JJJKK(KTKKKKL(LPLLLMMPMMMN(N`NNOO4OhOOOPPDPlPPPQ QLQxQQRR8RdRRRS(SlSSTTDTtTTUUXUUV@VtVVWW0WLWWWWWXX4XPXlXXXYYY4YPYlYYYYYZZ0ZLZhZZZZ[\t]]0]D]`]t]]]]]^^ ^<^X^^^_H_`alacccddDd`dddde$e@eheeeeff@f\ffffgg4g`g|gggh@hiiljdkkllhlmmtmn,nTn|no0oopp0p\ppqq0qLqdq|qqrrDrlrrs sHsst4tttu4uv4vvww,wXwtwwwxz@{{|X}t~0~$`(p,\0|<TxH88h(@   4Pd 0Lp 0Lp$Pt0Lp@d @\ L0\0Lp@d @\ L0\@d @dP<p@lD0Lp@d @\ L0\@d @dP<p@lD@d @dP<p@lD$P|DP@lD4p,p`0\4x<x@|¸Ìh$XŨ<ƀdǰPȠ`@ʰ<ˬt<ͬLΐp tLѨҌhhԸո4d֔(X׌׼L|ج <lٜ0dڔ4p۬$X܈ܸ$\ݨx|hHX(P|08h,`L Lx0` (Pp$T|H(x|l,4$|Xl(dhL$`  L  <   ( T     , X    <l(<<LH$<@40 X!d"#%<&( ) *\+T,p-X./h0|2H3D5 68@9:<;<=>>?\?l?@t@@AB<BCDDDF(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(F(FFFGGG$G4GDGTGdGtGGGGGGGGHHH$H4HDHTHdHtHHHHHHHHIII$I4IDITIdItIIIIIIIIJJJ$J4JDJTJdJtJJJJJJJJKKK$K4KDKTKdKtKKKKKKKKLLL$L4LDLTLdLtLLLLLLLLMMM$M4MDMTMdMtMMMMMMNLNhNNOODOxOOPP<PTPPQ$Q<QTRTRSpT|UtUVWW8WTWpWWWWWXX4XPXlXXXXXYY0YLYhYZH  +@ >_ :U !X  4 9 T     G &\ &  $ "4 :j & h    FCopyright (c) 2003 by Bitstream, Inc. All Rights Reserved. DejaVu changes are in public domain Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. DejaVu changes are in public domain DejaVu SerifDejaVu SerifItalicItalicDejaVu Serif ItalicDejaVu Serif ItalicDejaVu Serif ItalicDejaVu Serif ItalicVersion 2.32Version 2.32DejaVuSerif-ItalicDejaVuSerif-ItalicDejaVu fonts teamDejaVu fonts teamhttp://dejavu.sourceforge.nethttp://dejavu.sourceforge.netFonts are (c) Bitstream (see below). DejaVu changes are in public domain. Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Fonts are (c) Bitstream (see below). DejaVu changes are in public domain. Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. http://dejavu.sourceforge.net/wiki/index.php/Licensehttp://dejavu.sourceforge.net/wiki/index.php/LicenseDejaVu SerifDejaVu SerifItalicItalic~Z   !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghjikmlnoqprsutvwxzy{}|~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! 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Bu xd xu xd xd xu xd xd xu xd xu xu@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,@,du__::: J776676uuMM''''$$"pMM   )fB3R\\b1 c: =sH7NBNXx\qffiishc1 1 wwjff,O`qwP9w9Wqfffff+'fw1 wff,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,5| >t b` d8( dq[{es^Lq fXLfX @fX: Lu w3v3vLLLRsRs@ tnxj jX F X oX `X `XH `XDeXVvS@xX! @fX! 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All Rights Reserved. Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. DejaVu changes are in public domain Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. DejaVu changes are in public domain DejaVu SansDejaVu SansBoldBoldDejaVu Sans BoldDejaVu Sans BoldDejaVu Sans BoldDejaVu Sans BoldVersion 2.32Version 2.32DejaVuSans-BoldDejaVuSans-BoldDejaVu fonts teamDejaVu fonts teamhttp://dejavu.sourceforge.nethttp://dejavu.sourceforge.netFonts are (c) Bitstream (see below). DejaVu changes are in public domain. Glyphs imported from Arev fonts are (c) Tavmjung Bah (see below) Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Arev Fonts Copyright ------------------------------ Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the modifications to the Bitstream Vera Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Tavmjong Bah" or the word "Arev". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Tavmjong Bah Arev" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL TAVMJONG BAH BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the name of Tavmjong Bah shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from Tavmjong Bah. For further information, contact: tavmjong @ free . fr.Fonts are (c) Bitstream (see below). DejaVu changes are in public domain. Glyphs imported from Arev fonts are (c) Tavmjung Bah (see below) Bitstream Vera Fonts Copyright ------------------------------ Copyright (c) 2003 by Bitstream, Inc. All Rights Reserved. Bitstream Vera is a trademark of Bitstream, Inc. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Bitstream" or the word "Vera". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Bitstream Vera" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL BITSTREAM OR THE GNOME FOUNDATION BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the names of Gnome, the Gnome Foundation, and Bitstream Inc., shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from the Gnome Foundation or Bitstream Inc., respectively. For further information, contact: fonts at gnome dot org. Arev Fonts Copyright ------------------------------ Copyright (c) 2006 by Tavmjong Bah. All Rights Reserved. Permission is hereby granted, free of charge, to any person obtaining a copy of the fonts accompanying this license ("Fonts") and associated documentation files (the "Font Software"), to reproduce and distribute the modifications to the Bitstream Vera Font Software, including without limitation the rights to use, copy, merge, publish, distribute, and/or sell copies of the Font Software, and to permit persons to whom the Font Software is furnished to do so, subject to the following conditions: The above copyright and trademark notices and this permission notice shall be included in all copies of one or more of the Font Software typefaces. The Font Software may be modified, altered, or added to, and in particular the designs of glyphs or characters in the Fonts may be modified and additional glyphs or characters may be added to the Fonts, only if the fonts are renamed to names not containing either the words "Tavmjong Bah" or the word "Arev". This License becomes null and void to the extent applicable to Fonts or Font Software that has been modified and is distributed under the "Tavmjong Bah Arev" names. The Font Software may be sold as part of a larger software package but no copy of one or more of the Font Software typefaces may be sold by itself. THE FONT SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO ANY WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT OF COPYRIGHT, PATENT, TRADEMARK, OR OTHER RIGHT. IN NO EVENT SHALL TAVMJONG BAH BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER LIABILITY, INCLUDING ANY GENERAL, SPECIAL, INDIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM, OUT OF THE USE OR INABILITY TO USE THE FONT SOFTWARE OR FROM OTHER DEALINGS IN THE FONT SOFTWARE. Except as contained in this notice, the name of Tavmjong Bah shall not be used in advertising or otherwise to promote the sale, use or other dealings in this Font Software without prior written authorization from Tavmjong Bah. For further information, contact: tavmjong @ free . fr.http://dejavu.sourceforge.net/wiki/index.php/Licensehttp://dejavu.sourceforge.net/wiki/index.php/LicenseDejaVu SansDejaVu SansBoldBold~Z:  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghjikmlnoqprsutvwxzy{}|~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! 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arrowdblbothuni21D5uni21D6uni21D7uni21D8uni21D9uni21DAuni21DBuni21DCuni21DDuni21DEuni21DFuni21E0uni21E1uni21E2uni21E3uni21E4uni21E5uni21E6uni21E7uni21E8uni21E9uni21EAuni21EBuni21ECuni21EDuni21EEuni21EFuni21F0uni21F1uni21F2uni21F3uni21F4uni21F5uni21F6uni21F7uni21F8uni21F9uni21FAuni21FBuni21FCuni21FDuni21FEuni21FF universaluni2201 existentialuni2204emptysetgradientelement notelementuni220Asuchthatuni220Cuni220Duni220Euni2210uni2213uni2214uni2215uni2216 asteriskmathuni2218uni2219uni221Buni221C proportional orthogonalangleuni2221uni2222uni2223uni2224uni2225uni2226 logicaland logicalor intersectionunionuni222Cuni222Duni222Euni222Funi2230uni2231uni2232uni2233 thereforeuni2235uni2236uni2237uni2238uni2239uni223Auni223Bsimilaruni223Duni223Euni223Funi2240uni2241uni2242uni2243uni2244 congruentuni2246uni2247uni2249uni224Auni224Buni224Cuni224Duni224Euni224Funi2250uni2251uni2252uni2253uni2254uni2255uni2256uni2257uni2258uni2259uni225Auni225Buni225Cuni225Duni225Euni225F equivalenceuni2262uni2263uni2266uni2267uni2268uni2269uni226Auni226Buni226Cuni226Duni226Euni226Funi2270uni2271uni2272uni2273uni2274uni2275uni2276uni2277uni2278uni2279uni227Auni227Buni227Cuni227Duni227Euni227Funi2280uni2281 propersubsetpropersuperset notsubsetuni2285 reflexsubsetreflexsupersetuni2288uni2289uni228Auni228Buni228Cuni228Duni228Euni228Funi2290uni2291uni2292uni2293uni2294 circleplusuni2296circlemultiplyuni2298uni2299uni229Auni229Buni229Cuni229Duni229Euni229Funi22A0uni22A1uni22A2uni22A3uni22A4 perpendicularuni22A6uni22A7uni22A8uni22A9uni22AAuni22ABuni22ACuni22ADuni22AEuni22AFuni22B0uni22B1uni22B2uni22B3uni22B4uni22B5uni22B6uni22B7uni22B8uni22B9uni22BAuni22BBuni22BCuni22BDuni22BEuni22BFuni22C0uni22C1uni22C2uni22C3uni22C4dotmathuni22C6uni22C7uni22C8uni22C9uni22CAuni22CBuni22CCuni22CDuni22CEuni22CFuni22D0uni22D1uni22D2uni22D3uni22D4uni22D5uni22D6uni22D7uni22D8uni22D9uni22DAuni22DBuni22DCuni22DDuni22DEuni22DFuni22E0uni22E1uni22E2uni22E3uni22E4uni22E5uni22E6uni22E7uni22E8uni22E9uni22EAuni22EBuni22ECuni22EDuni22EEuni22EFuni22F0uni22F1uni22F2uni22F3uni22F4uni22F5uni22F6uni22F7uni22F8uni22F9uni22FAuni22FBuni22FCuni22FDuni22FEuni22FFuni2300uni2301houseuni2303uni2304uni2305uni2306uni2307uni2308uni2309uni230Auni230Buni230Cuni230Duni230Euni230F revlogicalnotuni2311uni2318uni2319uni231Cuni231Duni231Euni231F integraltp integralbtuni2324uni2325uni2326uni2327uni2328uni232Buni232Cuni2373uni2374uni2375uni237Auni237Duni2387uni2394uni239Buni239Cuni239Duni239Euni239Funi23A0uni23A1uni23A2uni23A3uni23A4uni23A5uni23A6uni23A7uni23A8uni23A9uni23AAuni23ABuni23ACuni23ADuni23AEuni23CEuni23CFuni23E3uni23E5uni23E8uni2422uni2423uni2460uni2461uni2462uni2463uni2464uni2465uni2466uni2467uni2468uni2469upblockuni2581uni2582uni2583dnblockuni2585uni2586uni2587blockuni2589uni258Auni258Blfblockuni258Duni258Euni258Frtblockltshadeshadedkshadeuni2594uni2595uni2596uni2597uni2598uni2599uni259Auni259Buni259Cuni259Duni259Euni259F filledboxH22073uni25A2uni25A3uni25A4uni25A5uni25A6uni25A7uni25A8uni25A9H18543H18551 filledrectuni25ADuni25AEuni25AFuni25B0uni25B1triagupuni25B3uni25B4uni25B5uni25B6uni25B7uni25B8uni25B9triagrtuni25BBtriagdnuni25BDuni25BEuni25BFuni25C0uni25C1uni25C2uni25C3triaglfuni25C5uni25C6uni25C7uni25C8uni25C9circleuni25CCuni25CDuni25CEH18533uni25D0uni25D1uni25D2uni25D3uni25D4uni25D5uni25D6uni25D7 invbullet invcircleuni25DAuni25DBuni25DCuni25DDuni25DEuni25DFuni25E0uni25E1uni25E2uni25E3uni25E4uni25E5 openbulletuni25E7uni25E8uni25E9uni25EAuni25EBuni25ECuni25EDuni25EEuni25EFuni25F0uni25F1uni25F2uni25F3uni25F4uni25F5uni25F6uni25F7uni25F8uni25F9uni25FAuni25FBuni25FCuni25FDuni25FEuni25FFuni2600uni2601uni2602uni2603uni2604uni2605uni2606uni2607uni2608uni2609uni260Auni260Buni260Cuni260Duni260Euni260Funi2610uni2611uni2612uni2613uni2614uni2615uni2616uni2617uni2618uni2619uni261Auni261Buni261Cuni261Duni261Euni261Funi2620uni2621uni2622uni2623uni2624uni2625uni2626uni2627uni2628uni2629uni262Auni262Buni262Cuni262Duni262Euni262Funi2630uni2631uni2632uni2633uni2634uni2635uni2636uni2637uni2638uni2639 smileface invsmilefacesununi263Duni263Euni263Ffemaleuni2641maleuni2643uni2644uni2645uni2646uni2647uni2648uni2649uni264Auni264Buni264Cuni264Duni264Euni264Funi2650uni2651uni2652uni2653uni2654uni2655uni2656uni2657uni2658uni2659uni265Auni265Buni265Cuni265Duni265Euni265Fspadeuni2661uni2662clubuni2664heartdiamonduni2667uni2668uni2669 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Antibody testing is not currently being used for confirmatory testing. In )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(addition to summarizing data related to both confirmed and probable cases, we also examined the differences )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(between secondary cases discovered around sporadic cases as a result of contact tracing. While the majority of )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(cases now reported have likely acquired infection through human-to-human transmission the primary sporadic )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(cases in clusters are more likely to have been acquired through contact with non-human sources of the virus. )] TJ ET BT 26.250 671.981 Td /F1 9.8 Tf [(The differences between them may provide clues as to relevant exposures that result in infection.)] TJ ET BT 26.250 649.037 Td /F4 9.8 Tf [(Characteristics of MERS-CoV Cases)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Between April 2012 and 22 October 2013, 144 laboratory-confirmed MERS-CoV cases have been identified in )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(nine countries: France, Germany, Italy, Jordan, KSA, Qatar, Tunisia, United Arab Emirates \(UAE\), and the United )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(Kingdom \(UK\) \(Figure 1a\). All cases have had a direct or indirect link with the Middle East. In KSA \(Figure 1b\), )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(from which more than 80% of laboratory-confirmed cases have been reported, cases have been reported from )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(six of its 13 provinces \(Al Qasim, Al Madinah, Ar Riyad, Asir, Ash Sharaqiyah and Makkah\))] TJ ET 0.267 0.267 0.267 rg BT 464.191 566.272 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 470.223 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.979 566.272 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 479.011 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 481.767 566.272 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 487.799 564.317 Td /F1 9.8 Tf [(. In addition, 17 )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(probable cases have been identified in Jordan \(n=11\), KSA \(n=4\) and Italy \(n=2\) )] TJ ET 0.267 0.267 0.267 rg BT 424.147 550.828 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 430.180 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 432.936 550.828 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 438.968 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 441.724 550.828 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 447.756 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 450.512 550.828 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 462.576 548.873 Td /F1 9.8 Tf [( and are included in )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(our analyses. The number of cases reported rose markedly starting in April 2013 compared with the previous )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(six months since virus discovery, with 21 laboratory-confirmed cases reported to have symptom onset in April, )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(22 in May, 22 cases in June, 14 cases in July, 20 cases in August, 28 cases in September, and 4 cases in October )] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(2013 \(Figure 2\))] TJ ET Q q 15.000 476.508 577.500 300.492 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(Probable cases are those that have a link with a confirmed case and a clinically compatible illness but without )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(definitive laboratory confirmation. Antibody testing is not currently being used for confirmatory testing. In )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(addition to summarizing data related to both confirmed and probable cases, we also examined the differences )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(between secondary cases discovered around sporadic cases as a result of contact tracing. While the majority of )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(cases now reported have likely acquired infection through human-to-human transmission the primary sporadic )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(cases in clusters are more likely to have been acquired through contact with non-human sources of the virus. )] TJ ET BT 26.250 671.981 Td /F1 9.8 Tf [(The differences between them may provide clues as to relevant exposures that result in infection.)] TJ ET BT 26.250 649.037 Td /F4 9.8 Tf [(Characteristics of MERS-CoV Cases)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Between April 2012 and 22 October 2013, 144 laboratory-confirmed MERS-CoV cases have been identified in )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(nine countries: France, Germany, Italy, Jordan, KSA, Qatar, Tunisia, United Arab Emirates \(UAE\), and the United )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(Kingdom \(UK\) \(Figure 1a\). All cases have had a direct or indirect link with the Middle East. In KSA \(Figure 1b\), )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(from which more than 80% of laboratory-confirmed cases have been reported, cases have been reported from )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(six of its 13 provinces \(Al Qasim, Al Madinah, Ar Riyad, Asir, Ash Sharaqiyah and Makkah\))] TJ ET 0.267 0.267 0.267 rg BT 464.191 566.272 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 470.223 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.979 566.272 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 479.011 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 481.767 566.272 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 487.799 564.317 Td /F1 9.8 Tf [(. In addition, 17 )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(probable cases have been identified in Jordan \(n=11\), KSA \(n=4\) and Italy \(n=2\) )] TJ ET 0.267 0.267 0.267 rg BT 424.147 550.828 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 430.180 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 432.936 550.828 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 438.968 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 441.724 550.828 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 447.756 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 450.512 550.828 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 462.576 548.873 Td /F1 9.8 Tf [( and are included in )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(our analyses. The number of cases reported rose markedly starting in April 2013 compared with the previous )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(six months since virus discovery, with 21 laboratory-confirmed cases reported to have symptom onset in April, )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(22 in May, 22 cases in June, 14 cases in July, 20 cases in August, 28 cases in September, and 4 cases in October )] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(2013 \(Figure 2\))] TJ ET Q q 15.000 476.508 577.500 300.492 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(Probable cases are those that have a link with a confirmed case and a clinically compatible illness but without )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(definitive laboratory confirmation. Antibody testing is not currently being used for confirmatory testing. In )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(addition to summarizing data related to both confirmed and probable cases, we also examined the differences )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(between secondary cases discovered around sporadic cases as a result of contact tracing. While the majority of )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(cases now reported have likely acquired infection through human-to-human transmission the primary sporadic )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(cases in clusters are more likely to have been acquired through contact with non-human sources of the virus. )] TJ ET BT 26.250 671.981 Td /F1 9.8 Tf [(The differences between them may provide clues as to relevant exposures that result in infection.)] TJ ET BT 26.250 649.037 Td /F4 9.8 Tf [(Characteristics of MERS-CoV Cases)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Between April 2012 and 22 October 2013, 144 laboratory-confirmed MERS-CoV cases have been identified in )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(nine countries: France, Germany, Italy, Jordan, KSA, Qatar, Tunisia, United Arab Emirates \(UAE\), and the United )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(Kingdom \(UK\) \(Figure 1a\). All cases have had a direct or indirect link with the Middle East. In KSA \(Figure 1b\), )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(from which more than 80% of laboratory-confirmed cases have been reported, cases have been reported from )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(six of its 13 provinces \(Al Qasim, Al Madinah, Ar Riyad, Asir, Ash Sharaqiyah and Makkah\))] TJ ET 0.267 0.267 0.267 rg BT 464.191 566.272 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 470.223 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.979 566.272 Td /F4 8.7 Tf [(8)] TJ ET 0.271 0.267 0.267 rg BT 479.011 569.361 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 481.767 566.272 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 487.799 564.317 Td /F1 9.8 Tf [(. In addition, 17 )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(probable cases have been identified in Jordan \(n=11\), KSA \(n=4\) and Italy \(n=2\) )] TJ ET 0.267 0.267 0.267 rg BT 424.147 550.828 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 430.180 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 432.936 550.828 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 438.968 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 441.724 550.828 Td /F4 8.7 Tf [(6)] TJ ET 0.271 0.267 0.267 rg BT 447.756 553.917 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 450.512 550.828 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 462.576 548.873 Td /F1 9.8 Tf [( and are included in )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(our analyses. The number of cases reported rose markedly starting in April 2013 compared with the previous )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(six months since virus discovery, with 21 laboratory-confirmed cases reported to have symptom onset in April, )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(22 in May, 22 cases in June, 14 cases in July, 20 cases in August, 28 cases in September, and 4 cases in October )] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(2013 \(Figure 2\))] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(4)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 142 0 obj << /Type /Annot /Subtype /Link /A 143 0 R /Border [0 0 0] /H /I /Rect [ 464.1907 565.2320 470.2228 576.6720 ] >> endobj 143 0 obj << /Type /Action >> endobj 144 0 obj << /Type /Annot /Subtype /Link /A 145 0 R /Border [0 0 0] /H /I /Rect [ 472.9788 565.2320 479.0108 576.6720 ] >> endobj 145 0 obj << /Type /Action >> endobj 146 0 obj << /Type /Annot /Subtype /Link /A 147 0 R /Border [0 0 0] /H /I /Rect [ 481.7668 565.2320 487.7988 576.6720 ] >> endobj 147 0 obj << /Type /Action >> endobj 148 0 obj << /Type /Annot /Subtype /Link /A 149 0 R /Border [0 0 0] /H /I /Rect [ 424.1475 549.7880 430.1795 561.2280 ] >> endobj 149 0 obj << /Type /Action >> endobj 150 0 obj << /Type /Annot /Subtype /Link /A 151 0 R /Border [0 0 0] /H /I /Rect [ 432.9355 549.7880 438.9675 561.2280 ] >> endobj 151 0 obj << /Type /Action >> endobj 152 0 obj << /Type /Annot /Subtype /Link /A 153 0 R /Border [0 0 0] /H /I /Rect [ 441.7235 549.7880 447.7555 561.2280 ] >> endobj 153 0 obj << /Type /Action >> endobj 154 0 obj << /Type /Annot /Subtype /Link /A 155 0 R /Border [0 0 0] /H /I /Rect [ 450.5115 549.7880 462.5755 561.2280 ] >> endobj 155 0 obj << /Type /Action >> endobj 156 0 obj << /Type /Annot /Subtype /Link /A 157 0 R /Border [0 0 0] /H /I /Rect [ 464.1907 565.2320 470.2228 576.6720 ] >> endobj 157 0 obj << /Type /Action >> endobj 158 0 obj << /Type /Annot /Subtype /Link /A 159 0 R /Border [0 0 0] /H /I /Rect [ 472.9788 565.2320 479.0108 576.6720 ] >> endobj 159 0 obj << /Type /Action >> endobj 160 0 obj << /Type /Annot /Subtype /Link /A 161 0 R /Border [0 0 0] /H /I /Rect [ 481.7668 565.2320 487.7988 576.6720 ] >> endobj 161 0 obj << /Type /Action >> endobj 162 0 obj << /Type /Annot /Subtype /Link /A 163 0 R /Border [0 0 0] /H /I /Rect [ 424.1475 549.7880 430.1795 561.2280 ] >> endobj 163 0 obj << /Type /Action >> endobj 164 0 obj << /Type /Annot /Subtype /Link /A 165 0 R /Border [0 0 0] /H /I /Rect [ 432.9355 549.7880 438.9675 561.2280 ] >> endobj 165 0 obj << /Type /Action >> endobj 166 0 obj << /Type /Annot /Subtype /Link /A 167 0 R /Border [0 0 0] /H /I /Rect [ 441.7235 549.7880 447.7555 561.2280 ] >> endobj 167 0 obj << /Type /Action >> endobj 168 0 obj << /Type /Annot /Subtype /Link /A 169 0 R /Border [0 0 0] /H /I /Rect [ 450.5115 549.7880 462.5755 561.2280 ] >> endobj 169 0 obj << /Type /Action >> endobj 170 0 obj << /Type /Annot /Subtype /Link /A 171 0 R /Border [0 0 0] /H /I /Rect [ 464.1907 565.2320 470.2228 576.6720 ] >> endobj 171 0 obj << /Type /Action >> endobj 172 0 obj << /Type /Annot /Subtype /Link /A 173 0 R /Border [0 0 0] /H /I /Rect [ 472.9788 565.2320 479.0108 576.6720 ] >> endobj 173 0 obj << /Type /Action >> endobj 174 0 obj << /Type /Annot /Subtype /Link /A 175 0 R /Border [0 0 0] /H /I /Rect [ 481.7668 565.2320 487.7988 576.6720 ] >> endobj 175 0 obj << /Type /Action >> endobj 176 0 obj << /Type /Annot /Subtype /Link /A 177 0 R /Border [0 0 0] /H /I /Rect [ 424.1475 549.7880 430.1795 561.2280 ] >> endobj 177 0 obj << /Type /Action >> endobj 178 0 obj << /Type /Annot /Subtype /Link /A 179 0 R /Border [0 0 0] /H /I /Rect [ 432.9355 549.7880 438.9675 561.2280 ] >> endobj 179 0 obj << /Type /Action >> endobj 180 0 obj << /Type /Annot /Subtype /Link /A 181 0 R /Border [0 0 0] /H /I /Rect [ 441.7235 549.7880 447.7555 561.2280 ] >> endobj 181 0 obj << /Type /Action >> endobj 182 0 obj << /Type /Annot /Subtype /Link /A 183 0 R /Border [0 0 0] /H /I /Rect [ 450.5115 549.7880 462.5755 561.2280 ] >> endobj 183 0 obj << /Type /Action >> endobj 184 0 obj << /Type /Page /Parent 3 0 R /Annots [ 186 0 R 190 0 R 194 0 R ] /Contents 185 0 R >> endobj 185 0 obj << /Length 20601 >> stream 0.271 0.267 0.267 rg q 15.000 27.132 577.500 749.868 re W n 0.965 0.965 0.965 rg 26.250 373.956 555.000 403.044 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 373.956 m 581.250 373.956 l 581.250 374.706 l 26.250 374.706 l f q 450.000 0 0 265.500 35.250 501.750 cm /I12 Do Q q 35.250 377.706 537.000 118.044 re W n 0.271 0.267 0.267 rg BT 35.250 483.395 Td /F4 9.8 Tf [(Fig. 2: Epidemiologic Curve of MERS-CoV Confirmed \(n=144\) and Probable Cases \(n=17\))] TJ ET BT 35.250 460.050 Td /F1 9.8 Tf [(*After week 24 in 2013, 58 cases were not reported with date for symptom onset. For these 58 cases, the )] TJ ET BT 35.250 442.230 Td /F1 9.8 Tf [(symptom onset date was estimated \(date of reporting to WHO minus median of difference between onset )] TJ ET BT 35.250 424.410 Td /F1 9.8 Tf [(date and reporting date of those cases that had both of these dates available; the median difference was )] TJ ET BT 35.250 406.590 Td /F1 9.8 Tf [(calculated by country\). Cases are reported by the location where infection is believed to have occurred. )] TJ ET BT 35.250 388.770 Td /F1 9.8 Tf [(Figure includes cases reported as of 22 October 2013.)] TJ ET Q BT 26.250 354.101 Td /F1 9.8 Tf [(Overall, the median age of MERS-CoV patients is 50 years \(range 14 months to 94 years\) and 64.5% of patients )] TJ ET BT 26.250 338.657 Td /F1 9.8 Tf [(were male \(Table 1\). As of 22 October 2013, WHO has confirmation that 65 patients \(40.4%\), of whom 62 were )] TJ ET BT 26.250 323.213 Td /F1 9.8 Tf [(confirmed and 3 probable, have died, of these 4 deaths could not be matched up to specific cases due to a lack )] TJ ET BT 26.250 307.769 Td /F1 9.8 Tf [(of identifying information. Outcome is unknown for 45 patients, either because they are still in hospital at the )] TJ ET BT 26.250 292.325 Td /F1 9.8 Tf [(time of writing, their outcome has not been reported, or we are unable to match a fatal case to our line list )] TJ ET BT 26.250 276.881 Td /F1 9.8 Tf [(\(n=4\). Age and sex varied by outcome, with a higher median age and proportion of male sex among patients )] TJ ET BT 26.250 261.437 Td /F1 9.8 Tf [(who died \(58 years old and 80.0%, respectively\) versus those who recovered or were asymptomatic \(34 years )] TJ ET BT 26.250 245.993 Td /F1 9.8 Tf [(old and 60.0%, respectively\).)] TJ ET BT 26.250 223.049 Td /F1 9.8 Tf [(The majority \(63.4%\) of patients experienced severe respiratory disease while 29.8% were reported to have non-)] TJ ET BT 26.250 207.605 Td /F1 9.8 Tf [(severe disease, including 18 cases reported as asymptomatic. Severe disease was defined as admission to an )] TJ ET BT 26.250 192.161 Td /F1 9.8 Tf [(intensive care unit [ICU]; use of extracorporeal membrane oxygenation \(ECMO\), mechanical ventilation, or )] TJ ET BT 26.250 176.717 Td /F1 9.8 Tf [(vasopressors; or reported by the member state as critical  or severe ; or who died. Severity is unknown for )] TJ ET BT 26.250 161.273 Td /F1 9.8 Tf [(6.8% of patients. Fifty-three of the 114 hospitalized patients, for whom we had data, died.)] TJ ET BT 26.250 138.329 Td /F1 9.8 Tf [(Seventy-six per cent of patients are reported to have at least one underlying medical condition and fatal cases )] TJ ET BT 26.250 122.885 Td /F1 9.8 Tf [(were more likely to have an underlying condition \(86.8% among fatal cases vs. 42.4% among recovered or )] TJ ET BT 26.250 107.441 Td /F1 9.8 Tf [(asymptomatic cases, p<0.001, Table 1\). Of those who were reported to have at least one comorbid condition, )] TJ ET BT 26.250 91.997 Td /F1 9.8 Tf [(specific comorbid diagnoses were not reported for 47.8% of patients. However, of those with data, the most )] TJ ET BT 26.250 76.553 Td /F1 9.8 Tf [(commonly reported conditions include chronic renal failure \(13.3%\), diabetes \(10.0%\), and heart disease )] TJ ET BT 26.250 61.109 Td /F1 9.8 Tf [(\(7.5%\). Of five patients who were immunocompromised, two reported use of immunosuppressive medication, )] TJ ET BT 26.250 45.665 Td /F1 9.8 Tf [(two reported multiple myeloma, and solid tissue cancer was reported in one patient. A published analysis of 47 )] TJ ET Q q 15.000 27.132 577.500 749.868 re W n 0.965 0.965 0.965 rg 26.250 373.956 555.000 403.044 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 373.956 m 581.250 373.956 l 581.250 374.706 l 26.250 374.706 l f q 450.000 0 0 265.500 35.250 501.750 cm /I14 Do Q q 35.250 377.706 537.000 118.044 re W n 0.271 0.267 0.267 rg BT 35.250 483.395 Td /F4 9.8 Tf [(Fig. 2: Epidemiologic Curve of MERS-CoV Confirmed \(n=144\) and Probable Cases \(n=17\))] TJ ET BT 35.250 460.050 Td /F1 9.8 Tf [(*After week 24 in 2013, 58 cases were not reported with date for symptom onset. For these 58 cases, the )] TJ ET BT 35.250 442.230 Td /F1 9.8 Tf [(symptom onset date was estimated \(date of reporting to WHO minus median of difference between onset )] TJ ET BT 35.250 424.410 Td /F1 9.8 Tf [(date and reporting date of those cases that had both of these dates available; the median difference was )] TJ ET BT 35.250 406.590 Td /F1 9.8 Tf [(calculated by country\). Cases are reported by the location where infection is believed to have occurred. )] TJ ET BT 35.250 388.770 Td /F1 9.8 Tf [(Figure includes cases reported as of 22 October 2013.)] TJ ET Q BT 26.250 354.101 Td /F1 9.8 Tf [(Overall, the median age of MERS-CoV patients is 50 years \(range 14 months to 94 years\) and 64.5% of patients )] TJ ET BT 26.250 338.657 Td /F1 9.8 Tf [(were male \(Table 1\). As of 22 October 2013, WHO has confirmation that 65 patients \(40.4%\), of whom 62 were )] TJ ET BT 26.250 323.213 Td /F1 9.8 Tf [(confirmed and 3 probable, have died, of these 4 deaths could not be matched up to specific cases due to a lack )] TJ ET BT 26.250 307.769 Td /F1 9.8 Tf [(of identifying information. Outcome is unknown for 45 patients, either because they are still in hospital at the )] TJ ET BT 26.250 292.325 Td /F1 9.8 Tf [(time of writing, their outcome has not been reported, or we are unable to match a fatal case to our line list )] TJ ET BT 26.250 276.881 Td /F1 9.8 Tf [(\(n=4\). Age and sex varied by outcome, with a higher median age and proportion of male sex among patients )] TJ ET BT 26.250 261.437 Td /F1 9.8 Tf [(who died \(58 years old and 80.0%, respectively\) versus those who recovered or were asymptomatic \(34 years )] TJ ET BT 26.250 245.993 Td /F1 9.8 Tf [(old and 60.0%, respectively\).)] TJ ET BT 26.250 223.049 Td /F1 9.8 Tf [(The majority \(63.4%\) of patients experienced severe respiratory disease while 29.8% were reported to have non-)] TJ ET BT 26.250 207.605 Td /F1 9.8 Tf [(severe disease, including 18 cases reported as asymptomatic. Severe disease was defined as admission to an )] TJ ET BT 26.250 192.161 Td /F1 9.8 Tf [(intensive care unit [ICU]; use of extracorporeal membrane oxygenation \(ECMO\), mechanical ventilation, or )] TJ ET BT 26.250 176.717 Td /F1 9.8 Tf [(vasopressors; or reported by the member state as critical  or severe ; or who died. Severity is unknown for )] TJ ET BT 26.250 161.273 Td /F1 9.8 Tf [(6.8% of patients. Fifty-three of the 114 hospitalized patients, for whom we had data, died.)] TJ ET BT 26.250 138.329 Td /F1 9.8 Tf [(Seventy-six per cent of patients are reported to have at least one underlying medical condition and fatal cases )] TJ ET BT 26.250 122.885 Td /F1 9.8 Tf [(were more likely to have an underlying condition \(86.8% among fatal cases vs. 42.4% among recovered or )] TJ ET BT 26.250 107.441 Td /F1 9.8 Tf [(asymptomatic cases, p<0.001, Table 1\). Of those who were reported to have at least one comorbid condition, )] TJ ET BT 26.250 91.997 Td /F1 9.8 Tf [(specific comorbid diagnoses were not reported for 47.8% of patients. However, of those with data, the most )] TJ ET BT 26.250 76.553 Td /F1 9.8 Tf [(commonly reported conditions include chronic renal failure \(13.3%\), diabetes \(10.0%\), and heart disease )] TJ ET BT 26.250 61.109 Td /F1 9.8 Tf [(\(7.5%\). Of five patients who were immunocompromised, two reported use of immunosuppressive medication, )] TJ ET BT 26.250 45.665 Td /F1 9.8 Tf [(two reported multiple myeloma, and solid tissue cancer was reported in one patient. A published analysis of 47 )] TJ ET Q q 15.000 27.132 577.500 749.868 re W n 0.965 0.965 0.965 rg 26.250 373.956 555.000 403.044 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 373.956 m 581.250 373.956 l 581.250 374.706 l 26.250 374.706 l f q 450.000 0 0 265.500 35.250 501.750 cm /I16 Do Q q 35.250 377.706 537.000 118.044 re W n 0.271 0.267 0.267 rg BT 35.250 483.395 Td /F4 9.8 Tf [(Fig. 2: Epidemiologic Curve of MERS-CoV Confirmed \(n=144\) and Probable Cases \(n=17\))] TJ ET BT 35.250 460.050 Td /F1 9.8 Tf [(*After week 24 in 2013, 58 cases were not reported with date for symptom onset. For these 58 cases, the )] TJ ET BT 35.250 442.230 Td /F1 9.8 Tf [(symptom onset date was estimated \(date of reporting to WHO minus median of difference between onset )] TJ ET BT 35.250 424.410 Td /F1 9.8 Tf [(date and reporting date of those cases that had both of these dates available; the median difference was )] TJ ET BT 35.250 406.590 Td /F1 9.8 Tf [(calculated by country\). Cases are reported by the location where infection is believed to have occurred. )] TJ ET BT 35.250 388.770 Td /F1 9.8 Tf [(Figure includes cases reported as of 22 October 2013.)] TJ ET Q BT 26.250 354.101 Td /F1 9.8 Tf [(Overall, the median age of MERS-CoV patients is 50 years \(range 14 months to 94 years\) and 64.5% of patients )] TJ ET BT 26.250 338.657 Td /F1 9.8 Tf [(were male \(Table 1\). As of 22 October 2013, WHO has confirmation that 65 patients \(40.4%\), of whom 62 were )] TJ ET BT 26.250 323.213 Td /F1 9.8 Tf [(confirmed and 3 probable, have died, of these 4 deaths could not be matched up to specific cases due to a lack )] TJ ET BT 26.250 307.769 Td /F1 9.8 Tf [(of identifying information. Outcome is unknown for 45 patients, either because they are still in hospital at the )] TJ ET BT 26.250 292.325 Td /F1 9.8 Tf [(time of writing, their outcome has not been reported, or we are unable to match a fatal case to our line list )] TJ ET BT 26.250 276.881 Td /F1 9.8 Tf [(\(n=4\). Age and sex varied by outcome, with a higher median age and proportion of male sex among patients )] TJ ET BT 26.250 261.437 Td /F1 9.8 Tf [(who died \(58 years old and 80.0%, respectively\) versus those who recovered or were asymptomatic \(34 years )] TJ ET BT 26.250 245.993 Td /F1 9.8 Tf [(old and 60.0%, respectively\).)] TJ ET BT 26.250 223.049 Td /F1 9.8 Tf [(The majority \(63.4%\) of patients experienced severe respiratory disease while 29.8% were reported to have non-)] TJ ET BT 26.250 207.605 Td /F1 9.8 Tf [(severe disease, including 18 cases reported as asymptomatic. Severe disease was defined as admission to an )] TJ ET BT 26.250 192.161 Td /F1 9.8 Tf [(intensive care unit [ICU]; use of extracorporeal membrane oxygenation \(ECMO\), mechanical ventilation, or )] TJ ET BT 26.250 176.717 Td /F1 9.8 Tf [(vasopressors; or reported by the member state as critical  or severe ; or who died. Severity is unknown for )] TJ ET BT 26.250 161.273 Td /F1 9.8 Tf [(6.8% of patients. Fifty-three of the 114 hospitalized patients, for whom we had data, died.)] TJ ET BT 26.250 138.329 Td /F1 9.8 Tf [(Seventy-six per cent of patients are reported to have at least one underlying medical condition and fatal cases )] TJ ET BT 26.250 122.885 Td /F1 9.8 Tf [(were more likely to have an underlying condition \(86.8% among fatal cases vs. 42.4% among recovered or )] TJ ET BT 26.250 107.441 Td /F1 9.8 Tf [(asymptomatic cases, p<0.001, Table 1\). Of those who were reported to have at least one comorbid condition, )] TJ ET BT 26.250 91.997 Td /F1 9.8 Tf [(specific comorbid diagnoses were not reported for 47.8% of patients. However, of those with data, the most )] TJ ET BT 26.250 76.553 Td /F1 9.8 Tf [(commonly reported conditions include chronic renal failure \(13.3%\), diabetes \(10.0%\), and heart disease )] TJ ET BT 26.250 61.109 Td /F1 9.8 Tf [(\(7.5%\). Of five patients who were immunocompromised, two reported use of immunosuppressive medication, )] TJ ET BT 26.250 45.665 Td /F1 9.8 Tf [(two reported multiple myeloma, and solid tissue cancer was reported in one patient. 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R (7&,D?oOdN&v2#=kuO|ƀ\6k[81OC]"񠉕,4$V'˰ ˗ނ˜dleuD6"/pG0 rML!Ik*ˆ0:2"\(CPT+skhhx\.(vOx?杻{ǎPqt]]v%MMMO<׾{̙3 +l]]]EEx`,Hv2>/0Ta786)"S8EB`^puMBC*/s`$fry _叁 ljJŴ ib ?0oㄳ;>%&ME͑Eb,A;Y,>ر`d}D^eBD]p`V؉ n=O&HBڐ:EIJJڻwoEE}4Ν;믿>00`FoooUU|W^p`pxx>zW\ill B]]]… 7oLqvvv>p{^NNΗׯ{޶6YWWG^UUgF0|###;wzl0lga!3_L% $/g@:zt0=i2<R5X#s/3ڈG`MP%0~S8kojc4z͓Fq>4LL$D| U&_"11eH8g| +YBZb&'R\p`Vd|x (",f>h<<[{P#/+.g͡52v8)$dKq%]K1_yY5?Y1_see֘0`L40!3É0ubY`'|R]]W^^~Ѭ;wWz饗y;v/ygzzz~XBQwyW_;u+BiګظgϞwy'p}*E*!77wҤIԑ?/қo8Χzj….?o~I&رcɒ%_:l6a,[y3t"/ dN4=TN P VɒK(KwD2Mq*aYD?SY+.üV A˖0blws &g9<8@gNr`̙mmmuuu?9sfwwwww>k}Fann'&&|_~pmln;99911177wtttllLP(p~Bu}ҤIqqqP;\bOض2 "t+F-4/B w3&+đ6aƲd!3-IP)D&ðD'*$tP!%/~9a1žxʌD!kB屒B "AGl!r$-,/,vL')4&ܤ55Μ9S/.\v}ل~: ၁YYYzկ8p੧{w{{{g̘q…ʏ?$>>^4_߷o߆ >u}ǴGoYxO?f͚G}tΜ9.nuttӟ; 4Y;L}!!B/^zPs`MebC" N&ML78M1ؖ͂1 %K4 ͆ڌ)pD9d֑)MLVEL&WL8gexqbH8eM1B f l?Ƭbj(#\KX1>0/I2w`L:D$2&exJ>kЉ؞Bq,hF P-2OPAڛu%RicN.C)̛Z^;f~MOacJaV n;KY2a3 m ⏱j`F#6 *J$CSu5E\1T|aABX%<@;—&Z )1OxbayaUeKu|&_>'$D'kH2`(&Ll EGF6 p9 P a# jBX#5PʔefA7)|O=[IhafZ< 8 2`ZB]waKE6F  0 [6Iƛ _ w7N s@;}2  (e3( oAB<162> U01j$ #\@K8@eaVD'çL 1a a&ba/ &C%)S}< G*E 1 W[WR^_ |-jߌm A J$?|@^e4 Xm)z(򖜽D(R^_FasS96{޲Y>kGʺcz x]"1 ΩX endstream endobj 200 0 obj << /Type /Page /Parent 3 0 R /Annots [ 202 0 R 204 0 R 206 0 R 208 0 R 210 0 R 212 0 R 214 0 R 216 0 R 218 0 R 220 0 R 222 0 R 224 0 R 226 0 R 228 0 R 230 0 R 232 0 R 234 0 R 236 0 R ] /Contents 201 0 R >> endobj 201 0 obj << /Length 24307 >> stream 0.271 0.267 0.267 rg q 15.000 253.236 577.500 523.764 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(confirmed patients from KSA, most of whom were part of the Al Hasa cluster, found that almost all \(45/47\) had )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(at least one underlying condition, including diabetes, hypertension, chronic cardiac disease and chronic renal )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(disease )] TJ ET 0.267 0.267 0.267 rg BT 66.381 735.712 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 72.413 733.757 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(We classified 51 patients as likely being sporadic \(n=29\) or index  cases \(n=22\) based on the following )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(criteria: 1\) a report of having no exposure to other known cases, 2\) occurring in an area with no previous cases )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(or no cases within the last 2 months, or 3\) reported as the index case in a cluster or being the first case )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(reported with symptoms in a cluster. Ninety-five cases were classified as secondary cases with epidemiologic )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(links to other confirmed MERS-CoV cases \(Table 1\). For 17 cases, epidemiological classifications remain unclear )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(as no information about contact with other cases is available.)] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(Seventy-three per cent of index/sporadic cases were male, as compared with 60.0% of secondary cases, though )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(this difference was not significant. Notably, this proportion has declined over time; more than 90% of the )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(earliest cases reported were male. Index/sporadic cases were older \(median age 59 years vs. 43 years, )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(p<0.001\), and more likely to experience severe disease requiring hospitalization or advanced care \(90.2% vs. )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(49.5%, p<0.001\) \(Table 1\). A similar proportion of index/sporadic cases and secondary cases reported at least )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(one underlying condition \(80.9% and 67.2%, respectively\), and diabetes, heart disease and immunosuppression )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(were most often reported among index/sporadic cases.)] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(The majority \(90.2%\) of index/sporadic cases had severe or fatal disease \(Table 1\). However, the proportion )] TJ ET BT 26.250 479.597 Td /F1 9.8 Tf [(with reported chronic renal failure was higher among secondary cases, which is related to the large outbreak )] TJ ET BT 26.250 464.153 Td /F1 9.8 Tf [(related to haemodialysis units in hospitals in Al Hasa )] TJ ET 0.267 0.267 0.267 rg BT 287.716 466.108 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 299.780 464.153 Td /F1 9.8 Tf [(. Only one of the secondary cases \(n=95\) that occurred )] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(outside of the Al Hasa outbreak reported chronic renal failure.)] TJ ET BT 26.250 425.765 Td /F1 9.8 Tf [(Among secondary cases, 13 MERS-CoV cases are believed to have been infected in household settings, 60 in )] TJ ET BT 26.250 410.321 Td /F1 9.8 Tf [(health care settings \(HCS\), and one in a workplace other than a HCS. For twenty-one cases, the place of )] TJ ET BT 26.250 394.877 Td /F1 9.8 Tf [(transmission was not reported. Cases associated with HCS in Jordan, France, KSA, UK, UAE, and Qatar )] TJ ET 0.267 0.267 0.267 rg BT 527.839 396.832 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 533.871 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 536.627 396.832 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 548.691 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.447 396.832 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.511 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 566.267 396.832 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 26.250 379.433 Td /F1 9.8 Tf [(included HCW \(30 cases\) treating MERS-CoV patients, patients seeking treatment in hospitals for conditions )] TJ ET BT 26.250 363.989 Td /F1 9.8 Tf [(unrelated to MERS-CoV \(19 cases\) and visitors \(6 cases\). The type of exposure of five additional secondary )] TJ ET BT 26.250 348.545 Td /F1 9.8 Tf [(cases associated with HCS is unknown. In households and the non-HCS workplace, secondary cases occurred )] TJ ET BT 26.250 333.101 Td /F1 9.8 Tf [(among family contacts or co-workers. The specific types of exposure resulting in transmission are currently )] TJ ET BT 26.250 317.657 Td /F1 9.8 Tf [(unknown.)] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(Only 49 cases have information on exposure to animals, including owning or visiting a farm with camels, goats, )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(sheep, chickens, ducks or other animals. Of these, exposure to animals has been reported for only a few cases )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(\(n=7; Table 1\).)] TJ ET Q q 15.000 253.236 577.500 523.764 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(confirmed patients from KSA, most of whom were part of the Al Hasa cluster, found that almost all \(45/47\) had )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(at least one underlying condition, including diabetes, hypertension, chronic cardiac disease and chronic renal )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(disease )] TJ ET 0.267 0.267 0.267 rg BT 66.381 735.712 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 72.413 733.757 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(We classified 51 patients as likely being sporadic \(n=29\) or index  cases \(n=22\) based on the following )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(criteria: 1\) a report of having no exposure to other known cases, 2\) occurring in an area with no previous cases )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(or no cases within the last 2 months, or 3\) reported as the index case in a cluster or being the first case )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(reported with symptoms in a cluster. Ninety-five cases were classified as secondary cases with epidemiologic )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(links to other confirmed MERS-CoV cases \(Table 1\). For 17 cases, epidemiological classifications remain unclear )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(as no information about contact with other cases is available.)] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(Seventy-three per cent of index/sporadic cases were male, as compared with 60.0% of secondary cases, though )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(this difference was not significant. Notably, this proportion has declined over time; more than 90% of the )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(earliest cases reported were male. Index/sporadic cases were older \(median age 59 years vs. 43 years, )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(p<0.001\), and more likely to experience severe disease requiring hospitalization or advanced care \(90.2% vs. )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(49.5%, p<0.001\) \(Table 1\). A similar proportion of index/sporadic cases and secondary cases reported at least )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(one underlying condition \(80.9% and 67.2%, respectively\), and diabetes, heart disease and immunosuppression )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(were most often reported among index/sporadic cases.)] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(The majority \(90.2%\) of index/sporadic cases had severe or fatal disease \(Table 1\). However, the proportion )] TJ ET BT 26.250 479.597 Td /F1 9.8 Tf [(with reported chronic renal failure was higher among secondary cases, which is related to the large outbreak )] TJ ET BT 26.250 464.153 Td /F1 9.8 Tf [(related to haemodialysis units in hospitals in Al Hasa )] TJ ET 0.267 0.267 0.267 rg BT 287.716 466.108 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 299.780 464.153 Td /F1 9.8 Tf [(. Only one of the secondary cases \(n=95\) that occurred )] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(outside of the Al Hasa outbreak reported chronic renal failure.)] TJ ET BT 26.250 425.765 Td /F1 9.8 Tf [(Among secondary cases, 13 MERS-CoV cases are believed to have been infected in household settings, 60 in )] TJ ET BT 26.250 410.321 Td /F1 9.8 Tf [(health care settings \(HCS\), and one in a workplace other than a HCS. For twenty-one cases, the place of )] TJ ET BT 26.250 394.877 Td /F1 9.8 Tf [(transmission was not reported. Cases associated with HCS in Jordan, France, KSA, UK, UAE, and Qatar )] TJ ET 0.267 0.267 0.267 rg BT 527.839 396.832 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 533.871 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 536.627 396.832 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 548.691 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.447 396.832 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.511 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 566.267 396.832 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 26.250 379.433 Td /F1 9.8 Tf [(included HCW \(30 cases\) treating MERS-CoV patients, patients seeking treatment in hospitals for conditions )] TJ ET BT 26.250 363.989 Td /F1 9.8 Tf [(unrelated to MERS-CoV \(19 cases\) and visitors \(6 cases\). The type of exposure of five additional secondary )] TJ ET BT 26.250 348.545 Td /F1 9.8 Tf [(cases associated with HCS is unknown. In households and the non-HCS workplace, secondary cases occurred )] TJ ET BT 26.250 333.101 Td /F1 9.8 Tf [(among family contacts or co-workers. The specific types of exposure resulting in transmission are currently )] TJ ET BT 26.250 317.657 Td /F1 9.8 Tf [(unknown.)] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(Only 49 cases have information on exposure to animals, including owning or visiting a farm with camels, goats, )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(sheep, chickens, ducks or other animals. Of these, exposure to animals has been reported for only a few cases )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(\(n=7; Table 1\).)] TJ ET Q q 15.000 253.236 577.500 523.764 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(confirmed patients from KSA, most of whom were part of the Al Hasa cluster, found that almost all \(45/47\) had )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(at least one underlying condition, including diabetes, hypertension, chronic cardiac disease and chronic renal )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(disease )] TJ ET 0.267 0.267 0.267 rg BT 66.381 735.712 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 72.413 733.757 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(We classified 51 patients as likely being sporadic \(n=29\) or index  cases \(n=22\) based on the following )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(criteria: 1\) a report of having no exposure to other known cases, 2\) occurring in an area with no previous cases )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(or no cases within the last 2 months, or 3\) reported as the index case in a cluster or being the first case )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(reported with symptoms in a cluster. Ninety-five cases were classified as secondary cases with epidemiologic )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(links to other confirmed MERS-CoV cases \(Table 1\). For 17 cases, epidemiological classifications remain unclear )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(as no information about contact with other cases is available.)] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(Seventy-three per cent of index/sporadic cases were male, as compared with 60.0% of secondary cases, though )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(this difference was not significant. Notably, this proportion has declined over time; more than 90% of the )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(earliest cases reported were male. Index/sporadic cases were older \(median age 59 years vs. 43 years, )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(p<0.001\), and more likely to experience severe disease requiring hospitalization or advanced care \(90.2% vs. )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(49.5%, p<0.001\) \(Table 1\). A similar proportion of index/sporadic cases and secondary cases reported at least )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(one underlying condition \(80.9% and 67.2%, respectively\), and diabetes, heart disease and immunosuppression )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(were most often reported among index/sporadic cases.)] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(The majority \(90.2%\) of index/sporadic cases had severe or fatal disease \(Table 1\). However, the proportion )] TJ ET BT 26.250 479.597 Td /F1 9.8 Tf [(with reported chronic renal failure was higher among secondary cases, which is related to the large outbreak )] TJ ET BT 26.250 464.153 Td /F1 9.8 Tf [(related to haemodialysis units in hospitals in Al Hasa )] TJ ET 0.267 0.267 0.267 rg BT 287.716 466.108 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 299.780 464.153 Td /F1 9.8 Tf [(. Only one of the secondary cases \(n=95\) that occurred )] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(outside of the Al Hasa outbreak reported chronic renal failure.)] TJ ET BT 26.250 425.765 Td /F1 9.8 Tf [(Among secondary cases, 13 MERS-CoV cases are believed to have been infected in household settings, 60 in )] TJ ET BT 26.250 410.321 Td /F1 9.8 Tf [(health care settings \(HCS\), and one in a workplace other than a HCS. For twenty-one cases, the place of )] TJ ET BT 26.250 394.877 Td /F1 9.8 Tf [(transmission was not reported. Cases associated with HCS in Jordan, France, KSA, UK, UAE, and Qatar )] TJ ET 0.267 0.267 0.267 rg BT 527.839 396.832 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 533.871 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 536.627 396.832 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 548.691 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.447 396.832 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.511 399.921 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 566.267 396.832 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 26.250 379.433 Td /F1 9.8 Tf [(included HCW \(30 cases\) treating MERS-CoV patients, patients seeking treatment in hospitals for conditions )] TJ ET BT 26.250 363.989 Td /F1 9.8 Tf [(unrelated to MERS-CoV \(19 cases\) and visitors \(6 cases\). The type of exposure of five additional secondary )] TJ ET BT 26.250 348.545 Td /F1 9.8 Tf [(cases associated with HCS is unknown. In households and the non-HCS workplace, secondary cases occurred )] TJ ET BT 26.250 333.101 Td /F1 9.8 Tf [(among family contacts or co-workers. The specific types of exposure resulting in transmission are currently )] TJ ET BT 26.250 317.657 Td /F1 9.8 Tf [(unknown.)] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(Only 49 cases have information on exposure to animals, including owning or visiting a farm with camels, goats, )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(sheep, chickens, ducks or other animals. Of these, exposure to animals has been reported for only a few cases )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(\(n=7; Table 1\).)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(6)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 202 0 obj << /Type /Annot /Subtype /Link /A 203 0 R /Border [0 0 0] /H /I /Rect [ 66.3810 734.6720 72.4130 746.1120 ] >> endobj 203 0 obj << /Type /Action >> endobj 204 0 obj << /Type /Annot /Subtype /Link /A 205 0 R /Border [0 0 0] /H /I /Rect [ 287.7158 465.0680 299.7798 476.5080 ] >> endobj 205 0 obj << /Type /Action >> endobj 206 0 obj << /Type /Annot /Subtype /Link /A 207 0 R /Border [0 0 0] /H /I /Rect [ 527.8388 395.7920 533.8708 407.2320 ] >> endobj 207 0 obj << /Type /Action >> endobj 208 0 obj << /Type /Annot /Subtype /Link /A 209 0 R /Border [0 0 0] /H /I /Rect [ 536.6268 395.7920 548.6908 407.2320 ] >> endobj 209 0 obj << /Type /Action >> endobj 210 0 obj << /Type /Annot /Subtype /Link /A 211 0 R /Border [0 0 0] /H /I /Rect [ 551.4468 395.7920 563.5108 407.2320 ] >> endobj 211 0 obj << /Type /Action >> endobj 212 0 obj << /Type /Annot /Subtype /Link /A 213 0 R /Border [0 0 0] /H /I /Rect [ 566.2668 395.7920 578.3308 407.2320 ] >> endobj 213 0 obj << /Type /Action >> endobj 214 0 obj << /Type /Annot /Subtype /Link /A 215 0 R /Border [0 0 0] /H /I /Rect [ 66.3810 734.6720 72.4130 746.1120 ] >> endobj 215 0 obj << /Type /Action >> endobj 216 0 obj << /Type /Annot /Subtype /Link /A 217 0 R /Border [0 0 0] /H /I /Rect [ 287.7158 465.0680 299.7798 476.5080 ] >> endobj 217 0 obj << /Type /Action >> endobj 218 0 obj << /Type /Annot /Subtype /Link /A 219 0 R /Border [0 0 0] /H /I /Rect [ 527.8388 395.7920 533.8708 407.2320 ] >> endobj 219 0 obj << /Type /Action >> endobj 220 0 obj << /Type /Annot /Subtype /Link /A 221 0 R /Border [0 0 0] /H /I /Rect [ 536.6268 395.7920 548.6908 407.2320 ] >> endobj 221 0 obj << /Type /Action >> endobj 222 0 obj << /Type /Annot /Subtype /Link /A 223 0 R /Border [0 0 0] /H /I /Rect [ 551.4468 395.7920 563.5108 407.2320 ] >> endobj 223 0 obj << /Type /Action >> endobj 224 0 obj << /Type /Annot /Subtype /Link /A 225 0 R /Border [0 0 0] /H /I /Rect [ 566.2668 395.7920 578.3308 407.2320 ] >> endobj 225 0 obj << /Type /Action >> endobj 226 0 obj << /Type /Annot /Subtype /Link /A 227 0 R /Border [0 0 0] /H /I /Rect [ 66.3810 734.6720 72.4130 746.1120 ] >> endobj 227 0 obj << /Type /Action >> endobj 228 0 obj << /Type /Annot /Subtype /Link /A 229 0 R /Border [0 0 0] /H /I /Rect [ 287.7158 465.0680 299.7798 476.5080 ] >> endobj 229 0 obj << /Type /Action >> endobj 230 0 obj << /Type /Annot /Subtype /Link /A 231 0 R /Border [0 0 0] /H /I /Rect [ 527.8388 395.7920 533.8708 407.2320 ] >> endobj 231 0 obj << /Type /Action >> endobj 232 0 obj << /Type /Annot /Subtype /Link /A 233 0 R /Border [0 0 0] /H /I /Rect [ 536.6268 395.7920 548.6908 407.2320 ] >> endobj 233 0 obj << /Type /Action >> endobj 234 0 obj << /Type /Annot /Subtype /Link /A 235 0 R /Border [0 0 0] /H /I /Rect [ 551.4468 395.7920 563.5108 407.2320 ] >> endobj 235 0 obj << /Type /Action >> endobj 236 0 obj << /Type /Annot /Subtype /Link /A 237 0 R /Border [0 0 0] /H /I /Rect [ 566.2668 395.7920 578.3308 407.2320 ] >> endobj 237 0 obj << /Type /Action >> endobj 238 0 obj << /Type /Page /Parent 3 0 R /Annots [ 240 0 R 244 0 R 246 0 R 248 0 R 250 0 R 252 0 R 254 0 R 256 0 R 258 0 R 260 0 R 262 0 R 264 0 R 266 0 R 268 0 R 270 0 R 272 0 R 274 0 R 276 0 R 278 0 R 280 0 R 282 0 R 284 0 R 286 0 R 288 0 R 290 0 R 294 0 R 296 0 R 298 0 R 300 0 R 302 0 R 304 0 R 306 0 R 308 0 R 310 0 R 312 0 R 314 0 R 316 0 R 318 0 R 320 0 R 322 0 R 324 0 R 326 0 R 328 0 R 330 0 R 332 0 R 334 0 R 336 0 R 338 0 R 340 0 R 344 0 R 346 0 R 348 0 R 350 0 R 352 0 R 354 0 R 356 0 R 358 0 R 360 0 R 362 0 R 364 0 R 366 0 R 368 0 R 370 0 R 372 0 R 374 0 R 376 0 R 378 0 R 380 0 R 382 0 R 384 0 R 386 0 R 388 0 R ] /Contents 239 0 R >> endobj 239 0 obj << /Length 27396 >> stream 0.271 0.267 0.267 rg q 15.000 32.400 577.500 744.600 re W n 0.965 0.965 0.965 rg 26.250 456.000 555.000 321.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 456.000 m 581.250 456.000 l 581.250 456.750 l 26.250 456.750 l f q 450.000 0 0 301.500 35.250 465.750 cm /I20 Do Q 0.271 0.267 0.267 rg BT 26.250 436.145 Td /F4 9.8 Tf [(Clinical Features of MERS-CoV infection in Humans)] TJ ET BT 26.250 413.201 Td /F1 9.8 Tf [(Data suggest that the clinical presentation of MERS-CoV infection ranges from asymptomatic to very severe )] TJ ET BT 26.250 397.757 Td /F1 9.8 Tf [(pneumonia with the acute respiratory distress syndrome \(ARDS\), septic shock and multi-organ failure resulting )] TJ ET BT 26.250 382.313 Td /F1 9.8 Tf [(in death. At least two cases had a consumptive coagulopathy during the course of their illness. The clinical )] TJ ET BT 26.250 366.869 Td /F1 9.8 Tf [(course is more severe in patients with immunocompromising conditions and more likely to be mild in individuals )] TJ ET BT 26.250 351.425 Td /F1 9.8 Tf [(without underlying medical conditions \(Table 1\). Only three cases have been reported in children under 5 years )] TJ ET BT 26.250 335.981 Td /F1 9.8 Tf [(of age )] TJ ET 0.267 0.267 0.267 rg BT 60.014 337.936 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 66.046 335.981 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 313.037 Td /F1 9.8 Tf [(Typically, the disease starts with fever and cough )] TJ ET 0.267 0.267 0.267 rg BT 272.262 314.992 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 278.294 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 281.050 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 287.082 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.838 314.992 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 301.902 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 304.658 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 316.722 313.037 Td /F1 9.8 Tf [(, chills, sore throat, myalgia and arthralgia)] TJ ET 0.267 0.267 0.267 rg BT 524.953 314.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 530.985 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 533.741 314.992 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 539.773 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 542.529 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 548.561 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.317 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.381 313.037 Td /F1 9.8 Tf [(, )] TJ ET BT 26.250 297.593 Td /F1 9.8 Tf [(followed by dyspnoea )] TJ ET 0.267 0.267 0.267 rg BT 135.820 299.548 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 141.853 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.609 299.548 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 150.641 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 153.397 299.548 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 165.461 297.593 Td /F1 9.8 Tf [(, and rapidly progresses to pneumonia, often requiring ventilatory and other organ )] TJ ET BT 26.250 282.149 Td /F1 9.8 Tf [(support. Nearly all symptomatic patients presented with respiratory symptoms; however, one )] TJ ET BT 26.250 266.705 Td /F1 9.8 Tf [(immunocompromised patient was initially admitted to hospital with fever, chills and diarrhoea and later found )] TJ ET BT 26.250 251.261 Td /F1 9.8 Tf [(to have pneumonia [11]. At least one-third of patients also had gastrointestinal symptoms, such as vomiting )] TJ ET BT 26.250 235.817 Td /F1 9.8 Tf [(and diarrhoea )] TJ ET 0.267 0.267 0.267 rg BT 97.815 237.772 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 103.847 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 106.603 237.772 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 112.635 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.391 237.772 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 127.455 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.211 237.772 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 142.275 235.817 Td /F1 9.8 Tf [(. Almost half of the patients developed pneumonia \(44.1%\), and 20 \(12.4%\) developed )] TJ ET BT 26.250 220.373 Td /F1 9.8 Tf [(ARDS \(Table 1\).)] TJ ET BT 26.250 197.429 Td /F1 9.8 Tf [(Chest radiograph findings vary but are consistent with viral pneumonitis and ARDS: bilateral hilar infiltration, )] TJ ET BT 26.250 181.985 Td /F1 9.8 Tf [(uni- or bilateral patchy densities or infiltrates, segmented or lobar opacities, ground glass appearance, and )] TJ ET BT 26.250 166.541 Td /F1 9.8 Tf [(small pleural effusions have been described. Lower lobes tend to be affected more than upper lobes early in the )] TJ ET BT 26.250 151.097 Td /F1 9.8 Tf [(course of illness; radiographic appearance progresses rapidly. Computed tomographic scans have shown )] TJ ET BT 26.250 135.653 Td /F1 9.8 Tf [(interstitial infiltrates and consolidation compatible with ARDS in severe cases. In some severe cases, renal )] TJ ET BT 26.250 120.209 Td /F1 9.8 Tf [(failure developed concurrently with respiratory failure.)] TJ ET BT 26.250 97.265 Td /F1 9.8 Tf [(Common laboratory findings include leucopoenia, particularly lymphopaenia )] TJ ET 0.267 0.267 0.267 rg BT 403.399 99.220 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 409.432 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 412.188 99.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 418.220 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 420.976 99.220 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 427.008 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 429.764 99.220 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 441.828 97.265 Td /F1 9.8 Tf [(. Reports from a few cases )] TJ ET BT 26.250 81.821 Td /F1 9.8 Tf [(found viral RNA in blood )] TJ ET 0.267 0.267 0.267 rg BT 147.540 83.776 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 159.604 81.821 Td /F1 9.8 Tf [(, urine )] TJ ET 0.267 0.267 0.267 rg BT 193.983 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 206.047 81.821 Td /F1 9.8 Tf [( and stool )] TJ ET 0.267 0.267 0.267 rg BT 257.244 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 269.308 81.821 Td /F1 9.8 Tf [( but at much lower viral loads than in the respiratory tract. )] TJ ET BT 26.250 66.377 Td /F1 9.8 Tf [(The viral load in upper respiratory tract specimens is general lower than in the lower respiratory specimens, )] TJ ET BT 26.250 50.933 Td /F1 9.8 Tf [(though data are limited. Co-infection with other respiratory viruses \(e.g., parainfluenza, rhinovirus, influenza )] TJ ET Q q 15.000 32.400 577.500 744.600 re W n 0.965 0.965 0.965 rg 26.250 456.000 555.000 321.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 456.000 m 581.250 456.000 l 581.250 456.750 l 26.250 456.750 l f q 450.000 0 0 301.500 35.250 465.750 cm /I22 Do Q 0.271 0.267 0.267 rg BT 26.250 436.145 Td /F4 9.8 Tf [(Clinical Features of MERS-CoV infection in Humans)] TJ ET BT 26.250 413.201 Td /F1 9.8 Tf [(Data suggest that the clinical presentation of MERS-CoV infection ranges from asymptomatic to very severe )] TJ ET BT 26.250 397.757 Td /F1 9.8 Tf [(pneumonia with the acute respiratory distress syndrome \(ARDS\), septic shock and multi-organ failure resulting )] TJ ET BT 26.250 382.313 Td /F1 9.8 Tf [(in death. At least two cases had a consumptive coagulopathy during the course of their illness. The clinical )] TJ ET BT 26.250 366.869 Td /F1 9.8 Tf [(course is more severe in patients with immunocompromising conditions and more likely to be mild in individuals )] TJ ET BT 26.250 351.425 Td /F1 9.8 Tf [(without underlying medical conditions \(Table 1\). Only three cases have been reported in children under 5 years )] TJ ET BT 26.250 335.981 Td /F1 9.8 Tf [(of age )] TJ ET 0.267 0.267 0.267 rg BT 60.014 337.936 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 66.046 335.981 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 313.037 Td /F1 9.8 Tf [(Typically, the disease starts with fever and cough )] TJ ET 0.267 0.267 0.267 rg BT 272.262 314.992 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 278.294 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 281.050 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 287.082 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.838 314.992 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 301.902 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 304.658 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 316.722 313.037 Td /F1 9.8 Tf [(, chills, sore throat, myalgia and arthralgia)] TJ ET 0.267 0.267 0.267 rg BT 524.953 314.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 530.985 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 533.741 314.992 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 539.773 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 542.529 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 548.561 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.317 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.381 313.037 Td /F1 9.8 Tf [(, )] TJ ET BT 26.250 297.593 Td /F1 9.8 Tf [(followed by dyspnoea )] TJ ET 0.267 0.267 0.267 rg BT 135.820 299.548 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 141.853 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.609 299.548 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 150.641 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 153.397 299.548 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 165.461 297.593 Td /F1 9.8 Tf [(, and rapidly progresses to pneumonia, often requiring ventilatory and other organ )] TJ ET BT 26.250 282.149 Td /F1 9.8 Tf [(support. Nearly all symptomatic patients presented with respiratory symptoms; however, one )] TJ ET BT 26.250 266.705 Td /F1 9.8 Tf [(immunocompromised patient was initially admitted to hospital with fever, chills and diarrhoea and later found )] TJ ET BT 26.250 251.261 Td /F1 9.8 Tf [(to have pneumonia [11]. At least one-third of patients also had gastrointestinal symptoms, such as vomiting )] TJ ET BT 26.250 235.817 Td /F1 9.8 Tf [(and diarrhoea )] TJ ET 0.267 0.267 0.267 rg BT 97.815 237.772 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 103.847 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 106.603 237.772 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 112.635 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.391 237.772 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 127.455 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.211 237.772 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 142.275 235.817 Td /F1 9.8 Tf [(. Almost half of the patients developed pneumonia \(44.1%\), and 20 \(12.4%\) developed )] TJ ET BT 26.250 220.373 Td /F1 9.8 Tf [(ARDS \(Table 1\).)] TJ ET BT 26.250 197.429 Td /F1 9.8 Tf [(Chest radiograph findings vary but are consistent with viral pneumonitis and ARDS: bilateral hilar infiltration, )] TJ ET BT 26.250 181.985 Td /F1 9.8 Tf [(uni- or bilateral patchy densities or infiltrates, segmented or lobar opacities, ground glass appearance, and )] TJ ET BT 26.250 166.541 Td /F1 9.8 Tf [(small pleural effusions have been described. Lower lobes tend to be affected more than upper lobes early in the )] TJ ET BT 26.250 151.097 Td /F1 9.8 Tf [(course of illness; radiographic appearance progresses rapidly. Computed tomographic scans have shown )] TJ ET BT 26.250 135.653 Td /F1 9.8 Tf [(interstitial infiltrates and consolidation compatible with ARDS in severe cases. In some severe cases, renal )] TJ ET BT 26.250 120.209 Td /F1 9.8 Tf [(failure developed concurrently with respiratory failure.)] TJ ET BT 26.250 97.265 Td /F1 9.8 Tf [(Common laboratory findings include leucopoenia, particularly lymphopaenia )] TJ ET 0.267 0.267 0.267 rg BT 403.399 99.220 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 409.432 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 412.188 99.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 418.220 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 420.976 99.220 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 427.008 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 429.764 99.220 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 441.828 97.265 Td /F1 9.8 Tf [(. Reports from a few cases )] TJ ET BT 26.250 81.821 Td /F1 9.8 Tf [(found viral RNA in blood )] TJ ET 0.267 0.267 0.267 rg BT 147.540 83.776 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 159.604 81.821 Td /F1 9.8 Tf [(, urine )] TJ ET 0.267 0.267 0.267 rg BT 193.983 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 206.047 81.821 Td /F1 9.8 Tf [( and stool )] TJ ET 0.267 0.267 0.267 rg BT 257.244 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 269.308 81.821 Td /F1 9.8 Tf [( but at much lower viral loads than in the respiratory tract. )] TJ ET BT 26.250 66.377 Td /F1 9.8 Tf [(The viral load in upper respiratory tract specimens is general lower than in the lower respiratory specimens, )] TJ ET BT 26.250 50.933 Td /F1 9.8 Tf [(though data are limited. Co-infection with other respiratory viruses \(e.g., parainfluenza, rhinovirus, influenza )] TJ ET Q q 15.000 32.400 577.500 744.600 re W n 0.965 0.965 0.965 rg 26.250 456.000 555.000 321.000 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 456.000 m 581.250 456.000 l 581.250 456.750 l 26.250 456.750 l f q 450.000 0 0 301.500 35.250 465.750 cm /I24 Do Q 0.271 0.267 0.267 rg BT 26.250 436.145 Td /F4 9.8 Tf [(Clinical Features of MERS-CoV infection in Humans)] TJ ET BT 26.250 413.201 Td /F1 9.8 Tf [(Data suggest that the clinical presentation of MERS-CoV infection ranges from asymptomatic to very severe )] TJ ET BT 26.250 397.757 Td /F1 9.8 Tf [(pneumonia with the acute respiratory distress syndrome \(ARDS\), septic shock and multi-organ failure resulting )] TJ ET BT 26.250 382.313 Td /F1 9.8 Tf [(in death. At least two cases had a consumptive coagulopathy during the course of their illness. The clinical )] TJ ET BT 26.250 366.869 Td /F1 9.8 Tf [(course is more severe in patients with immunocompromising conditions and more likely to be mild in individuals )] TJ ET BT 26.250 351.425 Td /F1 9.8 Tf [(without underlying medical conditions \(Table 1\). Only three cases have been reported in children under 5 years )] TJ ET BT 26.250 335.981 Td /F1 9.8 Tf [(of age )] TJ ET 0.267 0.267 0.267 rg BT 60.014 337.936 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 66.046 335.981 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 313.037 Td /F1 9.8 Tf [(Typically, the disease starts with fever and cough )] TJ ET 0.267 0.267 0.267 rg BT 272.262 314.992 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 278.294 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 281.050 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 287.082 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.838 314.992 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 301.902 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 304.658 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 316.722 313.037 Td /F1 9.8 Tf [(, chills, sore throat, myalgia and arthralgia)] TJ ET 0.267 0.267 0.267 rg BT 524.953 314.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 530.985 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 533.741 314.992 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 539.773 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 542.529 314.992 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 548.561 318.081 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 551.317 314.992 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 563.381 313.037 Td /F1 9.8 Tf [(, )] TJ ET BT 26.250 297.593 Td /F1 9.8 Tf [(followed by dyspnoea )] TJ ET 0.267 0.267 0.267 rg BT 135.820 299.548 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 141.853 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.609 299.548 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 150.641 302.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 153.397 299.548 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 165.461 297.593 Td /F1 9.8 Tf [(, and rapidly progresses to pneumonia, often requiring ventilatory and other organ )] TJ ET BT 26.250 282.149 Td /F1 9.8 Tf [(support. Nearly all symptomatic patients presented with respiratory symptoms; however, one )] TJ ET BT 26.250 266.705 Td /F1 9.8 Tf [(immunocompromised patient was initially admitted to hospital with fever, chills and diarrhoea and later found )] TJ ET BT 26.250 251.261 Td /F1 9.8 Tf [(to have pneumonia [11]. At least one-third of patients also had gastrointestinal symptoms, such as vomiting )] TJ ET BT 26.250 235.817 Td /F1 9.8 Tf [(and diarrhoea )] TJ ET 0.267 0.267 0.267 rg BT 97.815 237.772 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 103.847 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 106.603 237.772 Td /F4 8.7 Tf [(9)] TJ ET 0.271 0.267 0.267 rg BT 112.635 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.391 237.772 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 127.455 240.861 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.211 237.772 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 142.275 235.817 Td /F1 9.8 Tf [(. Almost half of the patients developed pneumonia \(44.1%\), and 20 \(12.4%\) developed )] TJ ET BT 26.250 220.373 Td /F1 9.8 Tf [(ARDS \(Table 1\).)] TJ ET BT 26.250 197.429 Td /F1 9.8 Tf [(Chest radiograph findings vary but are consistent with viral pneumonitis and ARDS: bilateral hilar infiltration, )] TJ ET BT 26.250 181.985 Td /F1 9.8 Tf [(uni- or bilateral patchy densities or infiltrates, segmented or lobar opacities, ground glass appearance, and )] TJ ET BT 26.250 166.541 Td /F1 9.8 Tf [(small pleural effusions have been described. Lower lobes tend to be affected more than upper lobes early in the )] TJ ET BT 26.250 151.097 Td /F1 9.8 Tf [(course of illness; radiographic appearance progresses rapidly. Computed tomographic scans have shown )] TJ ET BT 26.250 135.653 Td /F1 9.8 Tf [(interstitial infiltrates and consolidation compatible with ARDS in severe cases. In some severe cases, renal )] TJ ET BT 26.250 120.209 Td /F1 9.8 Tf [(failure developed concurrently with respiratory failure.)] TJ ET BT 26.250 97.265 Td /F1 9.8 Tf [(Common laboratory findings include leucopoenia, particularly lymphopaenia )] TJ ET 0.267 0.267 0.267 rg BT 403.399 99.220 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 409.432 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 412.188 99.220 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 418.220 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 420.976 99.220 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 427.008 102.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 429.764 99.220 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 441.828 97.265 Td /F1 9.8 Tf [(. Reports from a few cases )] TJ ET BT 26.250 81.821 Td /F1 9.8 Tf [(found viral RNA in blood )] TJ ET 0.267 0.267 0.267 rg BT 147.540 83.776 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 159.604 81.821 Td /F1 9.8 Tf [(, urine )] TJ ET 0.267 0.267 0.267 rg BT 193.983 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 206.047 81.821 Td /F1 9.8 Tf [( and stool )] TJ ET 0.267 0.267 0.267 rg BT 257.244 83.776 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 269.308 81.821 Td /F1 9.8 Tf [( but at much lower viral loads than in the respiratory tract. )] TJ ET BT 26.250 66.377 Td /F1 9.8 Tf [(The viral load in upper respiratory tract specimens is general lower than in the lower respiratory specimens, )] TJ ET BT 26.250 50.933 Td /F1 9.8 Tf [(though data are limited. Co-infection with other respiratory viruses \(e.g., parainfluenza, rhinovirus, influenza )] TJ ET Q q 450.000 0 0 301.500 35.250 465.750 cm /I26 Do Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(7)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 240 0 obj << /Type /Annot /Subtype /Link /A 241 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 465.7500 485.2500 767.2500 ] >> endobj 241 0 obj << /Type /Action /S /URI /URI (http://currents.plos.org/outbreaks/files/2013/11/MERSCoV-Table1-lbl.png) >> endobj 242 0 obj << /Type /XObject /Subtype /Image /Width 600 /Height 402 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 600 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 1033>> stream xA 0 =" ʝ<2;EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$EX$%& j endstream endobj 243 0 obj << /Type /XObject /Subtype /Image /Width 600 /Height 402 /SMask 242 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 600 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 195917>> stream x}gXWea(]U^Q,{(b4Xb#QQ+A@H,}Νy W3sfv4 8VSVM6xbF%|JbYx$Tst7*ABFu caxyޠ&fA"N#b3'1dNHӰ"ͧC(4,bv**:VLD/n^DO +JYRJ`IGcγ*Ou@z8j/ 3d74pk2{Y3EAFqVX Qf(ɦ@U!ܶ"@,ܶH0[&Ij".™Ǻ3.eZN T? 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The duration of hospitalization to either )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(discharge or death was relatively short, with a median of 7.0 days \(2-39, n=21\) and 9.0 \(2-293, n=24\) days, )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(respectively. One patient, who died after 298 days of symptom onset, had been treated with ECMO from the )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(third week of illness )] TJ ET 0.267 0.267 0.267 rg BT 127.046 650.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 133.078 649.037 Td /F1 9.8 Tf [(. Two additional cases died after 35 days or more in hospital, having undergone prolonged )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(ECMO support.)] TJ ET BT 26.250 610.649 Td /F4 9.8 Tf [(Treatment)] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(In the absence of pathogen-specific interventions, patient management largely depends on provision of organ )] TJ ET BT 26.250 572.261 Td /F1 9.8 Tf [(support, and vigilance for and prevention of complications. In specific circumstances, additional interventions )] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(have included empiric use of broad-spectrum antimicrobial agents, antivirals \(oseltamivir and/or acyclovir\), and )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(the addition of anti-fungal agents to minimize risk of co-infections with opportunistic pathogens.)] TJ ET BT 26.250 518.429 Td /F1 9.8 Tf [(Lung-protective ventilatory strategies for ARDS, cardiovascular support, antimicrobial therapy for co-infections, )] TJ ET BT 26.250 502.985 Td /F1 9.8 Tf [(and renal replacement therapy for acute renal failure have been used )] TJ ET 0.267 0.267 0.267 rg BT 371.634 504.940 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 377.666 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.422 504.940 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 386.454 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 389.210 504.940 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 401.274 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 404.030 504.940 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 416.094 502.985 Td /F1 9.8 Tf [(. Case reports of patients )] TJ ET BT 26.250 487.541 Td /F1 9.8 Tf [(supported with ECMO are available for six patients, five of whom have died )] TJ ET 0.267 0.267 0.267 rg BT 397.725 489.496 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 403.757 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 406.513 489.496 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 418.577 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 421.333 489.496 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 433.397 487.541 Td /F1 9.8 Tf [(. No case-control data exist )] TJ ET BT 26.250 472.097 Td /F1 9.8 Tf [(to evaluate the effectiveness of such interventions.)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Many patients with severe disease have been treated with systemic high-dose corticosteroids, which was )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(intended to reverse the progression of respiratory distress and to prevent lung fibrosis. This appears to have )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(been unsuccessful.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(None of the antimicrobial agents used so far, including the antivirals, appear to be successful in improving )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(severe progressive disease. A large number of pharmacological agents have been screened against MERS-CoV )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(and several agents have shown inhibitory effects against MERS-CoV in cell cultures. Among the agents tested in )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(vitro are interferons, cyclosporin A, ribavirin, nitazoxanide, immunoglobulins, lopinavir and SARS CoV )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(convalescent plasma)] TJ ET 0.267 0.267 0.267 rg BT 129.190 335.500 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 141.255 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.011 335.500 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 156.075 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 158.831 335.500 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 170.895 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 173.651 335.500 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 185.715 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 188.471 335.500 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 200.535 333.545 Td /F1 9.8 Tf [(. Currently, no clinical data support use of these agents. However, a recent )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(study has found favorable outcomes in MERS-CoV infected rhesus macaques treated with ribavirin and )] TJ ET BT 26.250 302.657 Td /F1 9.8 Tf [(interferon-alpha 2b)] TJ ET 0.267 0.267 0.267 rg BT 120.601 304.612 Td /F4 8.7 Tf [(65)] TJ ET 0.271 0.267 0.267 rg BT 26.250 261.862 Td /F4 12.0 Tf [(Transmission of MERS-CoV)] TJ ET BT 26.250 238.205 Td /F4 9.8 Tf [(Clusters)] TJ ET BT 71.373 243.249 Td /F4 8.7 Tf [([1])] TJ ET BT 26.250 213.098 Td /F1 8.7 Tf [([1] WHO defines a cluster  as two or more persons with onset of symptoms within the same 14 day period, and who are )] TJ ET BT 26.250 199.370 Td /F1 8.7 Tf [(associated with a specific setting, such as a classroom, workplace, household, extended family, hospital, other residential )] TJ ET BT 26.250 185.642 Td /F1 8.7 Tf [(institution, military barracks or recreational camp \(WHO Interim Surveillance Recommendations, 2013\).)] TJ ET BT 26.250 166.577 Td /F1 9.8 Tf [(A number of the cases in France, Italy, Jordan, KSA, Tunisia, UAE, UK and Qatar have been reported in clusters )] TJ ET 0.267 0.267 0.267 rg BT 569.822 168.532 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 575.854 171.621 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 26.250 153.088 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 32.282 151.133 Td /F1 9.8 Tf [(, providing evidence that human-to-human transmission has occurred in HCS, households, and the workplace )] TJ ET BT 26.250 135.689 Td /F1 9.8 Tf [(\(Table 2\) )] TJ ET 0.267 0.267 0.267 rg BT 73.089 137.644 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 79.121 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 81.877 137.644 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 87.909 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 90.665 137.644 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 102.729 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 105.485 137.644 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 117.549 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 120.305 137.644 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 132.369 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 135.125 137.644 Td /F4 8.7 Tf [(64)] TJ ET 0.271 0.267 0.267 rg BT 147.189 135.689 Td /F1 9.8 Tf [( . In France, Italy, Jordan, KSA, Qatar, Tunisia, UAE and UK, secondary cases were )] TJ ET BT 26.250 120.245 Td /F1 9.8 Tf [(identified through intense case-finding and follow-up of contacts. Intensity of follow-up of close contacts of )] TJ ET BT 26.250 104.801 Td /F1 9.8 Tf [(patients varies between countries and has included screening contacts for respiratory symptoms and evidence )] TJ ET BT 26.250 89.357 Td /F1 9.8 Tf [(of infection either using reverse-transcriptase PCR \(RT-PCR\) or, in some situations, serologic assays \(Table 2\).)] TJ ET BT 26.250 66.413 Td /F1 9.8 Tf [(As the exposure that results in sporadic infection is unknown, it is impossible to estimate the incubation period )] TJ ET BT 26.250 50.969 Td /F1 9.8 Tf [(in these cases. However, data for human-to-human transmission in the clusters are available from France )] TJ ET 0.267 0.267 0.267 rg BT 547.163 52.924 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 559.227 56.013 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 561.983 52.924 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 574.047 50.969 Td /F1 9.8 Tf [(, )] TJ ET Q q 15.000 32.436 577.500 744.564 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(A\(H1N1\)pdm09, herpes simplex, influenza B\) has been reported in some patients and secondary nosocomially )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(acquired bacterial infections \(Klebsiella pneumoniae, Staphylococcus aureus, Acinetobacter sp., Candida sp.\) )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(have been reported in patients who received mechanical ventilation )] TJ ET 0.267 0.267 0.267 rg BT 363.259 735.712 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 369.291 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 372.047 735.712 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 378.079 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.835 735.712 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 392.899 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 395.655 735.712 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 407.719 733.757 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(The median times from symptom onset to hospitalization, admission to an ICU or to death are 4.0 days \(range 0-)] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(16, n=62\), 5.0 \(1-15, n=35\) and 11.5 days \(4-298, n=40\), respectively. The duration of hospitalization to either )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(discharge or death was relatively short, with a median of 7.0 days \(2-39, n=21\) and 9.0 \(2-293, n=24\) days, )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(respectively. One patient, who died after 298 days of symptom onset, had been treated with ECMO from the )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(third week of illness )] TJ ET 0.267 0.267 0.267 rg BT 127.046 650.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 133.078 649.037 Td /F1 9.8 Tf [(. Two additional cases died after 35 days or more in hospital, having undergone prolonged )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(ECMO support.)] TJ ET BT 26.250 610.649 Td /F4 9.8 Tf [(Treatment)] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(In the absence of pathogen-specific interventions, patient management largely depends on provision of organ )] TJ ET BT 26.250 572.261 Td /F1 9.8 Tf [(support, and vigilance for and prevention of complications. In specific circumstances, additional interventions )] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(have included empiric use of broad-spectrum antimicrobial agents, antivirals \(oseltamivir and/or acyclovir\), and )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(the addition of anti-fungal agents to minimize risk of co-infections with opportunistic pathogens.)] TJ ET BT 26.250 518.429 Td /F1 9.8 Tf [(Lung-protective ventilatory strategies for ARDS, cardiovascular support, antimicrobial therapy for co-infections, )] TJ ET BT 26.250 502.985 Td /F1 9.8 Tf [(and renal replacement therapy for acute renal failure have been used )] TJ ET 0.267 0.267 0.267 rg BT 371.634 504.940 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 377.666 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.422 504.940 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 386.454 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 389.210 504.940 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 401.274 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 404.030 504.940 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 416.094 502.985 Td /F1 9.8 Tf [(. Case reports of patients )] TJ ET BT 26.250 487.541 Td /F1 9.8 Tf [(supported with ECMO are available for six patients, five of whom have died )] TJ ET 0.267 0.267 0.267 rg BT 397.725 489.496 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 403.757 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 406.513 489.496 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 418.577 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 421.333 489.496 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 433.397 487.541 Td /F1 9.8 Tf [(. No case-control data exist )] TJ ET BT 26.250 472.097 Td /F1 9.8 Tf [(to evaluate the effectiveness of such interventions.)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Many patients with severe disease have been treated with systemic high-dose corticosteroids, which was )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(intended to reverse the progression of respiratory distress and to prevent lung fibrosis. This appears to have )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(been unsuccessful.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(None of the antimicrobial agents used so far, including the antivirals, appear to be successful in improving )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(severe progressive disease. A large number of pharmacological agents have been screened against MERS-CoV )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(and several agents have shown inhibitory effects against MERS-CoV in cell cultures. Among the agents tested in )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(vitro are interferons, cyclosporin A, ribavirin, nitazoxanide, immunoglobulins, lopinavir and SARS CoV )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(convalescent plasma)] TJ ET 0.267 0.267 0.267 rg BT 129.190 335.500 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 141.255 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.011 335.500 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 156.075 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 158.831 335.500 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 170.895 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 173.651 335.500 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 185.715 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 188.471 335.500 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 200.535 333.545 Td /F1 9.8 Tf [(. Currently, no clinical data support use of these agents. However, a recent )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(study has found favorable outcomes in MERS-CoV infected rhesus macaques treated with ribavirin and )] TJ ET BT 26.250 302.657 Td /F1 9.8 Tf [(interferon-alpha 2b)] TJ ET 0.267 0.267 0.267 rg BT 120.601 304.612 Td /F4 8.7 Tf [(65)] TJ ET 0.271 0.267 0.267 rg BT 26.250 261.862 Td /F4 12.0 Tf [(Transmission of MERS-CoV)] TJ ET BT 26.250 238.205 Td /F4 9.8 Tf [(Clusters)] TJ ET BT 71.373 243.249 Td /F4 8.7 Tf [([1])] TJ ET BT 26.250 213.098 Td /F1 8.7 Tf [([1] WHO defines a cluster  as two or more persons with onset of symptoms within the same 14 day period, and who are )] TJ ET BT 26.250 199.370 Td /F1 8.7 Tf [(associated with a specific setting, such as a classroom, workplace, household, extended family, hospital, other residential )] TJ ET BT 26.250 185.642 Td /F1 8.7 Tf [(institution, military barracks or recreational camp \(WHO Interim Surveillance Recommendations, 2013\).)] TJ ET BT 26.250 166.577 Td /F1 9.8 Tf [(A number of the cases in France, Italy, Jordan, KSA, Tunisia, UAE, UK and Qatar have been reported in clusters )] TJ ET 0.267 0.267 0.267 rg BT 569.822 168.532 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 575.854 171.621 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 26.250 153.088 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 32.282 151.133 Td /F1 9.8 Tf [(, providing evidence that human-to-human transmission has occurred in HCS, households, and the workplace )] TJ ET BT 26.250 135.689 Td /F1 9.8 Tf [(\(Table 2\) )] TJ ET 0.267 0.267 0.267 rg BT 73.089 137.644 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 79.121 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 81.877 137.644 Td /F4 8.7 Tf [(5)] TJ ET 0.271 0.267 0.267 rg BT 87.909 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 90.665 137.644 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 102.729 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 105.485 137.644 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 117.549 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 120.305 137.644 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 132.369 140.733 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 135.125 137.644 Td /F4 8.7 Tf [(64)] TJ ET 0.271 0.267 0.267 rg BT 147.189 135.689 Td /F1 9.8 Tf [( . In France, Italy, Jordan, KSA, Qatar, Tunisia, UAE and UK, secondary cases were )] TJ ET BT 26.250 120.245 Td /F1 9.8 Tf [(identified through intense case-finding and follow-up of contacts. Intensity of follow-up of close contacts of )] TJ ET BT 26.250 104.801 Td /F1 9.8 Tf [(patients varies between countries and has included screening contacts for respiratory symptoms and evidence )] TJ ET BT 26.250 89.357 Td /F1 9.8 Tf [(of infection either using reverse-transcriptase PCR \(RT-PCR\) or, in some situations, serologic assays \(Table 2\).)] TJ ET BT 26.250 66.413 Td /F1 9.8 Tf [(As the exposure that results in sporadic infection is unknown, it is impossible to estimate the incubation period )] TJ ET BT 26.250 50.969 Td /F1 9.8 Tf [(in these cases. However, data for human-to-human transmission in the clusters are available from France )] TJ ET 0.267 0.267 0.267 rg BT 547.163 52.924 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 559.227 56.013 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 561.983 52.924 Td /F4 8.7 Tf [(19)] TJ ET 0.271 0.267 0.267 rg BT 574.047 50.969 Td /F1 9.8 Tf [(, )] TJ ET Q q 15.000 32.436 577.500 744.564 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(A\(H1N1\)pdm09, herpes simplex, influenza B\) has been reported in some patients and secondary nosocomially )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(acquired bacterial infections \(Klebsiella pneumoniae, Staphylococcus aureus, Acinetobacter sp., Candida sp.\) )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(have been reported in patients who received mechanical ventilation )] TJ ET 0.267 0.267 0.267 rg BT 363.259 735.712 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 369.291 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 372.047 735.712 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 378.079 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.835 735.712 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 392.899 738.801 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 395.655 735.712 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 407.719 733.757 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(The median times from symptom onset to hospitalization, admission to an ICU or to death are 4.0 days \(range 0-)] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(16, n=62\), 5.0 \(1-15, n=35\) and 11.5 days \(4-298, n=40\), respectively. The duration of hospitalization to either )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(discharge or death was relatively short, with a median of 7.0 days \(2-39, n=21\) and 9.0 \(2-293, n=24\) days, )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(respectively. One patient, who died after 298 days of symptom onset, had been treated with ECMO from the )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(third week of illness )] TJ ET 0.267 0.267 0.267 rg BT 127.046 650.992 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 133.078 649.037 Td /F1 9.8 Tf [(. Two additional cases died after 35 days or more in hospital, having undergone prolonged )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(ECMO support.)] TJ ET BT 26.250 610.649 Td /F4 9.8 Tf [(Treatment)] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(In the absence of pathogen-specific interventions, patient management largely depends on provision of organ )] TJ ET BT 26.250 572.261 Td /F1 9.8 Tf [(support, and vigilance for and prevention of complications. In specific circumstances, additional interventions )] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(have included empiric use of broad-spectrum antimicrobial agents, antivirals \(oseltamivir and/or acyclovir\), and )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(the addition of anti-fungal agents to minimize risk of co-infections with opportunistic pathogens.)] TJ ET BT 26.250 518.429 Td /F1 9.8 Tf [(Lung-protective ventilatory strategies for ARDS, cardiovascular support, antimicrobial therapy for co-infections, )] TJ ET BT 26.250 502.985 Td /F1 9.8 Tf [(and renal replacement therapy for acute renal failure have been used )] TJ ET 0.267 0.267 0.267 rg BT 371.634 504.940 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 377.666 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.422 504.940 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 386.454 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 389.210 504.940 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 401.274 508.029 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 404.030 504.940 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 416.094 502.985 Td /F1 9.8 Tf [(. Case reports of patients )] TJ ET BT 26.250 487.541 Td /F1 9.8 Tf [(supported with ECMO are available for six patients, five of whom have died )] TJ ET 0.267 0.267 0.267 rg BT 397.725 489.496 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 403.757 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 406.513 489.496 Td /F4 8.7 Tf [(11)] TJ ET 0.271 0.267 0.267 rg BT 418.577 492.585 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 421.333 489.496 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 433.397 487.541 Td /F1 9.8 Tf [(. No case-control data exist )] TJ ET BT 26.250 472.097 Td /F1 9.8 Tf [(to evaluate the effectiveness of such interventions.)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Many patients with severe disease have been treated with systemic high-dose corticosteroids, which was )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(intended to reverse the progression of respiratory distress and to prevent lung fibrosis. This appears to have )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(been unsuccessful.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(None of the antimicrobial agents used so far, including the antivirals, appear to be successful in improving )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(severe progressive disease. A large number of pharmacological agents have been screened against MERS-CoV )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(and several agents have shown inhibitory effects against MERS-CoV in cell cultures. Among the agents tested in )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(vitro are interferons, cyclosporin A, ribavirin, nitazoxanide, immunoglobulins, lopinavir and SARS CoV )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(convalescent plasma)] TJ ET 0.267 0.267 0.267 rg BT 129.190 335.500 Td /F4 8.7 Tf [(14)] TJ ET 0.271 0.267 0.267 rg BT 141.255 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 144.011 335.500 Td /F4 8.7 Tf [(15)] TJ ET 0.271 0.267 0.267 rg BT 156.075 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 158.831 335.500 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 170.895 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 173.651 335.500 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 185.715 338.589 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 188.471 335.500 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 200.535 333.545 Td /F1 9.8 Tf [(. Currently, no clinical data support use of these agents. 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In France, Italy, Jordan, KSA, Qatar, Tunisia, UAE and UK, secondary cases were )] TJ ET BT 26.250 120.245 Td /F1 9.8 Tf [(identified through intense case-finding and follow-up of contacts. Intensity of follow-up of close contacts of )] TJ ET BT 26.250 104.801 Td /F1 9.8 Tf [(patients varies between countries and has included screening contacts for respiratory symptoms and evidence )] TJ ET BT 26.250 89.357 Td /F1 9.8 Tf [(of infection either using reverse-transcriptase PCR \(RT-PCR\) or, in some situations, serologic assays \(Table 2\).)] TJ ET BT 26.250 66.413 Td /F1 9.8 Tf [(As the exposure that results in sporadic infection is unknown, it is impossible to estimate the incubation period )] TJ ET BT 26.250 50.969 Td /F1 9.8 Tf [(in these cases. 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Jl6olHẍ]c1diYB_lʘLr'gQ6olb endstream endobj 706 0 obj << /Type /Page /Parent 3 0 R /Annots [ 708 0 R 710 0 R 712 0 R 714 0 R 716 0 R 718 0 R 720 0 R 722 0 R 724 0 R 726 0 R 728 0 R 730 0 R 732 0 R 734 0 R 736 0 R 738 0 R 740 0 R 742 0 R 744 0 R 746 0 R 748 0 R 750 0 R 752 0 R 754 0 R 756 0 R 758 0 R 760 0 R 762 0 R 764 0 R 766 0 R 768 0 R 770 0 R 772 0 R 774 0 R 776 0 R 778 0 R 780 0 R 782 0 R 784 0 R 786 0 R 788 0 R 790 0 R 792 0 R 794 0 R 796 0 R 798 0 R 800 0 R 802 0 R 804 0 R 806 0 R 808 0 R 810 0 R 812 0 R 814 0 R 816 0 R 818 0 R 820 0 R 822 0 R 824 0 R 826 0 R ] /Contents 707 0 R >> endobj 707 0 obj << /Length 40194 >> stream 0.271 0.267 0.267 rg 0.267 0.267 0.267 RG q 15.000 18.900 577.500 758.100 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(population, R)] TJ ET BT 91.126 761.967 Td /F1 8.7 Tf [(0)] TJ ET BT 96.639 764.645 Td /F1 9.8 Tf [(\))] TJ ET 0.267 0.267 0.267 rg BT 100.441 766.600 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 112.505 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.261 766.600 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 127.325 764.645 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Breban and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 141.115 743.656 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 153.179 741.701 Td /F1 9.8 Tf [( used the first 55 laboratory-confirmed cases of MERS-CoV reported to WHO to assess )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(the inter-human transmissibility of MERS-CoV. The authors estimated R)] TJ ET BT 375.592 723.579 Td /F1 8.7 Tf [(0)] TJ ET BT 381.104 726.257 Td /F1 9.8 Tf [( from the distribution of sizes of case )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(transmission trees seen so far and compared their estimate with that of early data from the SARS-CoV epidemic )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(in 2003. Two scenarios were considered. With the most pessimistic scenario, the authors estimated MERS-CoV R)] TJ ET BT 26.250 677.247 Td /F1 8.7 Tf [(0)] TJ ET BT 31.762 679.925 Td /F1 9.8 Tf [( to be 0.69 \(95% CI 0.50 0.92\); by contrast, the R)] TJ ET BT 275.024 677.247 Td /F1 8.7 Tf [(0 )] TJ ET BT 283.293 679.925 Td /F1 9.8 Tf [(for SARS-CoV was 0.80 \(0.54 1.13\). The optimistic scenario )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(resulted in a R)] TJ ET BT 97.181 661.803 Td /F1 8.7 Tf [(0)] TJ ET BT 102.693 664.481 Td /F1 9.8 Tf [( of 0.60 \(0.42 0.80\). The authors suggest that, based on their analyses using PCR-confirmed )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(cases, MERS-CoV does not yet have pandemic potential.)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Cauchemez and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 163.189 628.048 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 175.253 626.093 Td /F1 9.8 Tf [( undertook independent analyses to assess the transmissibility and extent of )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(spread of MERS-CoV to date. Using publically available epidemiological data on 111 confirmed and probable )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(MERS-CoV patients and genetic sequence data from 10 cases, the study found central estimates of R)] TJ ET BT 521.716 592.527 Td /F1 8.7 Tf [(0)] TJ ET BT 527.228 595.205 Td /F1 9.8 Tf [( between )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(0.8 and 1.3. This work suggests that current data are consistent with two scenarios: \(a\) a sustained epidemic in )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(an animal reservoir with sporadic spill-over into humans, or \(b\) sustained human-to-human transmission )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(causing a slowly growing human epidemic. They also used epidemiological and genetic data to evaluate the )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(underlying scale of the epidemic so far. Analyses using numbers of exported cases of returning travellers from )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(countries in the Middle East \(n=4\) and average length of visitor stays to Jordan, Qatar, KSA and UAE suggest )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(that by now at least 900 symptomatic cases of MERS-CoV have occurred, implying substantial under-)] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(ascertainment of cases in the region. Genetic analyses suggest that approximately 17490 \(IQR 3900-95000\) )] TJ ET BT 26.250 471.653 Td /F1 9.8 Tf [(infections in humans and in the reservoir\(s\) may have occurred between June 2012 and August 2013 )] TJ ET 0.267 0.267 0.267 rg BT 524.485 473.608 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 536.549 471.653 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(An analysis of 21 genetic sequences from cases in KSA was compared to those already available in public )] TJ ET BT 26.250 433.265 Td /F1 9.8 Tf [(databases and concluded that the genetic diversity of available sequences supported multiple introductions )] TJ ET BT 26.250 417.821 Td /F1 9.8 Tf [(from a presumed zoonotic source, with subsequent human-to-human transmission)] TJ ET 0.267 0.267 0.267 rg BT 430.612 419.776 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 442.676 417.821 Td /F1 9.8 Tf [(. However, the authors )] TJ ET BT 26.250 402.377 Td /F1 9.8 Tf [(could not exclude the possibility of unrecognized sustained transmission in humans associated with frequent )] TJ ET BT 26.250 386.933 Td /F1 9.8 Tf [(movement of infected individuals to explain the observed genetic patterns)] TJ ET BT 26.250 363.989 Td /F4 9.8 Tf [(Animal Reservoir)] TJ ET BT 26.250 341.045 Td /F1 9.8 Tf [(Several lines of evidence support the hypothesis that the virus originates in animals. Limited phylogenetic )] TJ ET BT 26.250 325.601 Td /F1 9.8 Tf [(analyses using genetic material collected from MERS-CoV patients  specimens shows that MERS-CoV has a close )] TJ ET BT 26.250 310.157 Td /F1 9.8 Tf [(genetic relationship with coronaviruses found in hedgehogs \(Corman et al unpublished\) and in bats in Southern )] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(China)] TJ ET 0.267 0.267 0.267 rg BT 54.106 296.668 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.138 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 62.894 296.668 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 74.958 294.713 Td /F1 9.8 Tf [(, Europe)] TJ ET 0.267 0.267 0.267 rg BT 115.664 296.668 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 127.728 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.484 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 142.548 294.713 Td /F1 9.8 Tf [(, Thailand)] TJ ET 0.267 0.267 0.267 rg BT 190.635 296.668 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 202.699 294.713 Td /F1 9.8 Tf [(, Mexico)] TJ ET 0.267 0.267 0.267 rg BT 243.123 296.668 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 255.187 294.713 Td /F1 9.8 Tf [(,Ghana)] TJ ET 0.267 0.267 0.267 rg BT 290.160 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 302.224 294.713 Td /F1 9.8 Tf [(, and South Africa)] TJ ET 0.267 0.267 0.267 rg BT 389.477 296.668 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 401.541 294.713 Td /F1 9.8 Tf [(. A 190-nucleotide fragment of the )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(RNA-dependent RNA polymerase gene was recovered from a faecal sample from a Taphozous perforatesbat )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(collected in Bisha, KSA, near the home of the first MERS-CoV patient)] TJ ET 0.267 0.267 0.267 rg BT 360.919 265.780 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 372.983 263.825 Td /F1 9.8 Tf [(. The fragment had 100% nucleotide )] TJ ET BT 26.250 248.381 Td /F1 9.8 Tf [(identity with a MERS-CoV recovered from the human case that occurred in that area.)] TJ ET BT 26.250 225.437 Td /F1 9.8 Tf [(Neutralizing antibodies against MERS-CoV or a similar virus have been described in camels from the Spanish )] TJ ET BT 26.250 209.993 Td /F1 9.8 Tf [(Canary Islands, Oman)] TJ ET 0.267 0.267 0.267 rg BT 133.695 211.948 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 145.759 209.993 Td /F1 9.8 Tf [( and from Egypt)] TJ ET 0.267 0.267 0.267 rg BT 224.451 211.948 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 236.515 209.993 Td /F1 9.8 Tf [(. Approximately 15% of sera from camels from the Spanish Canary )] TJ ET BT 26.250 194.549 Td /F1 9.8 Tf [(Islands, 100% of sera from unrelated retired racing camels from Oman and more than 90% of dromedary )] TJ ET BT 26.250 179.105 Td /F1 9.8 Tf [(camels from Egypt were found to have antibody titres reactive with MERS-CoV using a variety of methods, )] TJ ET BT 26.250 163.661 Td /F1 9.8 Tf [(including neutralization. No viral genetic material was detected in a limited number of tested camel sera and )] TJ ET BT 26.250 148.217 Td /F1 9.8 Tf [(faecal samples.)] TJ ET BT 26.250 107.422 Td /F4 12.0 Tf [(Virological Characteristics of MERS-CoV)] TJ ET BT 26.250 83.765 Td /F1 9.8 Tf [(MERS-CoV is an enveloped, single-stranded, positive-sense RNA virus that is a newly recognized species in )] TJ ET BT 26.250 68.321 Td /F1 9.8 Tf [(lineage C of the genus Betacoronavirus within the subfamily Coronavirinae)] TJ ET 0.267 0.267 0.267 rg BT 392.840 70.276 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 398.872 73.365 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 401.628 70.276 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 413.692 68.321 Td /F1 9.8 Tf [(. The genome is approximately )] TJ ET BT 26.250 52.877 Td /F1 9.8 Tf [(30.1kb long and contains at least 10 predicted open reading frames \(ORF\) common to betacoronaviruses, which )] TJ ET BT 26.250 37.433 Td /F1 9.8 Tf [(are expressed from seven subgenomic mRNAs)] TJ ET 0.267 0.267 0.267 rg BT 254.644 39.388 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 266.708 37.433 Td /F1 9.8 Tf [(. These ORFs mainly include ORF 1a/1ab, which encode for )] TJ ET Q q 15.000 18.900 577.500 758.100 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(population, R)] TJ ET BT 91.126 761.967 Td /F1 8.7 Tf [(0)] TJ ET BT 96.639 764.645 Td /F1 9.8 Tf [(\))] TJ ET 0.267 0.267 0.267 rg BT 100.441 766.600 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 112.505 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.261 766.600 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 127.325 764.645 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Breban and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 141.115 743.656 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 153.179 741.701 Td /F1 9.8 Tf [( used the first 55 laboratory-confirmed cases of MERS-CoV reported to WHO to assess )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(the inter-human transmissibility of MERS-CoV. The authors estimated R)] TJ ET BT 375.592 723.579 Td /F1 8.7 Tf [(0)] TJ ET BT 381.104 726.257 Td /F1 9.8 Tf [( from the distribution of sizes of case )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(transmission trees seen so far and compared their estimate with that of early data from the SARS-CoV epidemic )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(in 2003. Two scenarios were considered. With the most pessimistic scenario, the authors estimated MERS-CoV R)] TJ ET BT 26.250 677.247 Td /F1 8.7 Tf [(0)] TJ ET BT 31.762 679.925 Td /F1 9.8 Tf [( to be 0.69 \(95% CI 0.50 0.92\); by contrast, the R)] TJ ET BT 275.024 677.247 Td /F1 8.7 Tf [(0 )] TJ ET BT 283.293 679.925 Td /F1 9.8 Tf [(for SARS-CoV was 0.80 \(0.54 1.13\). The optimistic scenario )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(resulted in a R)] TJ ET BT 97.181 661.803 Td /F1 8.7 Tf [(0)] TJ ET BT 102.693 664.481 Td /F1 9.8 Tf [( of 0.60 \(0.42 0.80\). The authors suggest that, based on their analyses using PCR-confirmed )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(cases, MERS-CoV does not yet have pandemic potential.)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Cauchemez and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 163.189 628.048 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 175.253 626.093 Td /F1 9.8 Tf [( undertook independent analyses to assess the transmissibility and extent of )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(spread of MERS-CoV to date. Using publically available epidemiological data on 111 confirmed and probable )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(MERS-CoV patients and genetic sequence data from 10 cases, the study found central estimates of R)] TJ ET BT 521.716 592.527 Td /F1 8.7 Tf [(0)] TJ ET BT 527.228 595.205 Td /F1 9.8 Tf [( between )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(0.8 and 1.3. This work suggests that current data are consistent with two scenarios: \(a\) a sustained epidemic in )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(an animal reservoir with sporadic spill-over into humans, or \(b\) sustained human-to-human transmission )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(causing a slowly growing human epidemic. They also used epidemiological and genetic data to evaluate the )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(underlying scale of the epidemic so far. Analyses using numbers of exported cases of returning travellers from )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(countries in the Middle East \(n=4\) and average length of visitor stays to Jordan, Qatar, KSA and UAE suggest )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(that by now at least 900 symptomatic cases of MERS-CoV have occurred, implying substantial under-)] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(ascertainment of cases in the region. Genetic analyses suggest that approximately 17490 \(IQR 3900-95000\) )] TJ ET BT 26.250 471.653 Td /F1 9.8 Tf [(infections in humans and in the reservoir\(s\) may have occurred between June 2012 and August 2013 )] TJ ET 0.267 0.267 0.267 rg BT 524.485 473.608 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 536.549 471.653 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(An analysis of 21 genetic sequences from cases in KSA was compared to those already available in public )] TJ ET BT 26.250 433.265 Td /F1 9.8 Tf [(databases and concluded that the genetic diversity of available sequences supported multiple introductions )] TJ ET BT 26.250 417.821 Td /F1 9.8 Tf [(from a presumed zoonotic source, with subsequent human-to-human transmission)] TJ ET 0.267 0.267 0.267 rg BT 430.612 419.776 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 442.676 417.821 Td /F1 9.8 Tf [(. However, the authors )] TJ ET BT 26.250 402.377 Td /F1 9.8 Tf [(could not exclude the possibility of unrecognized sustained transmission in humans associated with frequent )] TJ ET BT 26.250 386.933 Td /F1 9.8 Tf [(movement of infected individuals to explain the observed genetic patterns)] TJ ET BT 26.250 363.989 Td /F4 9.8 Tf [(Animal Reservoir)] TJ ET BT 26.250 341.045 Td /F1 9.8 Tf [(Several lines of evidence support the hypothesis that the virus originates in animals. Limited phylogenetic )] TJ ET BT 26.250 325.601 Td /F1 9.8 Tf [(analyses using genetic material collected from MERS-CoV patients  specimens shows that MERS-CoV has a close )] TJ ET BT 26.250 310.157 Td /F1 9.8 Tf [(genetic relationship with coronaviruses found in hedgehogs \(Corman et al unpublished\) and in bats in Southern )] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(China)] TJ ET 0.267 0.267 0.267 rg BT 54.106 296.668 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.138 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 62.894 296.668 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 74.958 294.713 Td /F1 9.8 Tf [(, Europe)] TJ ET 0.267 0.267 0.267 rg BT 115.664 296.668 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 127.728 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.484 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 142.548 294.713 Td /F1 9.8 Tf [(, Thailand)] TJ ET 0.267 0.267 0.267 rg BT 190.635 296.668 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 202.699 294.713 Td /F1 9.8 Tf [(, Mexico)] TJ ET 0.267 0.267 0.267 rg BT 243.123 296.668 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 255.187 294.713 Td /F1 9.8 Tf [(,Ghana)] TJ ET 0.267 0.267 0.267 rg BT 290.160 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 302.224 294.713 Td /F1 9.8 Tf [(, and South Africa)] TJ ET 0.267 0.267 0.267 rg BT 389.477 296.668 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 401.541 294.713 Td /F1 9.8 Tf [(. A 190-nucleotide fragment of the )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(RNA-dependent RNA polymerase gene was recovered from a faecal sample from a Taphozous perforatesbat )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(collected in Bisha, KSA, near the home of the first MERS-CoV patient)] TJ ET 0.267 0.267 0.267 rg BT 360.919 265.780 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 372.983 263.825 Td /F1 9.8 Tf [(. The fragment had 100% nucleotide )] TJ ET BT 26.250 248.381 Td /F1 9.8 Tf [(identity with a MERS-CoV recovered from the human case that occurred in that area.)] TJ ET BT 26.250 225.437 Td /F1 9.8 Tf [(Neutralizing antibodies against MERS-CoV or a similar virus have been described in camels from the Spanish )] TJ ET BT 26.250 209.993 Td /F1 9.8 Tf [(Canary Islands, Oman)] TJ ET 0.267 0.267 0.267 rg BT 133.695 211.948 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 145.759 209.993 Td /F1 9.8 Tf [( and from Egypt)] TJ ET 0.267 0.267 0.267 rg BT 224.451 211.948 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 236.515 209.993 Td /F1 9.8 Tf [(. Approximately 15% of sera from camels from the Spanish Canary )] TJ ET BT 26.250 194.549 Td /F1 9.8 Tf [(Islands, 100% of sera from unrelated retired racing camels from Oman and more than 90% of dromedary )] TJ ET BT 26.250 179.105 Td /F1 9.8 Tf [(camels from Egypt were found to have antibody titres reactive with MERS-CoV using a variety of methods, )] TJ ET BT 26.250 163.661 Td /F1 9.8 Tf [(including neutralization. No viral genetic material was detected in a limited number of tested camel sera and )] TJ ET BT 26.250 148.217 Td /F1 9.8 Tf [(faecal samples.)] TJ ET BT 26.250 107.422 Td /F4 12.0 Tf [(Virological Characteristics of MERS-CoV)] TJ ET BT 26.250 83.765 Td /F1 9.8 Tf [(MERS-CoV is an enveloped, single-stranded, positive-sense RNA virus that is a newly recognized species in )] TJ ET BT 26.250 68.321 Td /F1 9.8 Tf [(lineage C of the genus Betacoronavirus within the subfamily Coronavirinae)] TJ ET 0.267 0.267 0.267 rg BT 392.840 70.276 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 398.872 73.365 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 401.628 70.276 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 413.692 68.321 Td /F1 9.8 Tf [(. The genome is approximately )] TJ ET BT 26.250 52.877 Td /F1 9.8 Tf [(30.1kb long and contains at least 10 predicted open reading frames \(ORF\) common to betacoronaviruses, which )] TJ ET BT 26.250 37.433 Td /F1 9.8 Tf [(are expressed from seven subgenomic mRNAs)] TJ ET 0.267 0.267 0.267 rg BT 254.644 39.388 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 266.708 37.433 Td /F1 9.8 Tf [(. These ORFs mainly include ORF 1a/1ab, which encode for )] TJ ET Q q 15.000 18.900 577.500 758.100 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(population, R)] TJ ET BT 91.126 761.967 Td /F1 8.7 Tf [(0)] TJ ET BT 96.639 764.645 Td /F1 9.8 Tf [(\))] TJ ET 0.267 0.267 0.267 rg BT 100.441 766.600 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 112.505 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 115.261 766.600 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 127.325 764.645 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Breban and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 141.115 743.656 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 153.179 741.701 Td /F1 9.8 Tf [( used the first 55 laboratory-confirmed cases of MERS-CoV reported to WHO to assess )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(the inter-human transmissibility of MERS-CoV. The authors estimated R)] TJ ET BT 375.592 723.579 Td /F1 8.7 Tf [(0)] TJ ET BT 381.104 726.257 Td /F1 9.8 Tf [( from the distribution of sizes of case )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(transmission trees seen so far and compared their estimate with that of early data from the SARS-CoV epidemic )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(in 2003. Two scenarios were considered. With the most pessimistic scenario, the authors estimated MERS-CoV R)] TJ ET BT 26.250 677.247 Td /F1 8.7 Tf [(0)] TJ ET BT 31.762 679.925 Td /F1 9.8 Tf [( to be 0.69 \(95% CI 0.50 0.92\); by contrast, the R)] TJ ET BT 275.024 677.247 Td /F1 8.7 Tf [(0 )] TJ ET BT 283.293 679.925 Td /F1 9.8 Tf [(for SARS-CoV was 0.80 \(0.54 1.13\). The optimistic scenario )] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(resulted in a R)] TJ ET BT 97.181 661.803 Td /F1 8.7 Tf [(0)] TJ ET BT 102.693 664.481 Td /F1 9.8 Tf [( of 0.60 \(0.42 0.80\). The authors suggest that, based on their analyses using PCR-confirmed )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(cases, MERS-CoV does not yet have pandemic potential.)] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(Cauchemez and colleagues )] TJ ET 0.267 0.267 0.267 rg BT 163.189 628.048 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 175.253 626.093 Td /F1 9.8 Tf [( undertook independent analyses to assess the transmissibility and extent of )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(spread of MERS-CoV to date. Using publically available epidemiological data on 111 confirmed and probable )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(MERS-CoV patients and genetic sequence data from 10 cases, the study found central estimates of R)] TJ ET BT 521.716 592.527 Td /F1 8.7 Tf [(0)] TJ ET BT 527.228 595.205 Td /F1 9.8 Tf [( between )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(0.8 and 1.3. This work suggests that current data are consistent with two scenarios: \(a\) a sustained epidemic in )] TJ ET BT 26.250 564.317 Td /F1 9.8 Tf [(an animal reservoir with sporadic spill-over into humans, or \(b\) sustained human-to-human transmission )] TJ ET BT 26.250 548.873 Td /F1 9.8 Tf [(causing a slowly growing human epidemic. They also used epidemiological and genetic data to evaluate the )] TJ ET BT 26.250 533.429 Td /F1 9.8 Tf [(underlying scale of the epidemic so far. Analyses using numbers of exported cases of returning travellers from )] TJ ET BT 26.250 517.985 Td /F1 9.8 Tf [(countries in the Middle East \(n=4\) and average length of visitor stays to Jordan, Qatar, KSA and UAE suggest )] TJ ET BT 26.250 502.541 Td /F1 9.8 Tf [(that by now at least 900 symptomatic cases of MERS-CoV have occurred, implying substantial under-)] TJ ET BT 26.250 487.097 Td /F1 9.8 Tf [(ascertainment of cases in the region. Genetic analyses suggest that approximately 17490 \(IQR 3900-95000\) )] TJ ET BT 26.250 471.653 Td /F1 9.8 Tf [(infections in humans and in the reservoir\(s\) may have occurred between June 2012 and August 2013 )] TJ ET 0.267 0.267 0.267 rg BT 524.485 473.608 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 536.549 471.653 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.709 Td /F1 9.8 Tf [(An analysis of 21 genetic sequences from cases in KSA was compared to those already available in public )] TJ ET BT 26.250 433.265 Td /F1 9.8 Tf [(databases and concluded that the genetic diversity of available sequences supported multiple introductions )] TJ ET BT 26.250 417.821 Td /F1 9.8 Tf [(from a presumed zoonotic source, with subsequent human-to-human transmission)] TJ ET 0.267 0.267 0.267 rg BT 430.612 419.776 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 442.676 417.821 Td /F1 9.8 Tf [(. However, the authors )] TJ ET BT 26.250 402.377 Td /F1 9.8 Tf [(could not exclude the possibility of unrecognized sustained transmission in humans associated with frequent )] TJ ET BT 26.250 386.933 Td /F1 9.8 Tf [(movement of infected individuals to explain the observed genetic patterns)] TJ ET BT 26.250 363.989 Td /F4 9.8 Tf [(Animal Reservoir)] TJ ET BT 26.250 341.045 Td /F1 9.8 Tf [(Several lines of evidence support the hypothesis that the virus originates in animals. Limited phylogenetic )] TJ ET BT 26.250 325.601 Td /F1 9.8 Tf [(analyses using genetic material collected from MERS-CoV patients  specimens shows that MERS-CoV has a close )] TJ ET BT 26.250 310.157 Td /F1 9.8 Tf [(genetic relationship with coronaviruses found in hedgehogs \(Corman et al unpublished\) and in bats in Southern )] TJ ET BT 26.250 294.713 Td /F1 9.8 Tf [(China)] TJ ET 0.267 0.267 0.267 rg BT 54.106 296.668 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 60.138 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 62.894 296.668 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 74.958 294.713 Td /F1 9.8 Tf [(, Europe)] TJ ET 0.267 0.267 0.267 rg BT 115.664 296.668 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 127.728 299.757 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 130.484 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 142.548 294.713 Td /F1 9.8 Tf [(, Thailand)] TJ ET 0.267 0.267 0.267 rg BT 190.635 296.668 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 202.699 294.713 Td /F1 9.8 Tf [(, Mexico)] TJ ET 0.267 0.267 0.267 rg BT 243.123 296.668 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 255.187 294.713 Td /F1 9.8 Tf [(,Ghana)] TJ ET 0.267 0.267 0.267 rg BT 290.160 296.668 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 302.224 294.713 Td /F1 9.8 Tf [(, and South Africa)] TJ ET 0.267 0.267 0.267 rg BT 389.477 296.668 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 401.541 294.713 Td /F1 9.8 Tf [(. A 190-nucleotide fragment of the )] TJ ET BT 26.250 279.269 Td /F1 9.8 Tf [(RNA-dependent RNA polymerase gene was recovered from a faecal sample from a Taphozous perforatesbat )] TJ ET BT 26.250 263.825 Td /F1 9.8 Tf [(collected in Bisha, KSA, near the home of the first MERS-CoV patient)] TJ ET 0.267 0.267 0.267 rg BT 360.919 265.780 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 372.983 263.825 Td /F1 9.8 Tf [(. The fragment had 100% nucleotide )] TJ ET BT 26.250 248.381 Td /F1 9.8 Tf [(identity with a MERS-CoV recovered from the human case that occurred in that area.)] TJ ET BT 26.250 225.437 Td /F1 9.8 Tf [(Neutralizing antibodies against MERS-CoV or a similar virus have been described in camels from the Spanish )] TJ ET BT 26.250 209.993 Td /F1 9.8 Tf [(Canary Islands, Oman)] TJ ET 0.267 0.267 0.267 rg BT 133.695 211.948 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 145.759 209.993 Td /F1 9.8 Tf [( and from Egypt)] TJ ET 0.267 0.267 0.267 rg BT 224.451 211.948 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 236.515 209.993 Td /F1 9.8 Tf [(. Approximately 15% of sera from camels from the Spanish Canary )] TJ ET BT 26.250 194.549 Td /F1 9.8 Tf [(Islands, 100% of sera from unrelated retired racing camels from Oman and more than 90% of dromedary )] TJ ET BT 26.250 179.105 Td /F1 9.8 Tf [(camels from Egypt were found to have antibody titres reactive with MERS-CoV using a variety of methods, )] TJ ET BT 26.250 163.661 Td /F1 9.8 Tf [(including neutralization. No viral genetic material was detected in a limited number of tested camel sera and )] TJ ET BT 26.250 148.217 Td /F1 9.8 Tf [(faecal samples.)] TJ ET BT 26.250 107.422 Td /F4 12.0 Tf [(Virological Characteristics of MERS-CoV)] TJ ET BT 26.250 83.765 Td /F1 9.8 Tf [(MERS-CoV is an enveloped, single-stranded, positive-sense RNA virus that is a newly recognized species in )] TJ ET BT 26.250 68.321 Td /F1 9.8 Tf [(lineage C of the genus Betacoronavirus within the subfamily Coronavirinae)] TJ ET 0.267 0.267 0.267 rg BT 392.840 70.276 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 398.872 73.365 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 401.628 70.276 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 413.692 68.321 Td /F1 9.8 Tf [(. The genome is approximately )] TJ ET BT 26.250 52.877 Td /F1 9.8 Tf [(30.1kb long and contains at least 10 predicted open reading frames \(ORF\) common to betacoronaviruses, which )] TJ ET BT 26.250 37.433 Td /F1 9.8 Tf [(are expressed from seven subgenomic mRNAs)] TJ ET 0.267 0.267 0.267 rg BT 254.644 39.388 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 266.708 37.433 Td /F1 9.8 Tf [(. These ORFs mainly include ORF 1a/1ab, which encode for )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(11)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 708 0 obj << /Type /Annot /Subtype /Link /A 709 0 R /Border [0 0 0] /H /I /Rect [ 100.4410 765.5600 112.5050 777.0000 ] >> endobj 709 0 obj << /Type /Action >> endobj 710 0 obj << /Type /Annot /Subtype /Link /A 711 0 R /Border [0 0 0] /H /I /Rect [ 115.2610 765.5600 127.3250 777.0000 ] >> endobj 711 0 obj << /Type /Action >> endobj 712 0 obj << /Type /Annot /Subtype /Link /A 713 0 R /Border [0 0 0] /H /I /Rect [ 141.1148 742.6160 153.1788 754.0560 ] >> endobj 713 0 obj << /Type /Action >> endobj 714 0 obj << /Type /Annot /Subtype /Link /A 715 0 R /Border [0 0 0] /H /I /Rect [ 163.1887 627.0080 175.2528 638.4480 ] >> endobj 715 0 obj << /Type /Action >> endobj 716 0 obj << /Type /Annot /Subtype /Link /A 717 0 R /Border [0 0 0] /H /I /Rect [ 524.4848 472.5680 536.5488 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q 15.000 261.180 577.500 515.820 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(large replicase polyproteins containing conserved functional domains and several non-structural \(NS\) proteins )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(of CoV, the spike-surface glycoprotein \(S\), the small-envelope \(E\) protein, the matrix \(M\) protein, and the )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(nucleocapsid \(N\) protein.)] TJ ET BT 26.250 710.813 Td /F4 9.8 Tf [(Laboratory Testing of MERS-CoV)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Initial detection of viral genome in human clinical samples was made using pancorona primers targeting highly )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(conserved regions of the coronavirus genome. Specific assays for the detection of acute infection with MERS-)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(CoV by real-time RT-PCR \(rRT-PCR\) have subsequently been developed. Several assays are now in widespread )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(use, including those targeting a region upstream of the E gene \(upE\) or regions within ORF 1b \(nsp14 protein\))] TJ ET 0.267 0.267 0.267 rg BT 565.103 643.492 Td /F4 8.7 Tf [(37)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.093 Td /F1 9.8 Tf [(, ORF 1a \(nsp6 protein\))] TJ ET 0.267 0.267 0.267 rg BT 140.120 628.048 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 152.184 626.093 Td /F1 9.8 Tf [(, and the nucleocapsid protein gene)] TJ ET 0.267 0.267 0.267 rg BT 328.289 628.048 Td /F4 8.7 Tf [(38)] TJ ET 0.271 0.267 0.267 rg BT 340.353 626.093 Td /F1 9.8 Tf [(. The assays for the upE and the ORF 1a targets )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(are considered equally sensitive, while the ORF 1b assay is considered less sensitive than the ORF 1a assay. )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(The upE assay has been recommended for screening specimens with the ORF 1a assay or other specific gene )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(targets being used for confirmation)] TJ ET 0.267 0.267 0.267 rg BT 199.488 581.716 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 211.552 579.761 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(Currently, laboratory confirmation of a case is considered as a positive PCR result for at least two different )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(specific targets on the MERS-CoV genome or one positive PCR result for a specific target on the MERS-CoV )] TJ ET BT 26.250 525.929 Td /F1 9.8 Tf [(genome and an additional different PCR product sequenced, confirming identity to known sequences of MERS-)] TJ ET BT 26.250 510.485 Td /F1 9.8 Tf [(CoV)] TJ ET 0.267 0.267 0.267 rg BT 45.692 512.440 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 51.724 510.485 Td /F1 9.8 Tf [(. Two suitable targets for sequencing are an RNA-dependent RNA polymerase \(RdRp\) and nucleocapsid \(N\) )] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(protein genes. Serologic assays for MERS-CoV are under development by several laboratories.)] TJ ET BT 26.250 472.097 Td /F4 9.8 Tf [(Genetics and Emergence of MERS-CoV)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Twenty-two whole sequences, and partial genome sequences from 9 additional cases, have been published in )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(GenBank, from thirty different MERS-CoV infected patients \(Table 3\) )] TJ ET 0.267 0.267 0.267 rg BT 363.083 435.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 369.115 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 371.871 435.664 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 377.903 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.659 435.664 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 392.723 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 395.479 435.664 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 407.543 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 410.299 435.664 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 422.363 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 425.119 435.664 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 437.183 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 439.939 435.664 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 452.003 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 454.759 435.664 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 466.823 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 469.579 435.664 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 481.643 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 484.399 435.664 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 496.463 433.709 Td /F1 9.8 Tf [(. Phylogenetic )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(trees have been published by several groups)] TJ ET 0.267 0.267 0.267 rg BT 246.600 420.220 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 258.664 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 261.420 420.220 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 273.484 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 276.240 420.220 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 288.304 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 291.060 420.220 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 303.124 418.265 Td /F1 9.8 Tf [( and are not shown here.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Several estimates of the time frame of the emergence of MERS-CoV in humans have been developed using a )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(variety of analytical tools with different statistical assumptions, and using both whole-genome sequences and )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(individual genes derived from infections at different time points)] TJ ET 0.267 0.267 0.267 rg BT 338.591 366.388 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 350.655 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 353.411 366.388 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 365.475 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 368.231 366.388 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 380.295 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 383.051 366.388 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 395.115 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 397.871 366.388 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 409.935 364.433 Td /F1 9.8 Tf [(. All suggest the emergence of )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(MERS-CoV in mid-2011, with the range of possible dates ranging broadly from November 2009 April 2012. One )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(study of 10 full genome sequences, including one from a French patient)] TJ ET 0.267 0.267 0.267 rg BT 378.712 335.500 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 390.776 333.545 Td /F1 9.8 Tf [(, suggests the emergence in June )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(2011 with a narrower timeframe, from Sept 2010 Nov 2011 \(Table 3\). The study using most available )] TJ ET BT 26.250 302.657 Td /F1 9.8 Tf [(sequences, estimates emergence in July 2011 with a broad credible interval, from July 2007 to June 2012)] TJ ET 0.267 0.267 0.267 rg BT 540.982 304.612 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 287.213 Td /F1 9.8 Tf [(\(Table 3\). Future studies providing more genome sequences from humans and animals should add to our )] TJ ET BT 26.250 271.769 Td /F1 9.8 Tf [(understanding of transmission patterns and increase the accuracy of the estimated genomic evolutionary rate.)] TJ ET Q q 15.000 261.180 577.500 515.820 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(large replicase polyproteins containing conserved functional domains and several non-structural \(NS\) proteins )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(of CoV, the spike-surface glycoprotein \(S\), the small-envelope \(E\) protein, the matrix \(M\) protein, and the )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(nucleocapsid \(N\) protein.)] TJ ET BT 26.250 710.813 Td /F4 9.8 Tf [(Laboratory Testing of MERS-CoV)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Initial detection of viral genome in human clinical samples was made using pancorona primers targeting highly )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(conserved regions of the coronavirus genome. Specific assays for the detection of acute infection with MERS-)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(CoV by real-time RT-PCR \(rRT-PCR\) have subsequently been developed. Several assays are now in widespread )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(use, including those targeting a region upstream of the E gene \(upE\) or regions within ORF 1b \(nsp14 protein\))] TJ ET 0.267 0.267 0.267 rg BT 565.103 643.492 Td /F4 8.7 Tf [(37)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.093 Td /F1 9.8 Tf [(, ORF 1a \(nsp6 protein\))] TJ ET 0.267 0.267 0.267 rg BT 140.120 628.048 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 152.184 626.093 Td /F1 9.8 Tf [(, and the nucleocapsid protein gene)] TJ ET 0.267 0.267 0.267 rg BT 328.289 628.048 Td /F4 8.7 Tf [(38)] TJ ET 0.271 0.267 0.267 rg BT 340.353 626.093 Td /F1 9.8 Tf [(. The assays for the upE and the ORF 1a targets )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(are considered equally sensitive, while the ORF 1b assay is considered less sensitive than the ORF 1a assay. )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(The upE assay has been recommended for screening specimens with the ORF 1a assay or other specific gene )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(targets being used for confirmation)] TJ ET 0.267 0.267 0.267 rg BT 199.488 581.716 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 211.552 579.761 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(Currently, laboratory confirmation of a case is considered as a positive PCR result for at least two different )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(specific targets on the MERS-CoV genome or one positive PCR result for a specific target on the MERS-CoV )] TJ ET BT 26.250 525.929 Td /F1 9.8 Tf [(genome and an additional different PCR product sequenced, confirming identity to known sequences of MERS-)] TJ ET BT 26.250 510.485 Td /F1 9.8 Tf [(CoV)] TJ ET 0.267 0.267 0.267 rg BT 45.692 512.440 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 51.724 510.485 Td /F1 9.8 Tf [(. Two suitable targets for sequencing are an RNA-dependent RNA polymerase \(RdRp\) and nucleocapsid \(N\) )] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(protein genes. Serologic assays for MERS-CoV are under development by several laboratories.)] TJ ET BT 26.250 472.097 Td /F4 9.8 Tf [(Genetics and Emergence of MERS-CoV)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Twenty-two whole sequences, and partial genome sequences from 9 additional cases, have been published in )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(GenBank, from thirty different MERS-CoV infected patients \(Table 3\) )] TJ ET 0.267 0.267 0.267 rg BT 363.083 435.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 369.115 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 371.871 435.664 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 377.903 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.659 435.664 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 392.723 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 395.479 435.664 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 407.543 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 410.299 435.664 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 422.363 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 425.119 435.664 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 437.183 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 439.939 435.664 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 452.003 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 454.759 435.664 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 466.823 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 469.579 435.664 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 481.643 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 484.399 435.664 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 496.463 433.709 Td /F1 9.8 Tf [(. Phylogenetic )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(trees have been published by several groups)] TJ ET 0.267 0.267 0.267 rg BT 246.600 420.220 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 258.664 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 261.420 420.220 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 273.484 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 276.240 420.220 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 288.304 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 291.060 420.220 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 303.124 418.265 Td /F1 9.8 Tf [( and are not shown here.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Several estimates of the time frame of the emergence of MERS-CoV in humans have been developed using a )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(variety of analytical tools with different statistical assumptions, and using both whole-genome sequences and )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(individual genes derived from infections at different time points)] TJ ET 0.267 0.267 0.267 rg BT 338.591 366.388 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 350.655 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 353.411 366.388 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 365.475 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 368.231 366.388 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 380.295 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 383.051 366.388 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 395.115 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 397.871 366.388 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 409.935 364.433 Td /F1 9.8 Tf [(. All suggest the emergence of )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(MERS-CoV in mid-2011, with the range of possible dates ranging broadly from November 2009 April 2012. One )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(study of 10 full genome sequences, including one from a French patient)] TJ ET 0.267 0.267 0.267 rg BT 378.712 335.500 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 390.776 333.545 Td /F1 9.8 Tf [(, suggests the emergence in June )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(2011 with a narrower timeframe, from Sept 2010 Nov 2011 \(Table 3\). The study using most available )] TJ ET BT 26.250 302.657 Td /F1 9.8 Tf [(sequences, estimates emergence in July 2011 with a broad credible interval, from July 2007 to June 2012)] TJ ET 0.267 0.267 0.267 rg BT 540.982 304.612 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 287.213 Td /F1 9.8 Tf [(\(Table 3\). Future studies providing more genome sequences from humans and animals should add to our )] TJ ET BT 26.250 271.769 Td /F1 9.8 Tf [(understanding of transmission patterns and increase the accuracy of the estimated genomic evolutionary rate.)] TJ ET Q q 15.000 261.180 577.500 515.820 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(large replicase polyproteins containing conserved functional domains and several non-structural \(NS\) proteins )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(of CoV, the spike-surface glycoprotein \(S\), the small-envelope \(E\) protein, the matrix \(M\) protein, and the )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(nucleocapsid \(N\) protein.)] TJ ET BT 26.250 710.813 Td /F4 9.8 Tf [(Laboratory Testing of MERS-CoV)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Initial detection of viral genome in human clinical samples was made using pancorona primers targeting highly )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(conserved regions of the coronavirus genome. Specific assays for the detection of acute infection with MERS-)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(CoV by real-time RT-PCR \(rRT-PCR\) have subsequently been developed. Several assays are now in widespread )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(use, including those targeting a region upstream of the E gene \(upE\) or regions within ORF 1b \(nsp14 protein\))] TJ ET 0.267 0.267 0.267 rg BT 565.103 643.492 Td /F4 8.7 Tf [(37)] TJ ET 0.271 0.267 0.267 rg BT 26.250 626.093 Td /F1 9.8 Tf [(, ORF 1a \(nsp6 protein\))] TJ ET 0.267 0.267 0.267 rg BT 140.120 628.048 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 152.184 626.093 Td /F1 9.8 Tf [(, and the nucleocapsid protein gene)] TJ ET 0.267 0.267 0.267 rg BT 328.289 628.048 Td /F4 8.7 Tf [(38)] TJ ET 0.271 0.267 0.267 rg BT 340.353 626.093 Td /F1 9.8 Tf [(. The assays for the upE and the ORF 1a targets )] TJ ET BT 26.250 610.649 Td /F1 9.8 Tf [(are considered equally sensitive, while the ORF 1b assay is considered less sensitive than the ORF 1a assay. )] TJ ET BT 26.250 595.205 Td /F1 9.8 Tf [(The upE assay has been recommended for screening specimens with the ORF 1a assay or other specific gene )] TJ ET BT 26.250 579.761 Td /F1 9.8 Tf [(targets being used for confirmation)] TJ ET 0.267 0.267 0.267 rg BT 199.488 581.716 Td /F4 8.7 Tf [(39)] TJ ET 0.271 0.267 0.267 rg BT 211.552 579.761 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 556.817 Td /F1 9.8 Tf [(Currently, laboratory confirmation of a case is considered as a positive PCR result for at least two different )] TJ ET BT 26.250 541.373 Td /F1 9.8 Tf [(specific targets on the MERS-CoV genome or one positive PCR result for a specific target on the MERS-CoV )] TJ ET BT 26.250 525.929 Td /F1 9.8 Tf [(genome and an additional different PCR product sequenced, confirming identity to known sequences of MERS-)] TJ ET BT 26.250 510.485 Td /F1 9.8 Tf [(CoV)] TJ ET 0.267 0.267 0.267 rg BT 45.692 512.440 Td /F4 8.7 Tf [(7)] TJ ET 0.271 0.267 0.267 rg BT 51.724 510.485 Td /F1 9.8 Tf [(. Two suitable targets for sequencing are an RNA-dependent RNA polymerase \(RdRp\) and nucleocapsid \(N\) )] TJ ET BT 26.250 495.041 Td /F1 9.8 Tf [(protein genes. Serologic assays for MERS-CoV are under development by several laboratories.)] TJ ET BT 26.250 472.097 Td /F4 9.8 Tf [(Genetics and Emergence of MERS-CoV)] TJ ET BT 26.250 449.153 Td /F1 9.8 Tf [(Twenty-two whole sequences, and partial genome sequences from 9 additional cases, have been published in )] TJ ET BT 26.250 433.709 Td /F1 9.8 Tf [(GenBank, from thirty different MERS-CoV infected patients \(Table 3\) )] TJ ET 0.267 0.267 0.267 rg BT 363.083 435.664 Td /F4 8.7 Tf [(2)] TJ ET 0.271 0.267 0.267 rg BT 369.115 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 371.871 435.664 Td /F4 8.7 Tf [(3)] TJ ET 0.271 0.267 0.267 rg BT 377.903 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 380.659 435.664 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 392.723 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 395.479 435.664 Td /F4 8.7 Tf [(12)] TJ ET 0.271 0.267 0.267 rg BT 407.543 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 410.299 435.664 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 422.363 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 425.119 435.664 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 437.183 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 439.939 435.664 Td /F4 8.7 Tf [(23)] TJ ET 0.271 0.267 0.267 rg BT 452.003 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 454.759 435.664 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 466.823 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 469.579 435.664 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 481.643 438.753 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 484.399 435.664 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 496.463 433.709 Td /F1 9.8 Tf [(. Phylogenetic )] TJ ET BT 26.250 418.265 Td /F1 9.8 Tf [(trees have been published by several groups)] TJ ET 0.267 0.267 0.267 rg BT 246.600 420.220 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 258.664 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 261.420 420.220 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 273.484 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 276.240 420.220 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 288.304 423.309 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 291.060 420.220 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 303.124 418.265 Td /F1 9.8 Tf [( and are not shown here.)] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Several estimates of the time frame of the emergence of MERS-CoV in humans have been developed using a )] TJ ET BT 26.250 379.877 Td /F1 9.8 Tf [(variety of analytical tools with different statistical assumptions, and using both whole-genome sequences and )] TJ ET BT 26.250 364.433 Td /F1 9.8 Tf [(individual genes derived from infections at different time points)] TJ ET 0.267 0.267 0.267 rg BT 338.591 366.388 Td /F4 8.7 Tf [(10)] TJ ET 0.271 0.267 0.267 rg BT 350.655 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 353.411 366.388 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 365.475 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 368.231 366.388 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 380.295 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 383.051 366.388 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 395.115 369.477 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 397.871 366.388 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 409.935 364.433 Td /F1 9.8 Tf [(. All suggest the emergence of )] TJ ET BT 26.250 348.989 Td /F1 9.8 Tf [(MERS-CoV in mid-2011, with the range of possible dates ranging broadly from November 2009 April 2012. One )] TJ ET BT 26.250 333.545 Td /F1 9.8 Tf [(study of 10 full genome sequences, including one from a French patient)] TJ ET 0.267 0.267 0.267 rg BT 378.712 335.500 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 390.776 333.545 Td /F1 9.8 Tf [(, suggests the emergence in June )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(2011 with a narrower timeframe, from Sept 2010 Nov 2011 \(Table 3\). The study using most available )] TJ ET BT 26.250 302.657 Td /F1 9.8 Tf [(sequences, estimates emergence in July 2011 with a broad credible interval, from July 2007 to June 2012)] TJ ET 0.267 0.267 0.267 rg BT 540.982 304.612 Td /F4 8.7 Tf [(27)] TJ ET 0.271 0.267 0.267 rg BT 26.250 287.213 Td /F1 9.8 Tf [(\(Table 3\). 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0.965 0.965 0.965 rg 26.250 333.750 555.000 443.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 333.750 m 581.250 333.750 l 581.250 334.500 l 26.250 334.500 l f q 450.000 0 0 423.750 35.250 343.500 cm /I36 Do Q 0.271 0.267 0.267 rg BT 26.250 313.895 Td /F4 9.8 Tf [(MERS-CoV  Host Interactions)] TJ ET BT 26.250 290.951 Td /F1 9.8 Tf [(The S protein of coronaviruses is responsible for binding to the host cell receptor. The DPP4 \(dipeptidyl )] TJ ET BT 26.250 275.507 Td /F1 9.8 Tf [(peptidase 4, also known as CD26\))] TJ ET 0.267 0.267 0.267 rg BT 192.468 277.462 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 204.532 280.551 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 207.288 277.462 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 219.352 275.507 Td /F1 9.8 Tf [(, has been identified as the functional cellular receptor for MERS-CoV, in )] TJ ET BT 26.250 260.063 Td /F1 9.8 Tf [(contrast to the angiotensin-converting enzyme 2 \(ACE2\), used by the SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 417.478 262.018 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 429.543 260.063 Td /F1 9.8 Tf [( and hCoV-NL63. DPP4 )] TJ ET BT 26.250 244.619 Td /F1 9.8 Tf [(homologues permitting MERS-CoV infection are present in a variety of bat, pig, civet and rabbit cell lines, )] TJ ET BT 26.250 229.175 Td /F1 9.8 Tf [(whereas cell lines of canine, feline, rodent, chicken and insect origin were not susceptible)] TJ ET 0.267 0.267 0.267 rg BT 465.507 231.130 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 477.571 234.219 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 480.327 231.130 Td /F4 8.7 Tf [(43)] TJ ET 0.271 0.267 0.267 rg BT 492.391 229.175 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 206.231 Td /F1 9.8 Tf [(DPP4 is an exopeptidase and is involved in the regulation of chemokine and cytokine responses and in glucose )] TJ ET BT 26.250 190.787 Td /F1 9.8 Tf [(metabolism)] TJ ET 0.267 0.267 0.267 rg BT 83.697 192.742 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 95.761 190.787 Td /F1 9.8 Tf [(. Upon binding, the viral entry of MERS-CoV involves virus-cell fusion, which can be either )] TJ ET BT 26.250 175.343 Td /F1 9.8 Tf [(activated by type II transmembrane serine proteases TMPRSS2 or mediated by low pH and endosomal )] TJ ET BT 26.250 159.899 Td /F1 9.8 Tf [(cathepsins)] TJ ET 0.267 0.267 0.267 rg BT 78.832 161.854 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 90.896 159.899 Td /F1 9.8 Tf [(. The receptor-binding domain \(RBD\) in the S protein responsible for binding to DPP4 has also been )] TJ ET BT 26.250 144.455 Td /F1 9.8 Tf [(mapped. The RBD-S interaction falls within residues 358-662 of the S1 domain, where antibodies to this domain )] TJ ET BT 26.250 129.011 Td /F1 9.8 Tf [(were observed to efficiently neutralize infection)] TJ ET 0.267 0.267 0.267 rg BT 259.909 130.966 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 271.973 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.729 130.966 Td /F4 8.7 Tf [(46)] TJ ET 0.271 0.267 0.267 rg BT 286.793 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.549 130.966 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 301.613 129.011 Td /F1 9.8 Tf [(. Crystal structures of this binding interface showed a )] TJ ET BT 26.250 113.567 Td /F1 9.8 Tf [(homologous core subdomain but much variation in the external receptor binding motif region, compared with )] TJ ET BT 26.250 98.123 Td /F1 9.8 Tf [(that of SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 110.441 100.078 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 122.505 98.123 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 75.179 Td /F1 9.8 Tf [(In humans, DPP4 is primarily expressed on the epithelial cells in kidney, small intestine, liver and prostate, and )] TJ ET BT 26.250 59.735 Td /F1 9.8 Tf [(on activated leukocytes)] TJ ET 0.267 0.267 0.267 rg BT 142.762 61.690 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 154.827 64.779 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 157.583 61.690 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 169.647 59.735 Td /F1 9.8 Tf [(. MERS-CoV has been shown to infect non-ciliated bronchial epithelium, bronchiolar )] TJ ET BT 26.250 44.291 Td /F1 9.8 Tf [(epithelial cells, alveolar epithelial cells, endothelial cells, and lung ex vivo organ cultures at least as well as )] TJ ET Q q 15.000 25.758 577.500 751.242 re W n 0.965 0.965 0.965 rg 26.250 333.750 555.000 443.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 333.750 m 581.250 333.750 l 581.250 334.500 l 26.250 334.500 l f q 450.000 0 0 423.750 35.250 343.500 cm /I38 Do Q 0.271 0.267 0.267 rg BT 26.250 313.895 Td /F4 9.8 Tf [(MERS-CoV  Host Interactions)] TJ ET BT 26.250 290.951 Td /F1 9.8 Tf [(The S protein of coronaviruses is responsible for binding to the host cell receptor. The DPP4 \(dipeptidyl )] TJ ET BT 26.250 275.507 Td /F1 9.8 Tf [(peptidase 4, also known as CD26\))] TJ ET 0.267 0.267 0.267 rg BT 192.468 277.462 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 204.532 280.551 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 207.288 277.462 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 219.352 275.507 Td /F1 9.8 Tf [(, has been identified as the functional cellular receptor for MERS-CoV, in )] TJ ET BT 26.250 260.063 Td /F1 9.8 Tf [(contrast to the angiotensin-converting enzyme 2 \(ACE2\), used by the SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 417.478 262.018 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 429.543 260.063 Td /F1 9.8 Tf [( and hCoV-NL63. DPP4 )] TJ ET BT 26.250 244.619 Td /F1 9.8 Tf [(homologues permitting MERS-CoV infection are present in a variety of bat, pig, civet and rabbit cell lines, )] TJ ET BT 26.250 229.175 Td /F1 9.8 Tf [(whereas cell lines of canine, feline, rodent, chicken and insect origin were not susceptible)] TJ ET 0.267 0.267 0.267 rg BT 465.507 231.130 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 477.571 234.219 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 480.327 231.130 Td /F4 8.7 Tf [(43)] TJ ET 0.271 0.267 0.267 rg BT 492.391 229.175 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 206.231 Td /F1 9.8 Tf [(DPP4 is an exopeptidase and is involved in the regulation of chemokine and cytokine responses and in glucose )] TJ ET BT 26.250 190.787 Td /F1 9.8 Tf [(metabolism)] TJ ET 0.267 0.267 0.267 rg BT 83.697 192.742 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 95.761 190.787 Td /F1 9.8 Tf [(. Upon binding, the viral entry of MERS-CoV involves virus-cell fusion, which can be either )] TJ ET BT 26.250 175.343 Td /F1 9.8 Tf [(activated by type II transmembrane serine proteases TMPRSS2 or mediated by low pH and endosomal )] TJ ET BT 26.250 159.899 Td /F1 9.8 Tf [(cathepsins)] TJ ET 0.267 0.267 0.267 rg BT 78.832 161.854 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 90.896 159.899 Td /F1 9.8 Tf [(. The receptor-binding domain \(RBD\) in the S protein responsible for binding to DPP4 has also been )] TJ ET BT 26.250 144.455 Td /F1 9.8 Tf [(mapped. The RBD-S interaction falls within residues 358-662 of the S1 domain, where antibodies to this domain )] TJ ET BT 26.250 129.011 Td /F1 9.8 Tf [(were observed to efficiently neutralize infection)] TJ ET 0.267 0.267 0.267 rg BT 259.909 130.966 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 271.973 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.729 130.966 Td /F4 8.7 Tf [(46)] TJ ET 0.271 0.267 0.267 rg BT 286.793 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.549 130.966 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 301.613 129.011 Td /F1 9.8 Tf [(. Crystal structures of this binding interface showed a )] TJ ET BT 26.250 113.567 Td /F1 9.8 Tf [(homologous core subdomain but much variation in the external receptor binding motif region, compared with )] TJ ET BT 26.250 98.123 Td /F1 9.8 Tf [(that of SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 110.441 100.078 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 122.505 98.123 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 75.179 Td /F1 9.8 Tf [(In humans, DPP4 is primarily expressed on the epithelial cells in kidney, small intestine, liver and prostate, and )] TJ ET BT 26.250 59.735 Td /F1 9.8 Tf [(on activated leukocytes)] TJ ET 0.267 0.267 0.267 rg BT 142.762 61.690 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 154.827 64.779 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 157.583 61.690 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 169.647 59.735 Td /F1 9.8 Tf [(. MERS-CoV has been shown to infect non-ciliated bronchial epithelium, bronchiolar )] TJ ET BT 26.250 44.291 Td /F1 9.8 Tf [(epithelial cells, alveolar epithelial cells, endothelial cells, and lung ex vivo organ cultures at least as well as )] TJ ET Q q 15.000 25.758 577.500 751.242 re W n 0.965 0.965 0.965 rg 26.250 333.750 555.000 443.250 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 777.000 m 581.250 777.000 l 581.250 776.250 l 26.250 776.250 l f 26.250 333.750 m 581.250 333.750 l 581.250 334.500 l 26.250 334.500 l f q 450.000 0 0 423.750 35.250 343.500 cm /I40 Do Q 0.271 0.267 0.267 rg BT 26.250 313.895 Td /F4 9.8 Tf [(MERS-CoV  Host Interactions)] TJ ET BT 26.250 290.951 Td /F1 9.8 Tf [(The S protein of coronaviruses is responsible for binding to the host cell receptor. The DPP4 \(dipeptidyl )] TJ ET BT 26.250 275.507 Td /F1 9.8 Tf [(peptidase 4, also known as CD26\))] TJ ET 0.267 0.267 0.267 rg BT 192.468 277.462 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 204.532 280.551 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 207.288 277.462 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 219.352 275.507 Td /F1 9.8 Tf [(, has been identified as the functional cellular receptor for MERS-CoV, in )] TJ ET BT 26.250 260.063 Td /F1 9.8 Tf [(contrast to the angiotensin-converting enzyme 2 \(ACE2\), used by the SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 417.478 262.018 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 429.543 260.063 Td /F1 9.8 Tf [( and hCoV-NL63. DPP4 )] TJ ET BT 26.250 244.619 Td /F1 9.8 Tf [(homologues permitting MERS-CoV infection are present in a variety of bat, pig, civet and rabbit cell lines, )] TJ ET BT 26.250 229.175 Td /F1 9.8 Tf [(whereas cell lines of canine, feline, rodent, chicken and insect origin were not susceptible)] TJ ET 0.267 0.267 0.267 rg BT 465.507 231.130 Td /F4 8.7 Tf [(42)] TJ ET 0.271 0.267 0.267 rg BT 477.571 234.219 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 480.327 231.130 Td /F4 8.7 Tf [(43)] TJ ET 0.271 0.267 0.267 rg BT 492.391 229.175 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 206.231 Td /F1 9.8 Tf [(DPP4 is an exopeptidase and is involved in the regulation of chemokine and cytokine responses and in glucose )] TJ ET BT 26.250 190.787 Td /F1 9.8 Tf [(metabolism)] TJ ET 0.267 0.267 0.267 rg BT 83.697 192.742 Td /F4 8.7 Tf [(44)] TJ ET 0.271 0.267 0.267 rg BT 95.761 190.787 Td /F1 9.8 Tf [(. Upon binding, the viral entry of MERS-CoV involves virus-cell fusion, which can be either )] TJ ET BT 26.250 175.343 Td /F1 9.8 Tf [(activated by type II transmembrane serine proteases TMPRSS2 or mediated by low pH and endosomal )] TJ ET BT 26.250 159.899 Td /F1 9.8 Tf [(cathepsins)] TJ ET 0.267 0.267 0.267 rg BT 78.832 161.854 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 90.896 159.899 Td /F1 9.8 Tf [(. The receptor-binding domain \(RBD\) in the S protein responsible for binding to DPP4 has also been )] TJ ET BT 26.250 144.455 Td /F1 9.8 Tf [(mapped. The RBD-S interaction falls within residues 358-662 of the S1 domain, where antibodies to this domain )] TJ ET BT 26.250 129.011 Td /F1 9.8 Tf [(were observed to efficiently neutralize infection)] TJ ET 0.267 0.267 0.267 rg BT 259.909 130.966 Td /F4 8.7 Tf [(45)] TJ ET 0.271 0.267 0.267 rg BT 271.973 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 274.729 130.966 Td /F4 8.7 Tf [(46)] TJ ET 0.271 0.267 0.267 rg BT 286.793 134.055 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 289.549 130.966 Td /F4 8.7 Tf [(47)] TJ ET 0.271 0.267 0.267 rg BT 301.613 129.011 Td /F1 9.8 Tf [(. Crystal structures of this binding interface showed a )] TJ ET BT 26.250 113.567 Td /F1 9.8 Tf [(homologous core subdomain but much variation in the external receptor binding motif region, compared with )] TJ ET BT 26.250 98.123 Td /F1 9.8 Tf [(that of SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 110.441 100.078 Td /F4 8.7 Tf [(41)] TJ ET 0.271 0.267 0.267 rg BT 122.505 98.123 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 75.179 Td /F1 9.8 Tf [(In humans, DPP4 is primarily expressed on the epithelial cells in kidney, small intestine, liver and prostate, and )] TJ ET BT 26.250 59.735 Td /F1 9.8 Tf [(on activated leukocytes)] TJ ET 0.267 0.267 0.267 rg BT 142.762 61.690 Td /F4 8.7 Tf [(13)] TJ ET 0.271 0.267 0.267 rg BT 154.827 64.779 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 157.583 61.690 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 169.647 59.735 Td /F1 9.8 Tf [(. 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EUп0eRT1|L)-+ O% U qTVuJ >*i 3j9_'BHa\5Whbc̈́Vo\a .ry\XOi*_' Wp3W^3L(#Tɳlq bT1>T'VhLQVD kwQ&U&p (>fr\W׾:P6sĕ4t@SNq!lH,=޶mb!p}:4=s z;޸q# gLl&!E20B8UT'p < KmHQHJ2Ƀp5IHfBOqa4jf^E0(&b/+/~Hlxaј^QQt: \;W^^^SSò^:՚RZZjXz`0,Kiijw^UUq'5Vd2=|[,j^M߹stt:ftl6Et@kRK{*GT=j]` ԣjA1Q2r8h&F(T07QGHߩu',C3WOvFqE)I=p+ I.re6sSeH"իWϞ={SNussȨx}ݻٓa!CTUU;w|̙6m233Zmnn. ==tvib_pL&Z7rܹ#HZl9m4.NKHH8رcu:H$())yϝ;g6CCCe2X,?>QQfOuLNo&Q(Rq+, 5j+R;+aW&sEF=h+k2TBJaP cƕj z tСcǎgff1pX֐#F>C*jFQնnݺUViii%%%}.]>|0$$޽{AAA$77wm@fff~~~~~> ::h.)) $$ѣGaaa :B.3&%%jnݺzF0a9(YzIUH(/P(>|a1P$i$K H"y@%tgs,@zd,s] ;fpg?N3WM㊲حԩSddD"y;ֿZӶm۶m;vtݽ{:t~:ܩ2==_~2ӳ[nr\VO:bHҗ^zi߾}&Lf᫦Ф^z) }j4=zd277VZT*Y<<<1. Y0I4|s43&Œttk-\OuŤb@Fc\=-B+R$W"; 0lꉸj&>9V+h"S\n/d2Y=ɺ'ST THEs$*pIcZMrѪ'mU\^EO<+W~MӯU!/4 Zy-?Ѹ >WFnBj1N>NՌiL5^;DxIbX$m|PRaH0Z8Ci_pf6kT(>{(2Sm2ZUPd!b\=WO~_0 쟊+B5@eɆ͗ 2OZK!a'TAfRLBaB,0NP0i-@I-qE E:x@r2@ƹhQ"LSX>' 5g!p@B׸dH,ҳi3p+LK3W_0DϒM>'H #P:T@YW\pZl&.ԯv=\Փr%PuGg _Yp![ŗgJhLX& fNR$80j$F)uIu;K21gL'*]0 cpݑQ_b̠|\a*B $F5,'0_\a)fLgi-ٓ&A%V++3Ij՟+&*sE+Ӥ0 PJ@y9TGPV#43UJڏdb_>d-8#Km] 4V`sY S@0P% ` 6s p*+\m\qPp'WUX:Wf8s>[ADG g)K69|a G&ul?fPQK sE-(xP+6NvA@+pEvn7@* -&p%bYrEH4tdΒE:ar:j6i->>;ἆǦ$| TLrE2B'\QyHP~0-$WqEumE$D0WXxSbHd֖+ܳ '+lZV U3WU"T 1 $4tӇC6KRv6LXjYF|P6 "S;S@,1rS&MuI8 7jDcGqU" r!]N>Hg WRA׹U0((Md ()$j4ڨHKZ#ȳ(>f u,WA- 5 F4h|VQj$0 Pkr|\)) `6 j b\5+Ik>. ׹" by)f3W`hb¥,ƻ\t*04V"44\qhTXvEL@WӔ6U]ir]> endobj 1081 0 obj << /Length 43281 >> stream 0.271 0.267 0.267 rg 0.267 0.267 0.267 RG q 15.000 25.956 577.500 751.044 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 75.039 766.600 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 87.103 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 89.859 766.600 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 101.923 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 104.679 766.600 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 116.743 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 119.499 766.600 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 131.563 764.645 Td /F1 9.8 Tf [(. Receptor preference and underlying tissue tropism may influence the severity of highly )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(pathogenic coronaviruses compared with HCoV-229E infection, which is usually milder and has limited )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(infectivity of these lower respiratory tract cells. However, cellular tropism does not completely account for )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(severity of disease.)] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Cell-based studies have shown that MERS-CoV, like other coronaviruses, evades innate immune recognition, )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(perhaps accounting for the high proportion of cases observed with severe disease)] TJ ET 0.267 0.267 0.267 rg BT 428.262 681.880 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 440.326 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 443.082 681.880 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 455.146 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 457.902 681.880 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 469.966 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.722 681.880 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 484.786 679.925 Td /F1 9.8 Tf [(. However, MERS-)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(CoV was observed to have higher sensitivity to pegylated interferon treatment, compared with SARS-CoV. This )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(has been hypothesized to be due to the lack of a SARS-CoV ORF6 homologue in MERS-CoV, which has been )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(shown to inhibit the nuclear translocation of p-STAT1 and activation of downstream antiviral genes)] TJ ET 0.267 0.267 0.267 rg BT 510.562 635.548 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 522.626 638.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.382 635.548 Td /F4 8.7 Tf [(51)] TJ ET 0.271 0.267 0.267 rg BT 537.446 633.593 Td /F1 9.8 Tf [(. MERS-)] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(CoV was observed to induce a massive dysregulation of the host cellular transcriptome to a much greater )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(extent and in a shorter time after infection than SARS-CoV, resulting in profound apoptosis of surrounding cells)] TJ ET 0.267 0.267 0.267 rg BT 26.250 589.216 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 38.314 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 41.070 589.216 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 53.134 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 55.890 589.216 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 67.954 587.261 Td /F1 9.8 Tf [(. This involves the greater suppression of the antigen presentation pathway in MERS-CoV compared )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(with SARS-CoV. This phenomenon suggests that SARS-CoV and MERS-CoV may activate different cellular )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(mechanisms for viral replication and infection, and may delay the adaptive response in the infected host, )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(particularly the immunocompromised patients)] TJ ET 0.267 0.267 0.267 rg BT 253.259 542.884 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 265.323 540.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 500.134 Td /F4 12.0 Tf [(Discussion and gaps in knowledge)] TJ ET BT 26.250 476.477 Td /F1 9.8 Tf [(Much has been learned about the MERS-CoV and the disease syndrome it causes in humans since the first case )] TJ ET BT 26.250 461.033 Td /F1 9.8 Tf [(was reported in September 2012, but many critical questions remain unanswered. From the time of the first )] TJ ET BT 26.250 445.589 Td /F1 9.8 Tf [(cases reported to WHO, it was suspected that the virus was of animal origin and subsequent observations since )] TJ ET BT 26.250 430.145 Td /F1 9.8 Tf [(that time have reinforced this view. Current evidence suggests that the virus is most closely related genetically )] TJ ET BT 26.250 414.701 Td /F1 9.8 Tf [(to viruses found in a number of species of old world and new world insectivorous bats)] TJ ET 0.267 0.267 0.267 rg BT 446.446 416.656 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 452.478 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 455.234 416.656 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 467.298 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 470.054 416.656 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 482.118 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 484.874 416.656 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 496.938 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 499.694 416.656 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 511.758 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 514.514 416.656 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 526.578 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 529.334 416.656 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 541.398 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 544.154 416.656 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 556.218 414.701 Td /F1 9.8 Tf [(. )] TJ ET BT 26.250 399.257 Td /F1 9.8 Tf [(The finding of a gene fragment in a Saudi bat)] TJ ET 0.267 0.267 0.267 rg BT 248.843 401.212 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 260.907 399.257 Td /F1 9.8 Tf [(, which is homologous with that of viruses from humans, )] TJ ET BT 26.250 383.813 Td /F1 9.8 Tf [(suggests that bats may be the ultimate reservoir of virus; however, it is very possible that another intermediate )] TJ ET BT 26.250 368.369 Td /F1 9.8 Tf [(animal reservoir could be involved, as was the case with SARS and with Nipah virus in Malaysia. Serological )] TJ ET BT 26.250 352.925 Td /F1 9.8 Tf [(data suggest infections with MERS-CoV or a closely related virus in camels, however the virus itself has not )] TJ ET BT 26.250 337.481 Td /F1 9.8 Tf [(been detected in camels)] TJ ET 0.267 0.267 0.267 rg BT 146.809 339.436 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 158.873 342.525 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 161.629 339.436 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 173.693 337.481 Td /F1 9.8 Tf [(. Currently, all known cases have a direct or indirect link to the Middle East. )] TJ ET BT 26.250 322.037 Td /F1 9.8 Tf [(Although surveillance is more limited in some parts of the world, large clusters like those seen in Al Hasa, KSA )] TJ ET BT 26.250 306.593 Td /F1 9.8 Tf [(and Zarqa, Jordan have not been observed elsewhere. This apparent restriction of transmission from non-human )] TJ ET BT 26.250 291.149 Td /F1 9.8 Tf [(sources to one area of the world may provide clues to the source of exposures. The most likely explanations are )] TJ ET BT 26.250 275.705 Td /F1 9.8 Tf [(either a restriction in the range of the putative host species or exposures related to human behaviours that )] TJ ET BT 26.250 260.261 Td /F1 9.8 Tf [(occur only in the area. Regardless of the reservoir, however, the primary question to be answered is the route )] TJ ET BT 26.250 244.817 Td /F1 9.8 Tf [(of transmission from animal to human. Sporadic and index cases provide the best opportunity for identifying )] TJ ET BT 26.250 229.373 Td /F1 9.8 Tf [(exposures of interest as these are the infections most likely acquired from non-human exposures. The high )] TJ ET BT 26.250 213.929 Td /F1 9.8 Tf [(predominance of older individuals among these cases could be a clue to exposures and demands further )] TJ ET BT 26.250 198.485 Td /F1 9.8 Tf [(investigation using structured case-control studies)] TJ ET 0.267 0.267 0.267 rg BT 273.783 200.440 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 285.847 198.485 Td /F1 9.8 Tf [(. The recent increase in numbers of sporadic cases )] TJ ET BT 26.250 183.041 Td /F1 9.8 Tf [(associated with a change in the proportion of male and female cases is concerning. While it could represent )] TJ ET BT 26.250 167.597 Td /F1 9.8 Tf [(changes in surveillance strategies, it may also signal a change in the behaviour of the virus, an expansion of the )] TJ ET BT 26.250 152.153 Td /F1 9.8 Tf [(reservoir, or changes in human exposures.)] TJ ET BT 26.250 129.209 Td /F1 9.8 Tf [(It is now clear that the virus does transmit from person to person. However, sustained human-to-human )] TJ ET BT 26.250 113.765 Td /F1 9.8 Tf [(transmission has not been observed. The relative ease with which outbreaks have been extinguished without )] TJ ET BT 26.250 98.321 Td /F1 9.8 Tf [(resorting to overly aggressive isolation and quarantine measures and the limited secondary transmission )] TJ ET BT 26.250 82.877 Td /F1 9.8 Tf [(around clusters, suggest that transmission of virus may be readily stopped.)] TJ ET BT 26.250 59.933 Td /F1 9.8 Tf [(Genetic sequence data indicate that multiple independent introductions into human populations have occurred. )] TJ ET BT 26.250 44.489 Td /F1 9.8 Tf [(In addition, modelled estimates of R)] TJ ET BT 203.076 41.811 Td /F1 8.7 Tf [(0)] TJ ET BT 208.588 44.489 Td /F1 9.8 Tf [( suggest that R)] TJ ET BT 283.010 41.811 Td /F1 8.7 Tf [(0)] TJ ET BT 288.522 44.489 Td /F1 9.8 Tf [( is <1, though the upper range of estimates may slightly )] TJ ET Q q 15.000 25.956 577.500 751.044 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 75.039 766.600 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 87.103 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 89.859 766.600 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 101.923 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 104.679 766.600 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 116.743 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 119.499 766.600 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 131.563 764.645 Td /F1 9.8 Tf [(. Receptor preference and underlying tissue tropism may influence the severity of highly )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(pathogenic coronaviruses compared with HCoV-229E infection, which is usually milder and has limited )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(infectivity of these lower respiratory tract cells. However, cellular tropism does not completely account for )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(severity of disease.)] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Cell-based studies have shown that MERS-CoV, like other coronaviruses, evades innate immune recognition, )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(perhaps accounting for the high proportion of cases observed with severe disease)] TJ ET 0.267 0.267 0.267 rg BT 428.262 681.880 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 440.326 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 443.082 681.880 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 455.146 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 457.902 681.880 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 469.966 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.722 681.880 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 484.786 679.925 Td /F1 9.8 Tf [(. However, MERS-)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(CoV was observed to have higher sensitivity to pegylated interferon treatment, compared with SARS-CoV. This )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(has been hypothesized to be due to the lack of a SARS-CoV ORF6 homologue in MERS-CoV, which has been )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(shown to inhibit the nuclear translocation of p-STAT1 and activation of downstream antiviral genes)] TJ ET 0.267 0.267 0.267 rg BT 510.562 635.548 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 522.626 638.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.382 635.548 Td /F4 8.7 Tf [(51)] TJ ET 0.271 0.267 0.267 rg BT 537.446 633.593 Td /F1 9.8 Tf [(. MERS-)] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(CoV was observed to induce a massive dysregulation of the host cellular transcriptome to a much greater )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(extent and in a shorter time after infection than SARS-CoV, resulting in profound apoptosis of surrounding cells)] TJ ET 0.267 0.267 0.267 rg BT 26.250 589.216 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 38.314 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 41.070 589.216 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 53.134 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 55.890 589.216 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 67.954 587.261 Td /F1 9.8 Tf [(. This involves the greater suppression of the antigen presentation pathway in MERS-CoV compared )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(with SARS-CoV. This phenomenon suggests that SARS-CoV and MERS-CoV may activate different cellular )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(mechanisms for viral replication and infection, and may delay the adaptive response in the infected host, )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(particularly the immunocompromised patients)] TJ ET 0.267 0.267 0.267 rg BT 253.259 542.884 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 265.323 540.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 500.134 Td /F4 12.0 Tf [(Discussion and gaps in knowledge)] TJ ET BT 26.250 476.477 Td /F1 9.8 Tf [(Much has been learned about the MERS-CoV and the disease syndrome it causes in humans since the first case )] TJ ET BT 26.250 461.033 Td /F1 9.8 Tf [(was reported in September 2012, but many critical questions remain unanswered. From the time of the first )] TJ ET BT 26.250 445.589 Td /F1 9.8 Tf [(cases reported to WHO, it was suspected that the virus was of animal origin and subsequent observations since )] TJ ET BT 26.250 430.145 Td /F1 9.8 Tf [(that time have reinforced this view. Current evidence suggests that the virus is most closely related genetically )] TJ ET BT 26.250 414.701 Td /F1 9.8 Tf [(to viruses found in a number of species of old world and new world insectivorous bats)] TJ ET 0.267 0.267 0.267 rg BT 446.446 416.656 Td /F4 8.7 Tf [(1)] TJ ET 0.271 0.267 0.267 rg BT 452.478 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 455.234 416.656 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 467.298 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 470.054 416.656 Td /F4 8.7 Tf [(29)] TJ ET 0.271 0.267 0.267 rg BT 482.118 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 484.874 416.656 Td /F4 8.7 Tf [(30)] TJ ET 0.271 0.267 0.267 rg BT 496.938 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 499.694 416.656 Td /F4 8.7 Tf [(31)] TJ ET 0.271 0.267 0.267 rg BT 511.758 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 514.514 416.656 Td /F4 8.7 Tf [(32)] TJ ET 0.271 0.267 0.267 rg BT 526.578 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 529.334 416.656 Td /F4 8.7 Tf [(33)] TJ ET 0.271 0.267 0.267 rg BT 541.398 419.745 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 544.154 416.656 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 556.218 414.701 Td /F1 9.8 Tf [(. )] TJ ET BT 26.250 399.257 Td /F1 9.8 Tf [(The finding of a gene fragment in a Saudi bat)] TJ ET 0.267 0.267 0.267 rg BT 248.843 401.212 Td /F4 8.7 Tf [(34)] TJ ET 0.271 0.267 0.267 rg BT 260.907 399.257 Td /F1 9.8 Tf [(, which is homologous with that of viruses from humans, )] TJ ET BT 26.250 383.813 Td /F1 9.8 Tf [(suggests that bats may be the ultimate reservoir of virus; however, it is very possible that another intermediate )] TJ ET BT 26.250 368.369 Td /F1 9.8 Tf [(animal reservoir could be involved, as was the case with SARS and with Nipah virus in Malaysia. Serological )] TJ ET BT 26.250 352.925 Td /F1 9.8 Tf [(data suggest infections with MERS-CoV or a closely related virus in camels, however the virus itself has not )] TJ ET BT 26.250 337.481 Td /F1 9.8 Tf [(been detected in camels)] TJ ET 0.267 0.267 0.267 rg BT 146.809 339.436 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 158.873 342.525 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 161.629 339.436 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 173.693 337.481 Td /F1 9.8 Tf [(. Currently, all known cases have a direct or indirect link to the Middle East. )] TJ ET BT 26.250 322.037 Td /F1 9.8 Tf [(Although surveillance is more limited in some parts of the world, large clusters like those seen in Al Hasa, KSA )] TJ ET BT 26.250 306.593 Td /F1 9.8 Tf [(and Zarqa, Jordan have not been observed elsewhere. This apparent restriction of transmission from non-human )] TJ ET BT 26.250 291.149 Td /F1 9.8 Tf [(sources to one area of the world may provide clues to the source of exposures. The most likely explanations are )] TJ ET BT 26.250 275.705 Td /F1 9.8 Tf [(either a restriction in the range of the putative host species or exposures related to human behaviours that )] TJ ET BT 26.250 260.261 Td /F1 9.8 Tf [(occur only in the area. Regardless of the reservoir, however, the primary question to be answered is the route )] TJ ET BT 26.250 244.817 Td /F1 9.8 Tf [(of transmission from animal to human. Sporadic and index cases provide the best opportunity for identifying )] TJ ET BT 26.250 229.373 Td /F1 9.8 Tf [(exposures of interest as these are the infections most likely acquired from non-human exposures. The high )] TJ ET BT 26.250 213.929 Td /F1 9.8 Tf [(predominance of older individuals among these cases could be a clue to exposures and demands further )] TJ ET BT 26.250 198.485 Td /F1 9.8 Tf [(investigation using structured case-control studies)] TJ ET 0.267 0.267 0.267 rg BT 273.783 200.440 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 285.847 198.485 Td /F1 9.8 Tf [(. The recent increase in numbers of sporadic cases )] TJ ET BT 26.250 183.041 Td /F1 9.8 Tf [(associated with a change in the proportion of male and female cases is concerning. While it could represent )] TJ ET BT 26.250 167.597 Td /F1 9.8 Tf [(changes in surveillance strategies, it may also signal a change in the behaviour of the virus, an expansion of the )] TJ ET BT 26.250 152.153 Td /F1 9.8 Tf [(reservoir, or changes in human exposures.)] TJ ET BT 26.250 129.209 Td /F1 9.8 Tf [(It is now clear that the virus does transmit from person to person. However, sustained human-to-human )] TJ ET BT 26.250 113.765 Td /F1 9.8 Tf [(transmission has not been observed. The relative ease with which outbreaks have been extinguished without )] TJ ET BT 26.250 98.321 Td /F1 9.8 Tf [(resorting to overly aggressive isolation and quarantine measures and the limited secondary transmission )] TJ ET BT 26.250 82.877 Td /F1 9.8 Tf [(around clusters, suggest that transmission of virus may be readily stopped.)] TJ ET BT 26.250 59.933 Td /F1 9.8 Tf [(Genetic sequence data indicate that multiple independent introductions into human populations have occurred. )] TJ ET BT 26.250 44.489 Td /F1 9.8 Tf [(In addition, modelled estimates of R)] TJ ET BT 203.076 41.811 Td /F1 8.7 Tf [(0)] TJ ET BT 208.588 44.489 Td /F1 9.8 Tf [( suggest that R)] TJ ET BT 283.010 41.811 Td /F1 8.7 Tf [(0)] TJ ET BT 288.522 44.489 Td /F1 9.8 Tf [( is <1, though the upper range of estimates may slightly )] TJ ET Q q 15.000 25.956 577.500 751.044 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(SARS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 75.039 766.600 Td /F4 8.7 Tf [(40)] TJ ET 0.271 0.267 0.267 rg BT 87.103 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 89.859 766.600 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 101.923 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 104.679 766.600 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 116.743 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 119.499 766.600 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 131.563 764.645 Td /F1 9.8 Tf [(. Receptor preference and underlying tissue tropism may influence the severity of highly )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(pathogenic coronaviruses compared with HCoV-229E infection, which is usually milder and has limited )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(infectivity of these lower respiratory tract cells. However, cellular tropism does not completely account for )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(severity of disease.)] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Cell-based studies have shown that MERS-CoV, like other coronaviruses, evades innate immune recognition, )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(perhaps accounting for the high proportion of cases observed with severe disease)] TJ ET 0.267 0.267 0.267 rg BT 428.262 681.880 Td /F4 8.7 Tf [(16)] TJ ET 0.271 0.267 0.267 rg BT 440.326 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 443.082 681.880 Td /F4 8.7 Tf [(18)] TJ ET 0.271 0.267 0.267 rg BT 455.146 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 457.902 681.880 Td /F4 8.7 Tf [(48)] TJ ET 0.271 0.267 0.267 rg BT 469.966 684.969 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 472.722 681.880 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 484.786 679.925 Td /F1 9.8 Tf [(. However, MERS-)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(CoV was observed to have higher sensitivity to pegylated interferon treatment, compared with SARS-CoV. This )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(has been hypothesized to be due to the lack of a SARS-CoV ORF6 homologue in MERS-CoV, which has been )] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(shown to inhibit the nuclear translocation of p-STAT1 and activation of downstream antiviral genes)] TJ ET 0.267 0.267 0.267 rg BT 510.562 635.548 Td /F4 8.7 Tf [(28)] TJ ET 0.271 0.267 0.267 rg BT 522.626 638.637 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 525.382 635.548 Td /F4 8.7 Tf [(51)] TJ ET 0.271 0.267 0.267 rg BT 537.446 633.593 Td /F1 9.8 Tf [(. MERS-)] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(CoV was observed to induce a massive dysregulation of the host cellular transcriptome to a much greater )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(extent and in a shorter time after infection than SARS-CoV, resulting in profound apoptosis of surrounding cells)] TJ ET 0.267 0.267 0.267 rg BT 26.250 589.216 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 38.314 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 41.070 589.216 Td /F4 8.7 Tf [(49)] TJ ET 0.271 0.267 0.267 rg BT 53.134 592.305 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 55.890 589.216 Td /F4 8.7 Tf [(50)] TJ ET 0.271 0.267 0.267 rg BT 67.954 587.261 Td /F1 9.8 Tf [(. This involves the greater suppression of the antigen presentation pathway in MERS-CoV compared )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(with SARS-CoV. This phenomenon suggests that SARS-CoV and MERS-CoV may activate different cellular )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(mechanisms for viral replication and infection, and may delay the adaptive response in the infected host, )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(particularly the immunocompromised patients)] TJ ET 0.267 0.267 0.267 rg BT 253.259 542.884 Td /F4 8.7 Tf [(17)] TJ ET 0.271 0.267 0.267 rg BT 265.323 540.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 500.134 Td /F4 12.0 Tf [(Discussion and gaps in knowledge)] TJ ET BT 26.250 476.477 Td /F1 9.8 Tf [(Much has been learned about the MERS-CoV and the disease syndrome it causes in humans since the first case )] TJ ET BT 26.250 461.033 Td /F1 9.8 Tf [(was reported in September 2012, but many critical questions remain unanswered. From the time of the first )] TJ ET BT 26.250 445.589 Td /F1 9.8 Tf [(cases reported to WHO, it was suspected that the virus was of animal origin and subsequent observations since )] TJ ET BT 26.250 430.145 Td /F1 9.8 Tf [(that time have reinforced this view. 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Serological )] TJ ET BT 26.250 352.925 Td /F1 9.8 Tf [(data suggest infections with MERS-CoV or a closely related virus in camels, however the virus itself has not )] TJ ET BT 26.250 337.481 Td /F1 9.8 Tf [(been detected in camels)] TJ ET 0.267 0.267 0.267 rg BT 146.809 339.436 Td /F4 8.7 Tf [(36)] TJ ET 0.271 0.267 0.267 rg BT 158.873 342.525 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 161.629 339.436 Td /F4 8.7 Tf [(35)] TJ ET 0.271 0.267 0.267 rg BT 173.693 337.481 Td /F1 9.8 Tf [(. Currently, all known cases have a direct or indirect link to the Middle East. )] TJ ET BT 26.250 322.037 Td /F1 9.8 Tf [(Although surveillance is more limited in some parts of the world, large clusters like those seen in Al Hasa, KSA )] TJ ET BT 26.250 306.593 Td /F1 9.8 Tf [(and Zarqa, Jordan have not been observed elsewhere. This apparent restriction of transmission from non-human )] TJ ET BT 26.250 291.149 Td /F1 9.8 Tf [(sources to one area of the world may provide clues to the source of exposures. The most likely explanations are )] TJ ET BT 26.250 275.705 Td /F1 9.8 Tf [(either a restriction in the range of the putative host species or exposures related to human behaviours that )] TJ ET BT 26.250 260.261 Td /F1 9.8 Tf [(occur only in the area. Regardless of the reservoir, however, the primary question to be answered is the route )] TJ ET BT 26.250 244.817 Td /F1 9.8 Tf [(of transmission from animal to human. Sporadic and index cases provide the best opportunity for identifying )] TJ ET BT 26.250 229.373 Td /F1 9.8 Tf [(exposures of interest as these are the infections most likely acquired from non-human exposures. The high )] TJ ET BT 26.250 213.929 Td /F1 9.8 Tf [(predominance of older individuals among these cases could be a clue to exposures and demands further )] TJ ET BT 26.250 198.485 Td /F1 9.8 Tf [(investigation using structured case-control studies)] TJ ET 0.267 0.267 0.267 rg BT 273.783 200.440 Td /F4 8.7 Tf [(53)] TJ ET 0.271 0.267 0.267 rg BT 285.847 198.485 Td /F1 9.8 Tf [(. The recent increase in numbers of sporadic cases )] TJ ET BT 26.250 183.041 Td /F1 9.8 Tf [(associated with a change in the proportion of male and female cases is concerning. While it could represent )] TJ ET BT 26.250 167.597 Td /F1 9.8 Tf [(changes in surveillance strategies, it may also signal a change in the behaviour of the virus, an expansion of the )] TJ ET BT 26.250 152.153 Td /F1 9.8 Tf [(reservoir, or changes in human exposures.)] TJ ET BT 26.250 129.209 Td /F1 9.8 Tf [(It is now clear that the virus does transmit from person to person. 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Reports of mild and asymptomatic cases discovered through investigations and testing of )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(contacts of confirmed cases, suggest that the focus on severe disease as a surveillance strategy may miss )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(significant numbers of milder or asymptomatic cases)] TJ ET 0.267 0.267 0.267 rg BT 286.000 735.712 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 298.064 733.757 Td /F1 9.8 Tf [(. The importance of these milder cases in transmission, )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(however, is uncertain and needs to be assess with seroepidemiologic studies)] TJ ET 0.267 0.267 0.267 rg BT 403.526 720.268 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 415.590 718.313 Td /F1 9.8 Tf [(. Evidence from SARS, however, )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(suggests that asymptomatic cases did not transmit infection)] TJ ET 0.267 0.267 0.267 rg BT 323.069 704.824 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 335.133 702.869 Td /F1 9.8 Tf [(. It appears likely that the presence of comorbid )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(conditions, particularly when found in high concentrations such as in HCS, can facilitate transmission.)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(The basic clinical appearance and course of severe cases seen since the earliest reports has not substantially )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(changed; however, it is now clear that milder and even asymptomatic presentations do occur and that the case-)] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(fatality rate is lower than observed. The acute renal failure observed in many cases, especially those reported )] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(early on, has been primarily associated with hemodynamic compromise, suggesting that it is likely a secondary )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(process. However, receptors for the virus do occur in renal tissue and viral RNA has been detected at low titres )] TJ ET BT 26.250 587.261 Td /F1 9.8 Tf [(in urine. It is important to note that although the primary site of infection has been the respiratory tract, )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(approximately one-third of patients have experienced gastrointestinal symptoms and low titres of virus have )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(been detected in faeces. While generally this is not likely useful for diagnostic purposes, this finding supports )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(current recommendations for adding contact precautions in HCS and may have implications for infection control )] TJ ET BT 26.250 525.485 Td /F1 9.8 Tf [(in the community. The observed differences in proportion of cases that are severe between primary )] TJ ET BT 26.250 510.041 Td /F1 9.8 Tf [(\(index/sporadic\) and secondary cases is likely a reflection of the surveillance strategy that focuses on severe )] TJ ET BT 26.250 494.597 Td /F1 9.8 Tf [(disease for identifying primary cases and the additional case-finding carried out around them. However, the )] TJ ET BT 26.250 479.153 Td /F1 9.8 Tf [(possibility that the virulence of the virus is different when transmitted from humans than it is when transmitted )] TJ ET BT 26.250 463.709 Td /F1 9.8 Tf [(from non-human sources cannot be excluded based on available evidence. The presence of a pre-existing )] TJ ET BT 26.250 448.265 Td /F1 9.8 Tf [(chronic medical condition likely increases the chance of severe outcome and death.)] TJ ET BT 26.250 425.321 Td /F1 9.8 Tf [(At this time, treatment for MERS-CoV remains supportive. A number of licensed pharmaceuticals have been )] TJ ET BT 26.250 409.877 Td /F1 9.8 Tf [(tested in vitro and testing is currently underway in vivo; however, the lack of an appropriate animal model is )] TJ ET BT 26.250 394.433 Td /F1 9.8 Tf [(hampering these efforts. Clinical observation of patients infected with MERS-CoV and experience with other )] TJ ET BT 26.250 378.989 Td /F1 9.8 Tf [(infectious diseases suggest that high-dose corticosteroids are not effective in management of the disease and )] TJ ET BT 26.250 363.545 Td /F1 9.8 Tf [(may be contraindicated for other reasons. Considerable controversy exists about the value of high-dose )] TJ ET BT 26.250 348.101 Td /F1 9.8 Tf [(corticosteroids in the management of ARDS. There is substantial evidence of harm, and no evidence of benefit, )] TJ ET BT 26.250 332.657 Td /F1 9.8 Tf [(from high-dose corticosteroids when used for SARS and influenza A\(H1N1\)pdm09)] TJ ET 0.267 0.267 0.267 rg BT 424.567 334.612 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 430.599 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 433.355 334.612 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 445.419 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 448.175 334.612 Td /F4 8.7 Tf [(57)] TJ ET 0.271 0.267 0.267 rg BT 460.239 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 462.995 334.612 Td /F4 8.7 Tf [(58)] TJ ET 0.271 0.267 0.267 rg BT 475.059 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 477.815 334.612 Td /F4 8.7 Tf [(59)] TJ ET 0.271 0.267 0.267 rg BT 489.879 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 492.635 334.612 Td /F4 8.7 Tf [(60)] TJ ET 0.271 0.267 0.267 rg BT 504.699 332.657 Td /F1 9.8 Tf [(. For this )] TJ ET BT 26.250 317.213 Td /F1 9.8 Tf [(reason, WHO guidance does not recommend the systemic use of high-dose corticosteroids for MERS-CoV )] TJ ET BT 26.250 301.769 Td /F1 9.8 Tf [(treatment, with a few exceptions limited to, for example, patients with asthma or vasopressor refractory shock)] TJ ET 0.267 0.267 0.267 rg BT 26.250 288.280 Td /F4 8.7 Tf [(61)] TJ ET 0.271 0.267 0.267 rg BT 38.314 286.325 Td /F1 9.8 Tf [(. It may be that convalescent sera holds some promise until an effective pharmaceutical can be identified. If )] TJ ET BT 26.250 270.881 Td /F1 9.8 Tf [(indeed convalescent sera proves efficacious, specific human monoclonal antibodies may also be considered. )] TJ ET BT 26.250 255.437 Td /F1 9.8 Tf [(Sharing of clinical information and case-management experience is critical to better understand the natural )] TJ ET BT 26.250 239.993 Td /F1 9.8 Tf [(history of disease for MERS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 182.533 241.948 Td /F4 8.7 Tf [(62)] TJ ET 0.271 0.267 0.267 rg BT 194.597 239.993 Td /F1 9.8 Tf [( and improve management guidance. In addition to infection prevention and )] TJ ET BT 26.250 224.549 Td /F1 9.8 Tf [(control measures aiming to minimize transmission of MERS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 339.459 226.504 Td /F4 8.7 Tf [(63)] TJ ET 0.271 0.267 0.267 rg BT 351.523 224.549 Td /F1 9.8 Tf [(, attention should be paid to rigorous )] TJ ET BT 26.250 209.105 Td /F1 9.8 Tf [(implementation of safe practices to prevent acquisition of bacterial and fungal pathogens associated with )] TJ ET BT 26.250 193.661 Td /F1 9.8 Tf [(health care.)] TJ ET BT 26.250 170.717 Td /F1 9.8 Tf [(Many critical questions about MERS-CoV and its related disease remain. First among these is the nature of the )] TJ ET BT 26.250 155.273 Td /F1 9.8 Tf [(exposures that result in human infection. Although an animal reservoir of the virus is the most likely hypothesis, )] TJ ET BT 26.250 139.829 Td /F1 9.8 Tf [(the route of transmission could be either direct or indirect contact with the reservoir or an intermediate host, )] TJ ET BT 26.250 124.385 Td /F1 9.8 Tf [(including consumption of a contaminated food product, or contact with a contaminated fomite. Thus far, spread )] TJ ET BT 26.250 108.941 Td /F1 9.8 Tf [(among humans appears to be relatively easy to extinguish with conventional infection control measures and )] TJ ET BT 26.250 93.497 Td /F1 9.8 Tf [(has not required the aggressive measures that were used to contain SARS. Prevention of transmission from the )] TJ ET BT 26.250 78.053 Td /F1 9.8 Tf [(putative animal reservoir to humans is the critical step needed to halt the ongoing spread of this virus. The )] TJ ET BT 26.250 62.609 Td /F1 9.8 Tf [(answer to how to achieve this and other remaining questions requires formal, structured, multinational )] TJ ET BT 26.250 47.165 Td /F1 9.8 Tf [(collaborative research studies, including the development and implementation of effective surveillance )] TJ ET Q q 15.000 28.632 577.500 748.368 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(exceed 1)] TJ ET 0.267 0.267 0.267 rg BT 70.866 766.600 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 82.930 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 85.686 766.600 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 97.750 764.645 Td /F1 9.8 Tf [(. Reports of mild and asymptomatic cases discovered through investigations and testing of )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(contacts of confirmed cases, suggest that the focus on severe disease as a surveillance strategy may miss )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(significant numbers of milder or asymptomatic cases)] TJ ET 0.267 0.267 0.267 rg BT 286.000 735.712 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 298.064 733.757 Td /F1 9.8 Tf [(. The importance of these milder cases in transmission, )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(however, is uncertain and needs to be assess with seroepidemiologic studies)] TJ ET 0.267 0.267 0.267 rg BT 403.526 720.268 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 415.590 718.313 Td /F1 9.8 Tf [(. Evidence from SARS, however, )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(suggests that asymptomatic cases did not transmit infection)] TJ ET 0.267 0.267 0.267 rg BT 323.069 704.824 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 335.133 702.869 Td /F1 9.8 Tf [(. It appears likely that the presence of comorbid )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(conditions, particularly when found in high concentrations such as in HCS, can facilitate transmission.)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(The basic clinical appearance and course of severe cases seen since the earliest reports has not substantially )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(changed; however, it is now clear that milder and even asymptomatic presentations do occur and that the case-)] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(fatality rate is lower than observed. The acute renal failure observed in many cases, especially those reported )] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(early on, has been primarily associated with hemodynamic compromise, suggesting that it is likely a secondary )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(process. However, receptors for the virus do occur in renal tissue and viral RNA has been detected at low titres )] TJ ET BT 26.250 587.261 Td /F1 9.8 Tf [(in urine. It is important to note that although the primary site of infection has been the respiratory tract, )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(approximately one-third of patients have experienced gastrointestinal symptoms and low titres of virus have )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(been detected in faeces. While generally this is not likely useful for diagnostic purposes, this finding supports )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(current recommendations for adding contact precautions in HCS and may have implications for infection control )] TJ ET BT 26.250 525.485 Td /F1 9.8 Tf [(in the community. The observed differences in proportion of cases that are severe between primary )] TJ ET BT 26.250 510.041 Td /F1 9.8 Tf [(\(index/sporadic\) and secondary cases is likely a reflection of the surveillance strategy that focuses on severe )] TJ ET BT 26.250 494.597 Td /F1 9.8 Tf [(disease for identifying primary cases and the additional case-finding carried out around them. However, the )] TJ ET BT 26.250 479.153 Td /F1 9.8 Tf [(possibility that the virulence of the virus is different when transmitted from humans than it is when transmitted )] TJ ET BT 26.250 463.709 Td /F1 9.8 Tf [(from non-human sources cannot be excluded based on available evidence. The presence of a pre-existing )] TJ ET BT 26.250 448.265 Td /F1 9.8 Tf [(chronic medical condition likely increases the chance of severe outcome and death.)] TJ ET BT 26.250 425.321 Td /F1 9.8 Tf [(At this time, treatment for MERS-CoV remains supportive. A number of licensed pharmaceuticals have been )] TJ ET BT 26.250 409.877 Td /F1 9.8 Tf [(tested in vitro and testing is currently underway in vivo; however, the lack of an appropriate animal model is )] TJ ET BT 26.250 394.433 Td /F1 9.8 Tf [(hampering these efforts. Clinical observation of patients infected with MERS-CoV and experience with other )] TJ ET BT 26.250 378.989 Td /F1 9.8 Tf [(infectious diseases suggest that high-dose corticosteroids are not effective in management of the disease and )] TJ ET BT 26.250 363.545 Td /F1 9.8 Tf [(may be contraindicated for other reasons. Considerable controversy exists about the value of high-dose )] TJ ET BT 26.250 348.101 Td /F1 9.8 Tf [(corticosteroids in the management of ARDS. There is substantial evidence of harm, and no evidence of benefit, )] TJ ET BT 26.250 332.657 Td /F1 9.8 Tf [(from high-dose corticosteroids when used for SARS and influenza A\(H1N1\)pdm09)] TJ ET 0.267 0.267 0.267 rg BT 424.567 334.612 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 430.599 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 433.355 334.612 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 445.419 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 448.175 334.612 Td /F4 8.7 Tf [(57)] TJ ET 0.271 0.267 0.267 rg BT 460.239 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 462.995 334.612 Td /F4 8.7 Tf [(58)] TJ ET 0.271 0.267 0.267 rg BT 475.059 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 477.815 334.612 Td /F4 8.7 Tf [(59)] TJ ET 0.271 0.267 0.267 rg BT 489.879 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 492.635 334.612 Td /F4 8.7 Tf [(60)] TJ ET 0.271 0.267 0.267 rg BT 504.699 332.657 Td /F1 9.8 Tf [(. For this )] TJ ET BT 26.250 317.213 Td /F1 9.8 Tf [(reason, WHO guidance does not recommend the systemic use of high-dose corticosteroids for MERS-CoV )] TJ ET BT 26.250 301.769 Td /F1 9.8 Tf [(treatment, with a few exceptions limited to, for example, patients with asthma or vasopressor refractory shock)] TJ ET 0.267 0.267 0.267 rg BT 26.250 288.280 Td /F4 8.7 Tf [(61)] TJ ET 0.271 0.267 0.267 rg BT 38.314 286.325 Td /F1 9.8 Tf [(. It may be that convalescent sera holds some promise until an effective pharmaceutical can be identified. If )] TJ ET BT 26.250 270.881 Td /F1 9.8 Tf [(indeed convalescent sera proves efficacious, specific human monoclonal antibodies may also be considered. )] TJ ET BT 26.250 255.437 Td /F1 9.8 Tf [(Sharing of clinical information and case-management experience is critical to better understand the natural )] TJ ET BT 26.250 239.993 Td /F1 9.8 Tf [(history of disease for MERS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 182.533 241.948 Td /F4 8.7 Tf [(62)] TJ ET 0.271 0.267 0.267 rg BT 194.597 239.993 Td /F1 9.8 Tf [( and improve management guidance. In addition to infection prevention and )] TJ ET BT 26.250 224.549 Td /F1 9.8 Tf [(control measures aiming to minimize transmission of MERS-CoV)] TJ ET 0.267 0.267 0.267 rg BT 339.459 226.504 Td /F4 8.7 Tf [(63)] TJ ET 0.271 0.267 0.267 rg BT 351.523 224.549 Td /F1 9.8 Tf [(, attention should be paid to rigorous )] TJ ET BT 26.250 209.105 Td /F1 9.8 Tf [(implementation of safe practices to prevent acquisition of bacterial and fungal pathogens associated with )] TJ ET BT 26.250 193.661 Td /F1 9.8 Tf [(health care.)] TJ ET BT 26.250 170.717 Td /F1 9.8 Tf [(Many critical questions about MERS-CoV and its related disease remain. First among these is the nature of the )] TJ ET BT 26.250 155.273 Td /F1 9.8 Tf [(exposures that result in human infection. Although an animal reservoir of the virus is the most likely hypothesis, )] TJ ET BT 26.250 139.829 Td /F1 9.8 Tf [(the route of transmission could be either direct or indirect contact with the reservoir or an intermediate host, )] TJ ET BT 26.250 124.385 Td /F1 9.8 Tf [(including consumption of a contaminated food product, or contact with a contaminated fomite. Thus far, spread )] TJ ET BT 26.250 108.941 Td /F1 9.8 Tf [(among humans appears to be relatively easy to extinguish with conventional infection control measures and )] TJ ET BT 26.250 93.497 Td /F1 9.8 Tf [(has not required the aggressive measures that were used to contain SARS. Prevention of transmission from the )] TJ ET BT 26.250 78.053 Td /F1 9.8 Tf [(putative animal reservoir to humans is the critical step needed to halt the ongoing spread of this virus. The )] TJ ET BT 26.250 62.609 Td /F1 9.8 Tf [(answer to how to achieve this and other remaining questions requires formal, structured, multinational )] TJ ET BT 26.250 47.165 Td /F1 9.8 Tf [(collaborative research studies, including the development and implementation of effective surveillance )] TJ ET Q q 15.000 28.632 577.500 748.368 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(exceed 1)] TJ ET 0.267 0.267 0.267 rg BT 70.866 766.600 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 82.930 769.689 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 85.686 766.600 Td /F4 8.7 Tf [(26)] TJ ET 0.271 0.267 0.267 rg BT 97.750 764.645 Td /F1 9.8 Tf [(. Reports of mild and asymptomatic cases discovered through investigations and testing of )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(contacts of confirmed cases, suggest that the focus on severe disease as a surveillance strategy may miss )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(significant numbers of milder or asymptomatic cases)] TJ ET 0.267 0.267 0.267 rg BT 286.000 735.712 Td /F4 8.7 Tf [(22)] TJ ET 0.271 0.267 0.267 rg BT 298.064 733.757 Td /F1 9.8 Tf [(. The importance of these milder cases in transmission, )] TJ ET BT 26.250 718.313 Td /F1 9.8 Tf [(however, is uncertain and needs to be assess with seroepidemiologic studies)] TJ ET 0.267 0.267 0.267 rg BT 403.526 720.268 Td /F4 8.7 Tf [(54)] TJ ET 0.271 0.267 0.267 rg BT 415.590 718.313 Td /F1 9.8 Tf [(. Evidence from SARS, however, )] TJ ET BT 26.250 702.869 Td /F1 9.8 Tf [(suggests that asymptomatic cases did not transmit infection)] TJ ET 0.267 0.267 0.267 rg BT 323.069 704.824 Td /F4 8.7 Tf [(55)] TJ ET 0.271 0.267 0.267 rg BT 335.133 702.869 Td /F1 9.8 Tf [(. It appears likely that the presence of comorbid )] TJ ET BT 26.250 687.425 Td /F1 9.8 Tf [(conditions, particularly when found in high concentrations such as in HCS, can facilitate transmission.)] TJ ET BT 26.250 664.481 Td /F1 9.8 Tf [(The basic clinical appearance and course of severe cases seen since the earliest reports has not substantially )] TJ ET BT 26.250 649.037 Td /F1 9.8 Tf [(changed; however, it is now clear that milder and even asymptomatic presentations do occur and that the case-)] TJ ET BT 26.250 633.593 Td /F1 9.8 Tf [(fatality rate is lower than observed. The acute renal failure observed in many cases, especially those reported )] TJ ET BT 26.250 618.149 Td /F1 9.8 Tf [(early on, has been primarily associated with hemodynamic compromise, suggesting that it is likely a secondary )] TJ ET BT 26.250 602.705 Td /F1 9.8 Tf [(process. However, receptors for the virus do occur in renal tissue and viral RNA has been detected at low titres )] TJ ET BT 26.250 587.261 Td /F1 9.8 Tf [(in urine. It is important to note that although the primary site of infection has been the respiratory tract, )] TJ ET BT 26.250 571.817 Td /F1 9.8 Tf [(approximately one-third of patients have experienced gastrointestinal symptoms and low titres of virus have )] TJ ET BT 26.250 556.373 Td /F1 9.8 Tf [(been detected in faeces. While generally this is not likely useful for diagnostic purposes, this finding supports )] TJ ET BT 26.250 540.929 Td /F1 9.8 Tf [(current recommendations for adding contact precautions in HCS and may have implications for infection control )] TJ ET BT 26.250 525.485 Td /F1 9.8 Tf [(in the community. The observed differences in proportion of cases that are severe between primary )] TJ ET BT 26.250 510.041 Td /F1 9.8 Tf [(\(index/sporadic\) and secondary cases is likely a reflection of the surveillance strategy that focuses on severe )] TJ ET BT 26.250 494.597 Td /F1 9.8 Tf [(disease for identifying primary cases and the additional case-finding carried out around them. However, the )] TJ ET BT 26.250 479.153 Td /F1 9.8 Tf [(possibility that the virulence of the virus is different when transmitted from humans than it is when transmitted )] TJ ET BT 26.250 463.709 Td /F1 9.8 Tf [(from non-human sources cannot be excluded based on available evidence. The presence of a pre-existing )] TJ ET BT 26.250 448.265 Td /F1 9.8 Tf [(chronic medical condition likely increases the chance of severe outcome and death.)] TJ ET BT 26.250 425.321 Td /F1 9.8 Tf [(At this time, treatment for MERS-CoV remains supportive. A number of licensed pharmaceuticals have been )] TJ ET BT 26.250 409.877 Td /F1 9.8 Tf [(tested in vitro and testing is currently underway in vivo; however, the lack of an appropriate animal model is )] TJ ET BT 26.250 394.433 Td /F1 9.8 Tf [(hampering these efforts. Clinical observation of patients infected with MERS-CoV and experience with other )] TJ ET BT 26.250 378.989 Td /F1 9.8 Tf [(infectious diseases suggest that high-dose corticosteroids are not effective in management of the disease and )] TJ ET BT 26.250 363.545 Td /F1 9.8 Tf [(may be contraindicated for other reasons. Considerable controversy exists about the value of high-dose )] TJ ET BT 26.250 348.101 Td /F1 9.8 Tf [(corticosteroids in the management of ARDS. There is substantial evidence of harm, and no evidence of benefit, )] TJ ET BT 26.250 332.657 Td /F1 9.8 Tf [(from high-dose corticosteroids when used for SARS and influenza A\(H1N1\)pdm09)] TJ ET 0.267 0.267 0.267 rg BT 424.567 334.612 Td /F4 8.7 Tf [(4)] TJ ET 0.271 0.267 0.267 rg BT 430.599 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 433.355 334.612 Td /F4 8.7 Tf [(56)] TJ ET 0.271 0.267 0.267 rg BT 445.419 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 448.175 334.612 Td /F4 8.7 Tf [(57)] TJ ET 0.271 0.267 0.267 rg BT 460.239 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 462.995 334.612 Td /F4 8.7 Tf [(58)] TJ ET 0.271 0.267 0.267 rg BT 475.059 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 477.815 334.612 Td /F4 8.7 Tf [(59)] TJ ET 0.271 0.267 0.267 rg BT 489.879 337.701 Td /F1 8.7 Tf [(,)] TJ ET 0.267 0.267 0.267 rg BT 492.635 334.612 Td /F4 8.7 Tf [(60)] TJ ET 0.271 0.267 0.267 rg BT 504.699 332.657 Td /F1 9.8 Tf [(. For this )] TJ ET BT 26.250 317.213 Td /F1 9.8 Tf [(reason, WHO guidance does not recommend the systemic use of high-dose corticosteroids for MERS-CoV )] TJ ET BT 26.250 301.769 Td /F1 9.8 Tf [(treatment, with a few exceptions limited to, for example, patients with asthma or vasopressor refractory shock)] TJ ET 0.267 0.267 0.267 rg BT 26.250 288.280 Td /F4 8.7 Tf [(61)] TJ ET 0.271 0.267 0.267 rg BT 38.314 286.325 Td /F1 9.8 Tf [(. It may be that convalescent sera holds some promise until an effective pharmaceutical can be identified. 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PubMed PMID:23718156.)] TJ ET Q q 15.000 55.764 577.500 721.236 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(Institut Pasteur, CNRS)] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(University Paris Diderot Sorbonne Paris Cit)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(Paris, France)] TJ ET BT 26.250 695.813 Td /F4 9.8 Tf [(Maria D. 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Mounts)] TJ ET BT 26.250 424.865 Td /F1 9.8 Tf [(Global Influenza Programme, World Health Organization, Geneva, Switzerland)] TJ ET BT 26.250 401.921 Td /F1 9.8 Tf [(Email: mountsa@who.int; Telephone: +41227911062)] TJ ET BT 26.250 378.977 Td /F1 9.8 Tf [(The opinions expressed in this article are those of the authors and members of the working group and do not )] TJ ET BT 26.250 363.533 Td /F1 9.8 Tf [(necessarily reflect those of the institutions or organizations with which they are affiliated.)] TJ ET BT 26.250 322.738 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 291.581 Td /F1 9.8 Tf [(1.)] TJ ET BT 39.302 291.581 Td /F1 9.8 Tf [(Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a )] TJ ET BT 26.250 276.137 Td /F1 9.8 Tf [(man with pneumonia in Saudi Arabia. N Engl J Med. 2012 Nov 8;367\(19\):1814-20. PubMed PMID:23075143.)] TJ ET BT 26.250 253.193 Td /F1 9.8 Tf [(2.)] TJ ET BT 39.302 253.193 Td /F1 9.8 Tf [(Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C, Hoschler K, Brown K, Galiano M, Myers R, )] TJ ET BT 26.250 237.749 Td /F1 9.8 Tf [(Pebody RG, Green HK, Boddington NL, Gopal R, Price N, Newsholme W, Drosten C, Fouchier RA, Zambon M. )] TJ ET BT 26.250 222.305 Td /F1 9.8 Tf [(Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from )] TJ ET BT 26.250 206.861 Td /F1 9.8 Tf [(the Middle East, September 2012. Euro Surveill. 2012 Oct 4;17\(40\):20290. PubMed PMID:23078800.)] TJ ET BT 26.250 183.917 Td /F1 9.8 Tf [(3.)] TJ ET BT 39.302 183.917 Td /F1 9.8 Tf [(Hijawi B, Abdallat M, Sayaydeh A, Alqasrawi S, Haddadin A, Jaarour N, Alsheikh S, Alsanouri T. Novel )] TJ ET BT 26.250 168.473 Td /F1 9.8 Tf [(coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation. 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PubMed PMID:23718156.)] TJ ET Q q 15.000 55.764 577.500 721.236 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(Institut Pasteur, CNRS)] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(University Paris Diderot Sorbonne Paris Cit)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(Paris, France)] TJ ET BT 26.250 695.813 Td /F4 9.8 Tf [(Maria D. 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Mounts)] TJ ET BT 26.250 424.865 Td /F1 9.8 Tf [(Global Influenza Programme, World Health Organization, Geneva, Switzerland)] TJ ET BT 26.250 401.921 Td /F1 9.8 Tf [(Email: mountsa@who.int; Telephone: +41227911062)] TJ ET BT 26.250 378.977 Td /F1 9.8 Tf [(The opinions expressed in this article are those of the authors and members of the working group and do not )] TJ ET BT 26.250 363.533 Td /F1 9.8 Tf [(necessarily reflect those of the institutions or organizations with which they are affiliated.)] TJ ET BT 26.250 322.738 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 291.581 Td /F1 9.8 Tf [(1.)] TJ ET BT 39.302 291.581 Td /F1 9.8 Tf [(Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a )] TJ ET BT 26.250 276.137 Td /F1 9.8 Tf [(man with pneumonia in Saudi Arabia. N Engl J Med. 2012 Nov 8;367\(19\):1814-20. PubMed PMID:23075143.)] TJ ET BT 26.250 253.193 Td /F1 9.8 Tf [(2.)] TJ ET BT 39.302 253.193 Td /F1 9.8 Tf [(Bermingham A, Chand MA, Brown CS, Aarons E, Tong C, Langrish C, Hoschler K, Brown K, Galiano M, Myers R, )] TJ ET BT 26.250 237.749 Td /F1 9.8 Tf [(Pebody RG, Green HK, Boddington NL, Gopal R, Price N, Newsholme W, Drosten C, Fouchier RA, Zambon M. )] TJ ET BT 26.250 222.305 Td /F1 9.8 Tf [(Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from )] TJ ET BT 26.250 206.861 Td /F1 9.8 Tf [(the Middle East, September 2012. Euro Surveill. 2012 Oct 4;17\(40\):20290. PubMed PMID:23078800.)] TJ ET BT 26.250 183.917 Td /F1 9.8 Tf [(3.)] TJ ET BT 39.302 183.917 Td /F1 9.8 Tf [(Hijawi B, Abdallat M, Sayaydeh A, Alqasrawi S, Haddadin A, Jaarour N, Alsheikh S, Alsanouri T. Novel )] TJ ET BT 26.250 168.473 Td /F1 9.8 Tf [(coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation. East )] TJ ET BT 26.250 153.029 Td /F1 9.8 Tf [(Mediterr Health J. 2013;19 Suppl 1:S12-8. PubMed PMID:23888790.)] TJ ET BT 26.250 130.085 Td /F1 9.8 Tf [(4.)] TJ ET BT 39.302 130.085 Td /F1 9.8 Tf [(WHO \(2012-2013\) World Health Organization. Global Alert and Response. Coronavirus Infections. Available )] TJ ET BT 26.250 114.641 Td /F1 9.8 Tf [(at: http://wwwwhoint/csr/disease/coronavirus_infections/en/)] TJ ET 0.267 0.267 0.267 rg BT 26.250 103.632 Td /F1 7.5 Tf [(REFERENCE LINK)] TJ ET 0.271 0.267 0.267 rg BT 26.250 81.797 Td /F1 9.8 Tf [(5.)] TJ ET BT 39.302 81.797 Td /F1 9.8 Tf [(Memish ZA, Zumla AI, Al-Hakeem RF, Al-Rabeeah AA, Stephens GM. Family cluster of Middle East respiratory )] TJ ET BT 26.250 66.353 Td /F1 9.8 Tf [(syndrome coronavirus infections. N Engl J Med. 2013 Jun 27;368\(26\):2487-94. PubMed PMID:23718156.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(24)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1342 0 obj << /Type /Annot /Subtype /Link /A 1343 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 102.7320 90.0975 112.6320 ] >> endobj 1343 0 obj << /Type /Action /S /URI /URI (http://wwwwhoint/csr/disease/coronavirus_infections/en/) >> endobj 1344 0 obj << /Type /Annot /Subtype /Link /A 1345 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 102.7320 90.0975 112.6320 ] >> endobj 1345 0 obj << /Type /Action /S /URI /URI (http://wwwwhoint/csr/disease/coronavirus_infections/en/) >> endobj 1346 0 obj << /Type /Annot /Subtype /Link /A 1347 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 102.7320 90.0975 112.6320 ] >> endobj 1347 0 obj << /Type /Action /S /URI /URI (http://wwwwhoint/csr/disease/coronavirus_infections/en/) >> endobj 1348 0 obj << /Type /Page /Parent 3 0 R /Contents 1349 0 R >> endobj 1349 0 obj << /Length 29694 >> stream 0.271 0.267 0.267 rg q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(6.)] TJ ET BT 39.302 757.145 Td /F1 9.8 Tf [(WHO \(2012-2013\) World Health Organization. Disease Outbreak News Novel Coronavirus. Available at: )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(http://wwwwhoint/csr/don/archive/disease/coronavirus_infections/en/indexhtml Last Accessed 22 October 2013.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(7.)] TJ ET BT 39.302 718.757 Td /F1 9.8 Tf [(World Health Organization \(2012\) Laboratory testing for novel coronavirus. Interim Recommendations, 21 )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(December 2012. Available at: )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf. Last )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 649.481 Td /F1 9.8 Tf [(8.)] TJ ET BT 39.302 649.481 Td /F1 9.8 Tf [(Saudi Arabia Ministry of Health \(2013\) Media Statements. Corona. 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PubMed PMID:23891402.)] TJ ET BT 26.250 526.373 Td /F1 9.8 Tf [(10.)] TJ ET BT 45.502 526.373 Td /F1 9.8 Tf [(Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Alabdullatif ZN, Assad M, Almulhim A, )] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZA. )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013 Aug 1;369\(5\):407-16. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(PubMed PMID:23782161.)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(11.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Guery B, Poissy J, el Mansouf L, Sjourn C, Ettahar N, Lemaire X, Vuotto F, Goffard A, Behillil S, Enouf V, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Caro V, Mailles A, Che D, Manuguerra JC, Mathieu D, Fontanet A, van der Werf S. Clinical features and viral )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(transmission. Lancet. 2013 Jun 29;381\(9885\):2265-72. PubMed PMID:23727167.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(12.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Kingdom, February 2013. Euro Surveill. 2013 Mar 14;18\(11\):20427. PubMed PMID:23517868.)] TJ ET BT 26.250 349.433 Td /F1 9.8 Tf [(13.)] TJ ET BT 45.502 349.433 Td /F1 9.8 Tf [(Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, )] TJ ET BT 26.250 333.989 Td /F1 9.8 Tf [(Junglen S, Mller MA, Haas W, Guberina H, Rhnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, )] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(Graf P, Bonin F, Rambaut A, Wendtner CM. Clinical features and virological analysis of a case of Middle East )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013 Sep;13\(9\):745-51. PubMed PMID:23782859.)] TJ ET BT 26.250 280.157 Td /F1 9.8 Tf [(14.)] TJ ET BT 45.502 280.157 Td /F1 9.8 Tf [(Chan KH, Chan JF, Tse H, Chen H, Lau CC, Cai JP, Tsang AK, Xiao X, To KK, Lau SK, Woo PC, Zheng BJ, Wang )] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(M, Yuen KY. Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(coronavirus EMC \(2012\) by both immunofluorescent and neutralizing antibody tests. J Infect. 2013 )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(Aug;67\(2\):130-40. PubMed PMID:23583636.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(15.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Public Health England, ISARIC \(2013\) Treatment of MERS-CoV: Decision Support Tool. Clinical Decision )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Making Tool for Treatment of MERS-CoV v.1.0, 18 June, 2013. Available at: )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416, Last Accessed 22 October 2013.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(16.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(Meer Y, Brcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. MERS-coronavirus replication induces severe )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon- treatment. J Gen Virol. 2013 )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(Aug;94\(Pt 8\):1749-60. PubMed PMID:23620378.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(17.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, Yount BL, Graham RL, Baric RS, )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(Katze MG. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(important differences with SARS coronavirus. MBio. 2013 Apr 30;4\(3\):e00165-13. PubMed PMID:23631916.)] TJ ET Q q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(6.)] TJ ET BT 39.302 757.145 Td /F1 9.8 Tf [(WHO \(2012-2013\) World Health Organization. Disease Outbreak News Novel Coronavirus. Available at: )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(http://wwwwhoint/csr/don/archive/disease/coronavirus_infections/en/indexhtml Last Accessed 22 October 2013.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(7.)] TJ ET BT 39.302 718.757 Td /F1 9.8 Tf [(World Health Organization \(2012\) Laboratory testing for novel coronavirus. Interim Recommendations, 21 )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(December 2012. Available at: )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf. Last )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 649.481 Td /F1 9.8 Tf [(8.)] TJ ET BT 39.302 649.481 Td /F1 9.8 Tf [(Saudi Arabia Ministry of Health \(2013\) Media Statements. Corona. Available at: )] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(http://www.moh.gov.sa/en/HealthAwareness/Corona/Pages/PressStatements.aspx, last accessed 22 October )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(2013.)] TJ ET BT 26.250 595.649 Td /F1 9.8 Tf [(9.)] TJ ET BT 39.302 595.649 Td /F1 9.8 Tf [(Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, Flemban H, Al-Nassir WN, Balkhy )] TJ ET BT 26.250 580.205 Td /F1 9.8 Tf [(HH, Al-Hakeem RF, Makhdoom HQ, Zumla AI, Memish ZA. Epidemiological, demographic, and clinical )] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(descriptive study. Lancet Infect Dis. 2013 Sep;13\(9\):752-61. PubMed PMID:23891402.)] TJ ET BT 26.250 526.373 Td /F1 9.8 Tf [(10.)] TJ ET BT 45.502 526.373 Td /F1 9.8 Tf [(Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Alabdullatif ZN, Assad M, Almulhim A, )] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZA. )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013 Aug 1;369\(5\):407-16. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(PubMed PMID:23782161.)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(11.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Guery B, Poissy J, el Mansouf L, Sjourn C, Ettahar N, Lemaire X, Vuotto F, Goffard A, Behillil S, Enouf V, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Caro V, Mailles A, Che D, Manuguerra JC, Mathieu D, Fontanet A, van der Werf S. Clinical features and viral )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(transmission. Lancet. 2013 Jun 29;381\(9885\):2265-72. PubMed PMID:23727167.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(12.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Kingdom, February 2013. Euro Surveill. 2013 Mar 14;18\(11\):20427. PubMed PMID:23517868.)] TJ ET BT 26.250 349.433 Td /F1 9.8 Tf [(13.)] TJ ET BT 45.502 349.433 Td /F1 9.8 Tf [(Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, )] TJ ET BT 26.250 333.989 Td /F1 9.8 Tf [(Junglen S, Mller MA, Haas W, Guberina H, Rhnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, )] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(Graf P, Bonin F, Rambaut A, Wendtner CM. Clinical features and virological analysis of a case of Middle East )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013 Sep;13\(9\):745-51. PubMed PMID:23782859.)] TJ ET BT 26.250 280.157 Td /F1 9.8 Tf [(14.)] TJ ET BT 45.502 280.157 Td /F1 9.8 Tf [(Chan KH, Chan JF, Tse H, Chen H, Lau CC, Cai JP, Tsang AK, Xiao X, To KK, Lau SK, Woo PC, Zheng BJ, Wang )] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(M, Yuen KY. Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(coronavirus EMC \(2012\) by both immunofluorescent and neutralizing antibody tests. J Infect. 2013 )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(Aug;67\(2\):130-40. PubMed PMID:23583636.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(15.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Public Health England, ISARIC \(2013\) Treatment of MERS-CoV: Decision Support Tool. Clinical Decision )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Making Tool for Treatment of MERS-CoV v.1.0, 18 June, 2013. Available at: )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416, Last Accessed 22 October 2013.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(16.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(Meer Y, Brcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. MERS-coronavirus replication induces severe )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon- treatment. J Gen Virol. 2013 )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(Aug;94\(Pt 8\):1749-60. PubMed PMID:23620378.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(17.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, Yount BL, Graham RL, Baric RS, )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(Katze MG. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(important differences with SARS coronavirus. MBio. 2013 Apr 30;4\(3\):e00165-13. PubMed PMID:23631916.)] TJ ET Q q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(6.)] TJ ET BT 39.302 757.145 Td /F1 9.8 Tf [(WHO \(2012-2013\) World Health Organization. Disease Outbreak News Novel Coronavirus. Available at: )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(http://wwwwhoint/csr/don/archive/disease/coronavirus_infections/en/indexhtml Last Accessed 22 October 2013.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(7.)] TJ ET BT 39.302 718.757 Td /F1 9.8 Tf [(World Health Organization \(2012\) Laboratory testing for novel coronavirus. Interim Recommendations, 21 )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(December 2012. Available at: )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/LaboratoryTestingNovelCoronavirus_21Dec12.pdf. Last )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 649.481 Td /F1 9.8 Tf [(8.)] TJ ET BT 39.302 649.481 Td /F1 9.8 Tf [(Saudi Arabia Ministry of Health \(2013\) Media Statements. Corona. Available at: )] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(http://www.moh.gov.sa/en/HealthAwareness/Corona/Pages/PressStatements.aspx, last accessed 22 October )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(2013.)] TJ ET BT 26.250 595.649 Td /F1 9.8 Tf [(9.)] TJ ET BT 39.302 595.649 Td /F1 9.8 Tf [(Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, Flemban H, Al-Nassir WN, Balkhy )] TJ ET BT 26.250 580.205 Td /F1 9.8 Tf [(HH, Al-Hakeem RF, Makhdoom HQ, Zumla AI, Memish ZA. Epidemiological, demographic, and clinical )] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(descriptive study. Lancet Infect Dis. 2013 Sep;13\(9\):752-61. PubMed PMID:23891402.)] TJ ET BT 26.250 526.373 Td /F1 9.8 Tf [(10.)] TJ ET BT 45.502 526.373 Td /F1 9.8 Tf [(Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA, Cummings DA, Alabdullatif ZN, Assad M, Almulhim A, )] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(Makhdoom H, Madani H, Alhakeem R, Al-Tawfiq JA, Cotten M, Watson SJ, Kellam P, Zumla AI, Memish ZA. )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med. 2013 Aug 1;369\(5\):407-16. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(PubMed PMID:23782161.)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(11.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Guery B, Poissy J, el Mansouf L, Sjourn C, Ettahar N, Lemaire X, Vuotto F, Goffard A, Behillil S, Enouf V, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Caro V, Mailles A, Che D, Manuguerra JC, Mathieu D, Fontanet A, van der Werf S. Clinical features and viral )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(transmission. Lancet. 2013 Jun 29;381\(9885\):2265-72. PubMed PMID:23727167.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(12.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Kingdom, February 2013. Euro Surveill. 2013 Mar 14;18\(11\):20427. PubMed PMID:23517868.)] TJ ET BT 26.250 349.433 Td /F1 9.8 Tf [(13.)] TJ ET BT 45.502 349.433 Td /F1 9.8 Tf [(Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S, Guggemos W, Kallies R, Muth D, )] TJ ET BT 26.250 333.989 Td /F1 9.8 Tf [(Junglen S, Mller MA, Haas W, Guberina H, Rhnisch T, Schmid-Wendtner M, Aldabbagh S, Dittmer U, Gold H, )] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(Graf P, Bonin F, Rambaut A, Wendtner CM. Clinical features and virological analysis of a case of Middle East )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(respiratory syndrome coronavirus infection. Lancet Infect Dis. 2013 Sep;13\(9\):745-51. PubMed PMID:23782859.)] TJ ET BT 26.250 280.157 Td /F1 9.8 Tf [(14.)] TJ ET BT 45.502 280.157 Td /F1 9.8 Tf [(Chan KH, Chan JF, Tse H, Chen H, Lau CC, Cai JP, Tsang AK, Xiao X, To KK, Lau SK, Woo PC, Zheng BJ, Wang )] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(M, Yuen KY. Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(coronavirus EMC \(2012\) by both immunofluorescent and neutralizing antibody tests. J Infect. 2013 )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(Aug;67\(2\):130-40. PubMed PMID:23583636.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(15.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Public Health England, ISARIC \(2013\) Treatment of MERS-CoV: Decision Support Tool. Clinical Decision )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Making Tool for Treatment of MERS-CoV v.1.0, 18 June, 2013. Available at: )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317139281416, Last Accessed 22 October 2013.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(16.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(Meer Y, Brcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. MERS-coronavirus replication induces severe )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon- treatment. J Gen Virol. 2013 )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(Aug;94\(Pt 8\):1749-60. PubMed PMID:23620378.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(17.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, Yount BL, Graham RL, Baric RS, )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(Katze MG. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(important differences with SARS coronavirus. MBio. 2013 Apr 30;4\(3\):e00165-13. PubMed PMID:23631916.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(25)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1350 0 obj << /Type /Page /Parent 3 0 R /Contents 1351 0 R >> endobj 1351 0 obj << /Length 30948 >> stream 0.271 0.267 0.267 rg q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(18.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel  coronavirus )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(replication by a combination of interferon-2b and ribavirin. Sci Rep. 2013;3:1686. PubMed PMID:23594967.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(19.)] TJ ET BT 45.502 718.757 Td /F1 9.8 Tf [(Mailles A, Blanckaert K, Chaud P, van der Werf S, Lina B, Caro V, Campese C, Gury B, Prouvost H, Lemaire )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(X, Paty MC, Haeghebaert S, Antoine D, Ettahar N, Noel H, Behillil S, Hendricx S, Manuguerra JC, Enouf V, La )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Ruche G, Semaille C, Coignard B, Lvy-Bruhl D, Weber F, Saura C, Che D. First cases of Middle East Respiratory )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Syndrome Coronavirus \(MERS-CoV\) infections in France, investigations and implications for the prevention of )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(human-to-human transmission, France, May 2013. Euro Surveill. 2013 Jun 13;18\(24\). PubMed PMID:23787161.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(20.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Puzelli S, Azzi A, Santini MG, Di Martino A, Facchini M, Castrucci MR, Meola M, Arvia R, Corcioli F, Pierucci F, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Baretti S, Bartoloni A, Bartolozzi D, de Martino M, Galli L, Pompa MG, Rezza G, Balocchini E, Donatelli I. )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Investigation of an imported case of Middle East Respiratory Syndrome Coronavirus \(MERS-CoV\) infection in )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(Florence, Italy, May to June 2013. Euro Surveill. 2013 Aug 22;18\(34\). PubMed PMID:23987829.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(21.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(WHO \(2013\) World Health Organization: MERS-CoV summary and literature update  as of 20 June 2013. )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(Available at: http://www.who.int/csr/disease/coronavirus_infections/update_20130620/en/index.html. Last )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(22.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Cauchemez S, Fraser C, Van Kerkhove MD, Donnelly CA, Riley S, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus: Quantifying the extent of the epidemic, surveillance biases and transmissibility thus far. The )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(Lancet Infectious Diseases, Early Online Publication, 13 November 2013 doi:10.1016/S1473-3099\(13\)70304-9)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(23.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Buchholz U, Mller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Bonin F, Drosten C, Schweiger B, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Wolff T, Muth D, Meyer B, Buda S, Krause G, Schaade L, Haas W. Contact investigation of a case of human novel )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill. 2013 Feb 21;18\(8\). )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(PubMed PMID:23449231.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(24.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Pebody RG, Chand MA, Thomas HL, Green HK, Boddington NL, Carvalho C, Brown CS, Anderson SR, Rooney )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(C, Crawley-Boevey E, Irwin DJ, Aarons E, Tong C, Newsholme W, Price N, Langrish C, Tucker D, Zhao H, Phin N, )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(Crofts J, Bermingham A, Gilgunn-Jones E, Brown KE, Evans B, Catchpole M, Watson JM. The United Kingdom )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(public health response to an imported laboratory confirmed case of a novel coronavirus in September 2012. )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(Euro Surveill. 2012 Oct 4;17\(40\):20292. PubMed PMID:23078799.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(25.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Memish ZA, Alhakeem R, Stephens GM. Saudi Arabia and the emergence of a novel coronavirus. East )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(Mediterr Health J. 2013;19 Suppl 1:S7-11. PubMed PMID:23888789.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(26.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(estimation of pandemic risk. Lancet. 2013 Aug 24;382\(9893\):694-9. PubMed PMID:23831141.)] TJ ET BT 26.250 226.325 Td /F1 9.8 Tf [(27.)] TJ ET BT 45.502 226.325 Td /F1 9.8 Tf [(Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani )] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(H, Alrabiah FA, Hajjar SA, Al-Nassir WN, Albarrak A, Flemban H, Balkhy HH, Alsubaie S, Palser AL, Gall A, )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Bashford-Rogers R, Rambaut A, Zumla AI, Memish ZA. Transmission and evolution of the Middle East respiratory )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Lancet. 2013 Sep 19. PubMed )] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(PMID:24055451.)] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(28.)] TJ ET BT 45.502 141.605 Td /F1 9.8 Tf [(van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(Gorbalenya AE, Snijder EJ, Fouchier RA. Genomic characterization of a newly discovered coronavirus associated )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(with acute respiratory distress syndrome in humans. MBio. 2012 Nov 20;3\(6\). PubMed PMID:23170002.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(29.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Pybus OG, Rambaut A, Guan Y, Pillay D, Kellam )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(P, Nastouli E. Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(Infect Dis. 2013 May;19\(5\):736-42B. PubMed PMID:23693015.)] TJ ET Q q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(18.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel  coronavirus )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(replication by a combination of interferon-2b and ribavirin. Sci Rep. 2013;3:1686. PubMed PMID:23594967.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(19.)] TJ ET BT 45.502 718.757 Td /F1 9.8 Tf [(Mailles A, Blanckaert K, Chaud P, van der Werf S, Lina B, Caro V, Campese C, Gury B, Prouvost H, Lemaire )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(X, Paty MC, Haeghebaert S, Antoine D, Ettahar N, Noel H, Behillil S, Hendricx S, Manuguerra JC, Enouf V, La )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Ruche G, Semaille C, Coignard B, Lvy-Bruhl D, Weber F, Saura C, Che D. First cases of Middle East Respiratory )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Syndrome Coronavirus \(MERS-CoV\) infections in France, investigations and implications for the prevention of )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(human-to-human transmission, France, May 2013. Euro Surveill. 2013 Jun 13;18\(24\). PubMed PMID:23787161.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(20.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Puzelli S, Azzi A, Santini MG, Di Martino A, Facchini M, Castrucci MR, Meola M, Arvia R, Corcioli F, Pierucci F, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Baretti S, Bartoloni A, Bartolozzi D, de Martino M, Galli L, Pompa MG, Rezza G, Balocchini E, Donatelli I. )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Investigation of an imported case of Middle East Respiratory Syndrome Coronavirus \(MERS-CoV\) infection in )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(Florence, Italy, May to June 2013. Euro Surveill. 2013 Aug 22;18\(34\). PubMed PMID:23987829.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(21.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(WHO \(2013\) World Health Organization: MERS-CoV summary and literature update  as of 20 June 2013. )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(Available at: http://www.who.int/csr/disease/coronavirus_infections/update_20130620/en/index.html. Last )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(22.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Cauchemez S, Fraser C, Van Kerkhove MD, Donnelly CA, Riley S, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus: Quantifying the extent of the epidemic, surveillance biases and transmissibility thus far. The )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(Lancet Infectious Diseases, Early Online Publication, 13 November 2013 doi:10.1016/S1473-3099\(13\)70304-9)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(23.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Buchholz U, Mller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Bonin F, Drosten C, Schweiger B, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Wolff T, Muth D, Meyer B, Buda S, Krause G, Schaade L, Haas W. Contact investigation of a case of human novel )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill. 2013 Feb 21;18\(8\). )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(PubMed PMID:23449231.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(24.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Pebody RG, Chand MA, Thomas HL, Green HK, Boddington NL, Carvalho C, Brown CS, Anderson SR, Rooney )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(C, Crawley-Boevey E, Irwin DJ, Aarons E, Tong C, Newsholme W, Price N, Langrish C, Tucker D, Zhao H, Phin N, )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(Crofts J, Bermingham A, Gilgunn-Jones E, Brown KE, Evans B, Catchpole M, Watson JM. The United Kingdom )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(public health response to an imported laboratory confirmed case of a novel coronavirus in September 2012. )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(Euro Surveill. 2012 Oct 4;17\(40\):20292. PubMed PMID:23078799.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(25.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Memish ZA, Alhakeem R, Stephens GM. Saudi Arabia and the emergence of a novel coronavirus. East )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(Mediterr Health J. 2013;19 Suppl 1:S7-11. PubMed PMID:23888789.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(26.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(estimation of pandemic risk. Lancet. 2013 Aug 24;382\(9893\):694-9. PubMed PMID:23831141.)] TJ ET BT 26.250 226.325 Td /F1 9.8 Tf [(27.)] TJ ET BT 45.502 226.325 Td /F1 9.8 Tf [(Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani )] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(H, Alrabiah FA, Hajjar SA, Al-Nassir WN, Albarrak A, Flemban H, Balkhy HH, Alsubaie S, Palser AL, Gall A, )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Bashford-Rogers R, Rambaut A, Zumla AI, Memish ZA. Transmission and evolution of the Middle East respiratory )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Lancet. 2013 Sep 19. PubMed )] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(PMID:24055451.)] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(28.)] TJ ET BT 45.502 141.605 Td /F1 9.8 Tf [(van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(Gorbalenya AE, Snijder EJ, Fouchier RA. Genomic characterization of a newly discovered coronavirus associated )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(with acute respiratory distress syndrome in humans. MBio. 2012 Nov 20;3\(6\). PubMed PMID:23170002.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(29.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Pybus OG, Rambaut A, Guan Y, Pillay D, Kellam )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(P, Nastouli E. Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(Infect Dis. 2013 May;19\(5\):736-42B. PubMed PMID:23693015.)] TJ ET Q q 15.000 46.296 577.500 730.704 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(18.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H. Inhibition of novel  coronavirus )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(replication by a combination of interferon-2b and ribavirin. Sci Rep. 2013;3:1686. PubMed PMID:23594967.)] TJ ET BT 26.250 718.757 Td /F1 9.8 Tf [(19.)] TJ ET BT 45.502 718.757 Td /F1 9.8 Tf [(Mailles A, Blanckaert K, Chaud P, van der Werf S, Lina B, Caro V, Campese C, Gury B, Prouvost H, Lemaire )] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(X, Paty MC, Haeghebaert S, Antoine D, Ettahar N, Noel H, Behillil S, Hendricx S, Manuguerra JC, Enouf V, La )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Ruche G, Semaille C, Coignard B, Lvy-Bruhl D, Weber F, Saura C, Che D. First cases of Middle East Respiratory )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Syndrome Coronavirus \(MERS-CoV\) infections in France, investigations and implications for the prevention of )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(human-to-human transmission, France, May 2013. Euro Surveill. 2013 Jun 13;18\(24\). PubMed PMID:23787161.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(20.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Puzelli S, Azzi A, Santini MG, Di Martino A, Facchini M, Castrucci MR, Meola M, Arvia R, Corcioli F, Pierucci F, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Baretti S, Bartoloni A, Bartolozzi D, de Martino M, Galli L, Pompa MG, Rezza G, Balocchini E, Donatelli I. )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Investigation of an imported case of Middle East Respiratory Syndrome Coronavirus \(MERS-CoV\) infection in )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(Florence, Italy, May to June 2013. Euro Surveill. 2013 Aug 22;18\(34\). PubMed PMID:23987829.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(21.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(WHO \(2013\) World Health Organization: MERS-CoV summary and literature update  as of 20 June 2013. )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(Available at: http://www.who.int/csr/disease/coronavirus_infections/update_20130620/en/index.html. Last )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(22.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Cauchemez S, Fraser C, Van Kerkhove MD, Donnelly CA, Riley S, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus: Quantifying the extent of the epidemic, surveillance biases and transmissibility thus far. The )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(Lancet Infectious Diseases, Early Online Publication, 13 November 2013 doi:10.1016/S1473-3099\(13\)70304-9)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(23.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Buchholz U, Mller MA, Nitsche A, Sanewski A, Wevering N, Bauer-Balci T, Bonin F, Drosten C, Schweiger B, )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(Wolff T, Muth D, Meyer B, Buda S, Krause G, Schaade L, Haas W. Contact investigation of a case of human novel )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(coronavirus infection treated in a German hospital, October-November 2012. Euro Surveill. 2013 Feb 21;18\(8\). )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(PubMed PMID:23449231.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(24.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Pebody RG, Chand MA, Thomas HL, Green HK, Boddington NL, Carvalho C, Brown CS, Anderson SR, Rooney )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(C, Crawley-Boevey E, Irwin DJ, Aarons E, Tong C, Newsholme W, Price N, Langrish C, Tucker D, Zhao H, Phin N, )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(Crofts J, Bermingham A, Gilgunn-Jones E, Brown KE, Evans B, Catchpole M, Watson JM. The United Kingdom )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(public health response to an imported laboratory confirmed case of a novel coronavirus in September 2012. )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(Euro Surveill. 2012 Oct 4;17\(40\):20292. PubMed PMID:23078799.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(25.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Memish ZA, Alhakeem R, Stephens GM. Saudi Arabia and the emergence of a novel coronavirus. East )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(Mediterr Health J. 2013;19 Suppl 1:S7-11. PubMed PMID:23888789.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(26.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Breban R, Riou J, Fontanet A. Interhuman transmissibility of Middle East respiratory syndrome coronavirus: )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(estimation of pandemic risk. Lancet. 2013 Aug 24;382\(9893\):694-9. PubMed PMID:23831141.)] TJ ET BT 26.250 226.325 Td /F1 9.8 Tf [(27.)] TJ ET BT 45.502 226.325 Td /F1 9.8 Tf [(Cotten M, Watson SJ, Kellam P, Al-Rabeeah AA, Makhdoom HQ, Assiri A, Al-Tawfiq JA, Alhakeem RF, Madani )] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(H, Alrabiah FA, Hajjar SA, Al-Nassir WN, Albarrak A, Flemban H, Balkhy HH, Alsubaie S, Palser AL, Gall A, )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(Bashford-Rogers R, Rambaut A, Zumla AI, Memish ZA. Transmission and evolution of the Middle East respiratory )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(syndrome coronavirus in Saudi Arabia: a descriptive genomic study. Lancet. 2013 Sep 19. PubMed )] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(PMID:24055451.)] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(28.)] TJ ET BT 45.502 141.605 Td /F1 9.8 Tf [(van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus AD, Haagmans BL, )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(Gorbalenya AE, Snijder EJ, Fouchier RA. Genomic characterization of a newly discovered coronavirus associated )] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(with acute respiratory distress syndrome in humans. MBio. 2012 Nov 20;3\(6\). PubMed PMID:23170002.)] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(29.)] TJ ET BT 45.502 87.773 Td /F1 9.8 Tf [(Cotten M, Lam TT, Watson SJ, Palser AL, Petrova V, Grant P, Pybus OG, Rambaut A, Guan Y, Pillay D, Kellam )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(P, Nastouli E. Full-genome deep sequencing and phylogenetic analysis of novel human betacoronavirus. Emerg )] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(Infect Dis. 2013 May;19\(5\):736-42B. PubMed PMID:23693015.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(26)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1352 0 obj << /Type /Page /Parent 3 0 R /Contents 1353 0 R >> endobj 1353 0 obj << /Length 30216 >> stream 0.271 0.267 0.267 rg q 15.000 53.796 577.500 723.204 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(30.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Badu EK, Anti P, Agbenyega O, Meyer B, )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Oppong S, Sarkodie YA, Kalko EK, Lina PH, Godlevska EV, Reusken C, Seebens A, Gloza-Rausch F, Vallo P, )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Tschapka M, Drosten C, Drexler JF. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(Europe. Emerg Infect Dis. 2013 Mar;19\(3\):456-9. PubMed PMID:23622767.)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(31.)] TJ ET BT 45.502 687.869 Td /F1 9.8 Tf [(Wacharapluesadee S, Sintunawa C, Kaewpom T, Khongnomnan K, Olival KJ, Epstein JH, Rodpan A, Sangsri P, )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Intarut N, Chindamporn A, Suksawa K, Hemachudha T. Group C betacoronavirus in bat guano fertilizer, Thailand. )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(Emerg Infect Dis. 2013 Aug;19\(8\):1349-51. PubMed PMID:23880503.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(32.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Anthony SJ, Ojeda-Flores R, Rico-Chvez O, Navarrete-Macias I, Zambrana-Torrelio CM, Rostal MK, Epstein )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(JH, Tipps T, Liang E, Sanchez-Leon M, Sotomayor-Bonilla J, Aguirre AA, vila-Flores R, Medelln RA, Goldstein T, )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Suzn G, Daszak P, Lipkin WI. Coronaviruses in bats from Mexico. J Gen Virol. 2013 May;94\(Pt 5\):1028-38. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23364191.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(33.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, Preiser )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(W. Close relative of human middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis. )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(2013 Oct;19\(10\):1697-9. PubMed PMID:24050621.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(34.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus in bats, Saudi Arabia. Emerg Infect Dis [Internet]. 2013 Nov [date cited]. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(http://dx.doi.org/10.3201/eid1911.131172)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(35.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Reusken CB, Haagmans BL, Mller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Vries LS, Corman )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(Bosch BJ, Rottier P, Osterhaus A, Gortzar-Schmidt C, Drosten C, Koopmans MP. Middle East respiratory )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. )] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Lancet Infect Dis. 2013 Oct;13\(10\):859-66. PubMed PMID:23933067.)] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(36.)] TJ ET BT 45.502 372.377 Td /F1 9.8 Tf [(Perera R, Wang P, Gomaa M, El-Shesheny R, Kandeil A, Bagato O, Siu L, Shehata M, Kayed A, Moatasim Y, Li )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(M, Poon L, Guan Y, Webby R, Ali M, Peiris J, Kayali G. Seroepidemiology for MERS coronavirus using )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(dromedary camels in Egypt, June 2013. Euro Surveill. 2013 Sep 5;18\(36\). PubMed PMID:24079378.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(37.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M, van Boheemen S, Gopal R, Ballhause )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(M, Bestebroer TM, Muth D, Mller MA, Drexler JF, Zambon M, Osterhaus AD, Fouchier RM, Drosten C. Detection )] TJ ET BT 26.250 272.213 Td /F1 9.8 Tf [(of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill. 2012 )] TJ ET BT 26.250 256.769 Td /F1 9.8 Tf [(Sep 27;17\(39\). PubMed PMID:23041020.)] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(38.)] TJ ET BT 45.502 233.825 Td /F1 9.8 Tf [(United States Centers for Disease Control and Prevention \(2013\) Interim Guidelines for Collecting, Handling, )] TJ ET BT 26.250 218.381 Td /F1 9.8 Tf [(and Testing Clinical Specimens from Patients Under Investigation \(PUIs\) for Middle East Respiratory Syndrome )] TJ ET BT 26.250 202.937 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\)  Version 2. Available at: http://www.cdc.gov/coronavirus/mers/guidelines-clinical-)] TJ ET BT 26.250 187.493 Td /F1 9.8 Tf [(specimens.html. Last Accessed 22 October 2013.)] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(39.)] TJ ET BT 45.502 164.549 Td /F1 9.8 Tf [(Corman VM, Mller MA, Costabel U, Timm J, Binger T, Meyer B, Kreher P, Lattwein E, Eschbach-Bludau M, )] TJ ET BT 26.250 149.105 Td /F1 9.8 Tf [(Nitsche A, Bleicker T, Landt O, Schweiger B, Drexler JF, Osterhaus AD, Haagmans BL, Dittmer U, Bonin F, Wolff )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(T, Drosten C. Assays for laboratory confirmation of novel human coronavirus \(hCoV-EMC\) infections. Euro )] TJ ET BT 26.250 118.217 Td /F1 9.8 Tf [(Surveill. 2012 Dec 6;17\(49\). PubMed PMID:23231891.)] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(40.)] TJ ET BT 45.502 95.273 Td /F1 9.8 Tf [(Raj VS, Mou H, Smits SL, Dekkers DH, Mller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor )] TJ ET BT 26.250 64.385 Td /F1 9.8 Tf [(for the emerging human coronavirus-EMC. Nature. 2013 Mar 14;495\(7440\):251-4. PubMed PMID:23486063.)] TJ ET Q q 15.000 53.796 577.500 723.204 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(30.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Badu EK, Anti P, Agbenyega O, Meyer B, )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Oppong S, Sarkodie YA, Kalko EK, Lina PH, Godlevska EV, Reusken C, Seebens A, Gloza-Rausch F, Vallo P, )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Tschapka M, Drosten C, Drexler JF. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(Europe. Emerg Infect Dis. 2013 Mar;19\(3\):456-9. PubMed PMID:23622767.)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(31.)] TJ ET BT 45.502 687.869 Td /F1 9.8 Tf [(Wacharapluesadee S, Sintunawa C, Kaewpom T, Khongnomnan K, Olival KJ, Epstein JH, Rodpan A, Sangsri P, )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Intarut N, Chindamporn A, Suksawa K, Hemachudha T. Group C betacoronavirus in bat guano fertilizer, Thailand. )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(Emerg Infect Dis. 2013 Aug;19\(8\):1349-51. PubMed PMID:23880503.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(32.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Anthony SJ, Ojeda-Flores R, Rico-Chvez O, Navarrete-Macias I, Zambrana-Torrelio CM, Rostal MK, Epstein )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(JH, Tipps T, Liang E, Sanchez-Leon M, Sotomayor-Bonilla J, Aguirre AA, vila-Flores R, Medelln RA, Goldstein T, )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Suzn G, Daszak P, Lipkin WI. Coronaviruses in bats from Mexico. J Gen Virol. 2013 May;94\(Pt 5\):1028-38. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23364191.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(33.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, Preiser )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(W. Close relative of human middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis. )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(2013 Oct;19\(10\):1697-9. PubMed PMID:24050621.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(34.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus in bats, Saudi Arabia. Emerg Infect Dis [Internet]. 2013 Nov [date cited]. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(http://dx.doi.org/10.3201/eid1911.131172)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(35.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Reusken CB, Haagmans BL, Mller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Vries LS, Corman )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(Bosch BJ, Rottier P, Osterhaus A, Gortzar-Schmidt C, Drosten C, Koopmans MP. Middle East respiratory )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. )] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Lancet Infect Dis. 2013 Oct;13\(10\):859-66. PubMed PMID:23933067.)] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(36.)] TJ ET BT 45.502 372.377 Td /F1 9.8 Tf [(Perera R, Wang P, Gomaa M, El-Shesheny R, Kandeil A, Bagato O, Siu L, Shehata M, Kayed A, Moatasim Y, Li )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(M, Poon L, Guan Y, Webby R, Ali M, Peiris J, Kayali G. Seroepidemiology for MERS coronavirus using )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(dromedary camels in Egypt, June 2013. Euro Surveill. 2013 Sep 5;18\(36\). PubMed PMID:24079378.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(37.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M, van Boheemen S, Gopal R, Ballhause )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(M, Bestebroer TM, Muth D, Mller MA, Drexler JF, Zambon M, Osterhaus AD, Fouchier RM, Drosten C. Detection )] TJ ET BT 26.250 272.213 Td /F1 9.8 Tf [(of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill. 2012 )] TJ ET BT 26.250 256.769 Td /F1 9.8 Tf [(Sep 27;17\(39\). PubMed PMID:23041020.)] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(38.)] TJ ET BT 45.502 233.825 Td /F1 9.8 Tf [(United States Centers for Disease Control and Prevention \(2013\) Interim Guidelines for Collecting, Handling, )] TJ ET BT 26.250 218.381 Td /F1 9.8 Tf [(and Testing Clinical Specimens from Patients Under Investigation \(PUIs\) for Middle East Respiratory Syndrome )] TJ ET BT 26.250 202.937 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\)  Version 2. Available at: http://www.cdc.gov/coronavirus/mers/guidelines-clinical-)] TJ ET BT 26.250 187.493 Td /F1 9.8 Tf [(specimens.html. Last Accessed 22 October 2013.)] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(39.)] TJ ET BT 45.502 164.549 Td /F1 9.8 Tf [(Corman VM, Mller MA, Costabel U, Timm J, Binger T, Meyer B, Kreher P, Lattwein E, Eschbach-Bludau M, )] TJ ET BT 26.250 149.105 Td /F1 9.8 Tf [(Nitsche A, Bleicker T, Landt O, Schweiger B, Drexler JF, Osterhaus AD, Haagmans BL, Dittmer U, Bonin F, Wolff )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(T, Drosten C. Assays for laboratory confirmation of novel human coronavirus \(hCoV-EMC\) infections. Euro )] TJ ET BT 26.250 118.217 Td /F1 9.8 Tf [(Surveill. 2012 Dec 6;17\(49\). PubMed PMID:23231891.)] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(40.)] TJ ET BT 45.502 95.273 Td /F1 9.8 Tf [(Raj VS, Mou H, Smits SL, Dekkers DH, Mller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor )] TJ ET BT 26.250 64.385 Td /F1 9.8 Tf [(for the emerging human coronavirus-EMC. Nature. 2013 Mar 14;495\(7440\):251-4. PubMed PMID:23486063.)] TJ ET Q q 15.000 53.796 577.500 723.204 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(30.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Annan A, Baldwin HJ, Corman VM, Klose SM, Owusu M, Nkrumah EE, Badu EK, Anti P, Agbenyega O, Meyer B, )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Oppong S, Sarkodie YA, Kalko EK, Lina PH, Godlevska EV, Reusken C, Seebens A, Gloza-Rausch F, Vallo P, )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Tschapka M, Drosten C, Drexler JF. Human betacoronavirus 2c EMC/2012-related viruses in bats, Ghana and )] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(Europe. Emerg Infect Dis. 2013 Mar;19\(3\):456-9. PubMed PMID:23622767.)] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(31.)] TJ ET BT 45.502 687.869 Td /F1 9.8 Tf [(Wacharapluesadee S, Sintunawa C, Kaewpom T, Khongnomnan K, Olival KJ, Epstein JH, Rodpan A, Sangsri P, )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Intarut N, Chindamporn A, Suksawa K, Hemachudha T. Group C betacoronavirus in bat guano fertilizer, Thailand. )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(Emerg Infect Dis. 2013 Aug;19\(8\):1349-51. PubMed PMID:23880503.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(32.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Anthony SJ, Ojeda-Flores R, Rico-Chvez O, Navarrete-Macias I, Zambrana-Torrelio CM, Rostal MK, Epstein )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(JH, Tipps T, Liang E, Sanchez-Leon M, Sotomayor-Bonilla J, Aguirre AA, vila-Flores R, Medelln RA, Goldstein T, )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(Suzn G, Daszak P, Lipkin WI. Coronaviruses in bats from Mexico. J Gen Virol. 2013 May;94\(Pt 5\):1028-38. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23364191.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(33.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, Preiser )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(W. Close relative of human middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis. )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(2013 Oct;19\(10\):1697-9. PubMed PMID:24050621.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(34.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, et al. Middle East respiratory syndrome )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(coronavirus in bats, Saudi Arabia. Emerg Infect Dis [Internet]. 2013 Nov [date cited]. )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(http://dx.doi.org/10.3201/eid1911.131172)] TJ ET BT 26.250 457.097 Td /F1 9.8 Tf [(35.)] TJ ET BT 45.502 457.097 Td /F1 9.8 Tf [(Reusken CB, Haagmans BL, Mller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Vries LS, Corman )] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(Bosch BJ, Rottier P, Osterhaus A, Gortzar-Schmidt C, Drosten C, Koopmans MP. Middle East respiratory )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. )] TJ ET BT 26.250 395.321 Td /F1 9.8 Tf [(Lancet Infect Dis. 2013 Oct;13\(10\):859-66. PubMed PMID:23933067.)] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(36.)] TJ ET BT 45.502 372.377 Td /F1 9.8 Tf [(Perera R, Wang P, Gomaa M, El-Shesheny R, Kandeil A, Bagato O, Siu L, Shehata M, Kayed A, Moatasim Y, Li )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(M, Poon L, Guan Y, Webby R, Ali M, Peiris J, Kayali G. Seroepidemiology for MERS coronavirus using )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in )] TJ ET BT 26.250 326.045 Td /F1 9.8 Tf [(dromedary camels in Egypt, June 2013. Euro Surveill. 2013 Sep 5;18\(36\). PubMed PMID:24079378.)] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(37.)] TJ ET BT 45.502 303.101 Td /F1 9.8 Tf [(Corman VM, Eckerle I, Bleicker T, Zaki A, Landt O, Eschbach-Bludau M, van Boheemen S, Gopal R, Ballhause )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(M, Bestebroer TM, Muth D, Mller MA, Drexler JF, Zambon M, Osterhaus AD, Fouchier RM, Drosten C. Detection )] TJ ET BT 26.250 272.213 Td /F1 9.8 Tf [(of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro Surveill. 2012 )] TJ ET BT 26.250 256.769 Td /F1 9.8 Tf [(Sep 27;17\(39\). PubMed PMID:23041020.)] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(38.)] TJ ET BT 45.502 233.825 Td /F1 9.8 Tf [(United States Centers for Disease Control and Prevention \(2013\) Interim Guidelines for Collecting, Handling, )] TJ ET BT 26.250 218.381 Td /F1 9.8 Tf [(and Testing Clinical Specimens from Patients Under Investigation \(PUIs\) for Middle East Respiratory Syndrome )] TJ ET BT 26.250 202.937 Td /F1 9.8 Tf [(Coronavirus \(MERS-CoV\)  Version 2. Available at: http://www.cdc.gov/coronavirus/mers/guidelines-clinical-)] TJ ET BT 26.250 187.493 Td /F1 9.8 Tf [(specimens.html. Last Accessed 22 October 2013.)] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(39.)] TJ ET BT 45.502 164.549 Td /F1 9.8 Tf [(Corman VM, Mller MA, Costabel U, Timm J, Binger T, Meyer B, Kreher P, Lattwein E, Eschbach-Bludau M, )] TJ ET BT 26.250 149.105 Td /F1 9.8 Tf [(Nitsche A, Bleicker T, Landt O, Schweiger B, Drexler JF, Osterhaus AD, Haagmans BL, Dittmer U, Bonin F, Wolff )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(T, Drosten C. Assays for laboratory confirmation of novel human coronavirus \(hCoV-EMC\) infections. Euro )] TJ ET BT 26.250 118.217 Td /F1 9.8 Tf [(Surveill. 2012 Dec 6;17\(49\). PubMed PMID:23231891.)] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(40.)] TJ ET BT 45.502 95.273 Td /F1 9.8 Tf [(Raj VS, Mou H, Smits SL, Dekkers DH, Mller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor )] TJ ET BT 26.250 64.385 Td /F1 9.8 Tf [(for the emerging human coronavirus-EMC. Nature. 2013 Mar 14;495\(7440\):251-4. PubMed PMID:23486063.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(27)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1354 0 obj << /Type /Page /Parent 3 0 R /Contents 1355 0 R >> endobj 1355 0 obj << /Length 30696 >> stream 0.271 0.267 0.267 rg q 15.000 30.852 577.500 746.148 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(41.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF. )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013 )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Aug 8;500\(7461\):227-31. PubMed PMID:23831647.)] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(42.)] TJ ET BT 45.502 703.313 Td /F1 9.8 Tf [(Mller MA, Raj VS, Muth D, Meyer B, Kallies S, Smits SL, Wollny R, Bestebroer TM, Specht S, Suliman T, )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Zimmermann K, Binger T, Eckerle I, Tschapka M, Zaki AM, Osterhaus AD, Fouchier RA, Haagmans BL, Drosten C. )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(capability in mammalian cell lines. MBio. 2012 Dec 11;3\(6\). PubMed PMID:23232719.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(43.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Chan JF, Chan KH, Choi GK, To KK, Tse H, Cai JP, Yeung ML, Cheng VC, Chen H, Che XY, Lau SK, Woo PC, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Yuen KY. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(implications for disease pathogenesis and clinical manifestation. J Infect Dis. 2013 Jun 1;207\(11\):1743-52. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23532101.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(44.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Lambeir AM, Durinx C, Scharp S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003 )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(Jun;40\(3\):209-94. PubMed PMID:12892317.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(45.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krmer-Khl A, Welsch K, Winkler M, Meyer B, Drosten C, )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Dittmer U, von Hahn T, Simmons G, Hofmann H, Phlmann S. The spike protein of the emerging betacoronavirus )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing )] TJ ET BT 26.250 464.597 Td /F1 9.8 Tf [(antibodies. J Virol. 2013 May;87\(10\):5502-11. PubMed PMID:23468491.)] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(46.)] TJ ET BT 45.502 441.653 Td /F1 9.8 Tf [(Mou H, Raj VS, van Kuppeveld FJ, Rottier PJ, Haagmans BL, Bosch BJ. The receptor binding domain of the )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(efficiently elicits neutralizing antibodies. J Virol. 2013 Aug;87\(16\):9379-83. PubMed PMID:23785207.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(47.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Du L, Zhao G, Kou Z, Ma C, Sun S, Poon VK, Lu L, Wang L, Debnath AK, Zheng BJ, Zhou Y, Jiang S. )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Identification of a receptor-binding domain in the s protein of the novel human coronavirus Middle East )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(respiratory syndrome coronavirus as an essential target for vaccine development. J Virol. 2013 Sep;87\(17\):9939-)] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(42. PubMed PMID:23824801.)] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(48.)] TJ ET BT 45.502 318.545 Td /F1 9.8 Tf [(Kindler E, Jnsdttir HR, Muth D, Hamming OJ, Hartmann R, Rodriguez R, Geffers R, Fouchier RA, Drosten C, )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(Mller MA, Dijkman R, Thiel V. Efficient replication of the novel human betacoronavirus EMC on primary human )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(epithelium highlights its zoonotic potential. MBio. 2013 Feb 19;4\(1\):e00611-12. PubMed PMID:23422412.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(49.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Chan RW, Chan MC, Agnihothram S, Chan LL, Kuok DI, Fong JH, Guan Y, Poon LL, Baric RS, Nicholls JM, Peiris )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(JS. Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(vivo respiratory organ cultures. J Virol. 2013 Jun;87\(12\):6604-14. PubMed PMID:23552422.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(50.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Tao X, Hill TE, Morimoto C, Peters CJ, Ksiazek TG, Tseng CT. Bilateral entry and release of Middle East )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(respiratory syndrome coronavirus induces profound apoptosis of human bronchial epithelial cells. J Virol. 2013 )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(Sep;87\(17\):9953-8. PubMed PMID:23824802.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(51.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(Kopecky-Bromberg SA, Martnez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(syndrome coronavirus open reading frame \(ORF\) 3b, ORF 6, and nucleocapsid proteins function as interferon )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(antagonists. J Virol. 2007 Jan;81\(2\):548-57. PubMed PMID:17108024.)] TJ ET BT 26.250 103.217 Td /F1 9.8 Tf [(52.)] TJ ET BT 45.502 103.217 Td /F1 9.8 Tf [(Reusken C, Mou H, Godeke GJ, van der Hoek L, Meyer B, Mller MA, Haagmans B, de Sousa R, Schuurman N, )] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(Dittmer U, Rottier P, Osterhaus A, Drosten C, Bosch BJ, Koopmans M. Specific serology for emerging human )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(coronaviruses by protein microarray. Euro Surveill. 2013 Apr 4;18\(14\):20441. PubMed PMID:23594517.)] TJ ET BT 26.250 49.385 Td /F1 9.8 Tf [(53.)] TJ ET BT 45.502 49.385 Td /F1 9.8 Tf [(World Health Organization \(2013\) WHO guidelines for investigation of cases of human infection with Middle )] TJ ET Q q 15.000 30.852 577.500 746.148 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(41.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF. )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013 )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Aug 8;500\(7461\):227-31. PubMed PMID:23831647.)] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(42.)] TJ ET BT 45.502 703.313 Td /F1 9.8 Tf [(Mller MA, Raj VS, Muth D, Meyer B, Kallies S, Smits SL, Wollny R, Bestebroer TM, Specht S, Suliman T, )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Zimmermann K, Binger T, Eckerle I, Tschapka M, Zaki AM, Osterhaus AD, Fouchier RA, Haagmans BL, Drosten C. )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(capability in mammalian cell lines. MBio. 2012 Dec 11;3\(6\). PubMed PMID:23232719.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(43.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Chan JF, Chan KH, Choi GK, To KK, Tse H, Cai JP, Yeung ML, Cheng VC, Chen H, Che XY, Lau SK, Woo PC, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Yuen KY. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(implications for disease pathogenesis and clinical manifestation. J Infect Dis. 2013 Jun 1;207\(11\):1743-52. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23532101.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(44.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Lambeir AM, Durinx C, Scharp S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003 )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(Jun;40\(3\):209-94. PubMed PMID:12892317.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(45.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krmer-Khl A, Welsch K, Winkler M, Meyer B, Drosten C, )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Dittmer U, von Hahn T, Simmons G, Hofmann H, Phlmann S. The spike protein of the emerging betacoronavirus )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing )] TJ ET BT 26.250 464.597 Td /F1 9.8 Tf [(antibodies. J Virol. 2013 May;87\(10\):5502-11. PubMed PMID:23468491.)] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(46.)] TJ ET BT 45.502 441.653 Td /F1 9.8 Tf [(Mou H, Raj VS, van Kuppeveld FJ, Rottier PJ, Haagmans BL, Bosch BJ. The receptor binding domain of the )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(efficiently elicits neutralizing antibodies. J Virol. 2013 Aug;87\(16\):9379-83. PubMed PMID:23785207.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(47.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Du L, Zhao G, Kou Z, Ma C, Sun S, Poon VK, Lu L, Wang L, Debnath AK, Zheng BJ, Zhou Y, Jiang S. )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Identification of a receptor-binding domain in the s protein of the novel human coronavirus Middle East )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(respiratory syndrome coronavirus as an essential target for vaccine development. J Virol. 2013 Sep;87\(17\):9939-)] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(42. PubMed PMID:23824801.)] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(48.)] TJ ET BT 45.502 318.545 Td /F1 9.8 Tf [(Kindler E, Jnsdttir HR, Muth D, Hamming OJ, Hartmann R, Rodriguez R, Geffers R, Fouchier RA, Drosten C, )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(Mller MA, Dijkman R, Thiel V. Efficient replication of the novel human betacoronavirus EMC on primary human )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(epithelium highlights its zoonotic potential. MBio. 2013 Feb 19;4\(1\):e00611-12. PubMed PMID:23422412.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(49.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Chan RW, Chan MC, Agnihothram S, Chan LL, Kuok DI, Fong JH, Guan Y, Poon LL, Baric RS, Nicholls JM, Peiris )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(JS. Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(vivo respiratory organ cultures. J Virol. 2013 Jun;87\(12\):6604-14. PubMed PMID:23552422.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(50.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Tao X, Hill TE, Morimoto C, Peters CJ, Ksiazek TG, Tseng CT. Bilateral entry and release of Middle East )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(respiratory syndrome coronavirus induces profound apoptosis of human bronchial epithelial cells. J Virol. 2013 )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(Sep;87\(17\):9953-8. PubMed PMID:23824802.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(51.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(Kopecky-Bromberg SA, Martnez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(syndrome coronavirus open reading frame \(ORF\) 3b, ORF 6, and nucleocapsid proteins function as interferon )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(antagonists. J Virol. 2007 Jan;81\(2\):548-57. PubMed PMID:17108024.)] TJ ET BT 26.250 103.217 Td /F1 9.8 Tf [(52.)] TJ ET BT 45.502 103.217 Td /F1 9.8 Tf [(Reusken C, Mou H, Godeke GJ, van der Hoek L, Meyer B, Mller MA, Haagmans B, de Sousa R, Schuurman N, )] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(Dittmer U, Rottier P, Osterhaus A, Drosten C, Bosch BJ, Koopmans M. Specific serology for emerging human )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(coronaviruses by protein microarray. Euro Surveill. 2013 Apr 4;18\(14\):20441. PubMed PMID:23594517.)] TJ ET BT 26.250 49.385 Td /F1 9.8 Tf [(53.)] TJ ET BT 45.502 49.385 Td /F1 9.8 Tf [(World Health Organization \(2013\) WHO guidelines for investigation of cases of human infection with Middle )] TJ ET Q q 15.000 30.852 577.500 746.148 re W n 0.271 0.267 0.267 rg BT 26.250 757.145 Td /F1 9.8 Tf [(41.)] TJ ET BT 45.502 757.145 Td /F1 9.8 Tf [(Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF. )] TJ ET BT 26.250 741.701 Td /F1 9.8 Tf [(Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature. 2013 )] TJ ET BT 26.250 726.257 Td /F1 9.8 Tf [(Aug 8;500\(7461\):227-31. PubMed PMID:23831647.)] TJ ET BT 26.250 703.313 Td /F1 9.8 Tf [(42.)] TJ ET BT 45.502 703.313 Td /F1 9.8 Tf [(Mller MA, Raj VS, Muth D, Meyer B, Kallies S, Smits SL, Wollny R, Bestebroer TM, Specht S, Suliman T, )] TJ ET BT 26.250 687.869 Td /F1 9.8 Tf [(Zimmermann K, Binger T, Eckerle I, Tschapka M, Zaki AM, Osterhaus AD, Fouchier RA, Haagmans BL, Drosten C. )] TJ ET BT 26.250 672.425 Td /F1 9.8 Tf [(Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative )] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(capability in mammalian cell lines. MBio. 2012 Dec 11;3\(6\). PubMed PMID:23232719.)] TJ ET BT 26.250 634.037 Td /F1 9.8 Tf [(43.)] TJ ET BT 45.502 634.037 Td /F1 9.8 Tf [(Chan JF, Chan KH, Choi GK, To KK, Tse H, Cai JP, Yeung ML, Cheng VC, Chen H, Che XY, Lau SK, Woo PC, )] TJ ET BT 26.250 618.593 Td /F1 9.8 Tf [(Yuen KY. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: )] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(implications for disease pathogenesis and clinical manifestation. J Infect Dis. 2013 Jun 1;207\(11\):1743-52. )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(PubMed PMID:23532101.)] TJ ET BT 26.250 564.761 Td /F1 9.8 Tf [(44.)] TJ ET BT 45.502 564.761 Td /F1 9.8 Tf [(Lambeir AM, Durinx C, Scharp S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update )] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003 )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(Jun;40\(3\):209-94. PubMed PMID:12892317.)] TJ ET BT 26.250 510.929 Td /F1 9.8 Tf [(45.)] TJ ET BT 45.502 510.929 Td /F1 9.8 Tf [(Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krmer-Khl A, Welsch K, Winkler M, Meyer B, Drosten C, )] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(Dittmer U, von Hahn T, Simmons G, Hofmann H, Phlmann S. The spike protein of the emerging betacoronavirus )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing )] TJ ET BT 26.250 464.597 Td /F1 9.8 Tf [(antibodies. J Virol. 2013 May;87\(10\):5502-11. PubMed PMID:23468491.)] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(46.)] TJ ET BT 45.502 441.653 Td /F1 9.8 Tf [(Mou H, Raj VS, van Kuppeveld FJ, Rottier PJ, Haagmans BL, Bosch BJ. The receptor binding domain of the )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(efficiently elicits neutralizing antibodies. J Virol. 2013 Aug;87\(16\):9379-83. PubMed PMID:23785207.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(47.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Du L, Zhao G, Kou Z, Ma C, Sun S, Poon VK, Lu L, Wang L, Debnath AK, Zheng BJ, Zhou Y, Jiang S. )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Identification of a receptor-binding domain in the s protein of the novel human coronavirus Middle East )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(respiratory syndrome coronavirus as an essential target for vaccine development. J Virol. 2013 Sep;87\(17\):9939-)] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(42. PubMed PMID:23824801.)] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(48.)] TJ ET BT 45.502 318.545 Td /F1 9.8 Tf [(Kindler E, Jnsdttir HR, Muth D, Hamming OJ, Hartmann R, Rodriguez R, Geffers R, Fouchier RA, Drosten C, )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(Mller MA, Dijkman R, Thiel V. Efficient replication of the novel human betacoronavirus EMC on primary human )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(epithelium highlights its zoonotic potential. MBio. 2013 Feb 19;4\(1\):e00611-12. PubMed PMID:23422412.)] TJ ET BT 26.250 264.713 Td /F1 9.8 Tf [(49.)] TJ ET BT 45.502 264.713 Td /F1 9.8 Tf [(Chan RW, Chan MC, Agnihothram S, Chan LL, Kuok DI, Fong JH, Guan Y, Poon LL, Baric RS, Nicholls JM, Peiris )] TJ ET BT 26.250 249.269 Td /F1 9.8 Tf [(JS. Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex )] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(vivo respiratory organ cultures. J Virol. 2013 Jun;87\(12\):6604-14. PubMed PMID:23552422.)] TJ ET BT 26.250 210.881 Td /F1 9.8 Tf [(50.)] TJ ET BT 45.502 210.881 Td /F1 9.8 Tf [(Tao X, Hill TE, Morimoto C, Peters CJ, Ksiazek TG, Tseng CT. Bilateral entry and release of Middle East )] TJ ET BT 26.250 195.437 Td /F1 9.8 Tf [(respiratory syndrome coronavirus induces profound apoptosis of human bronchial epithelial cells. J Virol. 2013 )] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(Sep;87\(17\):9953-8. PubMed PMID:23824802.)] TJ ET BT 26.250 157.049 Td /F1 9.8 Tf [(51.)] TJ ET BT 45.502 157.049 Td /F1 9.8 Tf [(Kopecky-Bromberg SA, Martnez-Sobrido L, Frieman M, Baric RA, Palese P. Severe acute respiratory )] TJ ET BT 26.250 141.605 Td /F1 9.8 Tf [(syndrome coronavirus open reading frame \(ORF\) 3b, ORF 6, and nucleocapsid proteins function as interferon )] TJ ET BT 26.250 126.161 Td /F1 9.8 Tf [(antagonists. J Virol. 2007 Jan;81\(2\):548-57. PubMed PMID:17108024.)] TJ ET BT 26.250 103.217 Td /F1 9.8 Tf [(52.)] TJ ET BT 45.502 103.217 Td /F1 9.8 Tf [(Reusken C, Mou H, Godeke GJ, van der Hoek L, Meyer B, Mller MA, Haagmans B, de Sousa R, Schuurman N, )] TJ ET BT 26.250 87.773 Td /F1 9.8 Tf [(Dittmer U, Rottier P, Osterhaus A, Drosten C, Bosch BJ, Koopmans M. Specific serology for emerging human )] TJ ET BT 26.250 72.329 Td /F1 9.8 Tf [(coronaviruses by protein microarray. Euro Surveill. 2013 Apr 4;18\(14\):20441. PubMed PMID:23594517.)] TJ ET BT 26.250 49.385 Td /F1 9.8 Tf [(53.)] TJ ET BT 45.502 49.385 Td /F1 9.8 Tf [(World Health Organization \(2013\) WHO guidelines for investigation of cases of human infection with Middle )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(28)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1356 0 obj << /Type /Page /Parent 3 0 R /Contents 1357 0 R >> endobj 1357 0 obj << /Length 28482 >> stream 0.271 0.267 0.267 rg q 15.000 38.352 577.500 738.648 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(East Respiratory Syndrome Coronavirus \(MERS-CoV\) July 2013. Avaiable at: )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_investigation_guideline_Jul13.pdf. Last )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(54.)] TJ ET BT 45.502 710.813 Td /F1 9.8 Tf [(Consortium for the Standardization of Influenza Seroepidemiology \(CONSISE\) \(2013\) CONSISE and Novel )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Coronavirus Resources. Available at: http://consise.tghn.org/articles/novel-coronavirus-ncov/. Last accessed 22 )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(55.)] TJ ET BT 45.502 656.981 Td /F1 9.8 Tf [(Leung GM, Lim WW, Ho LM, Lam TH, Ghani AC, Donnelly CA, Fraser C, Riley S, Ferguson NM, Anderson RM, )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(Hedley AJ. Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population )] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(groups. Epidemiol Infect. 2006 Apr;134\(2\):211-21. PubMed PMID:16490123.)] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(56.)] TJ ET BT 45.502 603.149 Td /F1 9.8 Tf [(Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, Chiu RW, Wong VW, Chan PK, Wong KT, Wong E, Cockram CS, )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(Tam JS, Sung JJ, Lo YM. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA )] TJ ET BT 26.250 572.261 Td /F1 9.8 Tf [(concentrations in adult patients. J Clin Virol. 2004 Dec;31\(4\):304-9. PubMed PMID:15494274.)] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(57.)] TJ ET BT 45.502 549.317 Td /F1 9.8 Tf [(Brun-Buisson C, Richard JC, Mercat A, Thibaut AC, Brochard L. Early corticosteroids in severe influenza )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May )] TJ ET BT 26.250 518.429 Td /F1 9.8 Tf [(1;183\(9\):1200-6. PubMed PMID:21471082.)] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(58.)] TJ ET BT 45.502 495.485 Td /F1 9.8 Tf [(Han K, Ma H, An X, Su Y, Chen J, Lian Z, Zhao J, Zhu BP, Fontaine RE, Feng Z, Zeng G. Early use of )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(glucocorticoids was a risk factor for critical disease and death from pH1N1 infection. Clin Infect Dis. 2011 )] TJ ET BT 26.250 464.597 Td /F1 9.8 Tf [(Aug;53\(4\):326-33. PubMed PMID:21810744.)] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(59.)] TJ ET BT 45.502 441.653 Td /F1 9.8 Tf [(Kim SH, Hong SB, Yun SC, Choi WI, Ahn JJ, Lee YJ, Lee HB, Lim CM, Koh Y. Corticosteroid treatment in )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(Am J Respir Crit Care Med. 2011 May 1;183\(9\):1207-14. PubMed PMID:21471084.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(60.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C, Chiche JD, Barahona D, Villabon M, )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Balasini C, Pearse RM, Matos R, Rello J. Use of early corticosteroid therapy on ICU admission in patients affected )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(by severe pandemic \(H1N1\)v influenza A infection. Intensive Care Med. 2011 Feb;37\(2\):272-83. PubMed )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(PMID:21107529.)] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(61.)] TJ ET BT 45.502 318.545 Td /F1 9.8 Tf [(Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R. Surviving Sepsis Campaign: international )] TJ ET BT 26.250 272.213 Td /F1 9.8 Tf [(guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39\(2\):165-)] TJ ET BT 26.250 256.769 Td /F1 9.8 Tf [(228. PubMed PMID:23361625.)] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(62.)] TJ ET BT 45.502 233.825 Td /F1 9.8 Tf [(International Severe Acute Respiratory and Emerging Infection Consortium \(ISARIC\) \(2013\) ISARIC and WHO )] TJ ET BT 26.250 218.381 Td /F1 9.8 Tf [(SARI and Natural History Protocols. Available at: http://isaric.tghn.org/articles/isaric-and-who-sari-and-natural-)] TJ ET BT 26.250 202.937 Td /F1 9.8 Tf [(history-protocols/. Last accessed 22 October 2013.)] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(63.)] TJ ET BT 45.502 179.993 Td /F1 9.8 Tf [(World Health Organization \(2013\) Infection prevention and control during health care for probable or )] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(confirmed cases of novel coronavirus \(nCoV\) infection. WHO, 2013 )] TJ ET BT 26.250 149.105 Td /F1 9.8 Tf [(\(http://www.who.int/csr/disease/coronavirus_infections/IPCnCoVguidance_06May13.pdf\). Last Accessed 22 )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(64.)] TJ ET BT 45.502 110.717 Td /F1 9.8 Tf [(Omrani AS, Matin MA, Haddad Q, Al-Nakhli D, Memish ZA, Albarrak AM. A family cluster of Middle East )] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(Infect Dis. 2013 Sep;17\(9\):e668-72. PubMed PMID:23916548.)] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(65.)] TJ ET BT 45.502 56.885 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro )] TJ ET Q q 15.000 38.352 577.500 738.648 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(East Respiratory Syndrome Coronavirus \(MERS-CoV\) July 2013. Avaiable at: )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_investigation_guideline_Jul13.pdf. Last )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(54.)] TJ ET BT 45.502 710.813 Td /F1 9.8 Tf [(Consortium for the Standardization of Influenza Seroepidemiology \(CONSISE\) \(2013\) CONSISE and Novel )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Coronavirus Resources. Available at: http://consise.tghn.org/articles/novel-coronavirus-ncov/. Last accessed 22 )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(55.)] TJ ET BT 45.502 656.981 Td /F1 9.8 Tf [(Leung GM, Lim WW, Ho LM, Lam TH, Ghani AC, Donnelly CA, Fraser C, Riley S, Ferguson NM, Anderson RM, )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(Hedley AJ. Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population )] TJ ET BT 26.250 626.093 Td /F1 9.8 Tf [(groups. Epidemiol Infect. 2006 Apr;134\(2\):211-21. PubMed PMID:16490123.)] TJ ET BT 26.250 603.149 Td /F1 9.8 Tf [(56.)] TJ ET BT 45.502 603.149 Td /F1 9.8 Tf [(Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, Chiu RW, Wong VW, Chan PK, Wong KT, Wong E, Cockram CS, )] TJ ET BT 26.250 587.705 Td /F1 9.8 Tf [(Tam JS, Sung JJ, Lo YM. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA )] TJ ET BT 26.250 572.261 Td /F1 9.8 Tf [(concentrations in adult patients. J Clin Virol. 2004 Dec;31\(4\):304-9. PubMed PMID:15494274.)] TJ ET BT 26.250 549.317 Td /F1 9.8 Tf [(57.)] TJ ET BT 45.502 549.317 Td /F1 9.8 Tf [(Brun-Buisson C, Richard JC, Mercat A, Thibaut AC, Brochard L. Early corticosteroids in severe influenza )] TJ ET BT 26.250 533.873 Td /F1 9.8 Tf [(A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2011 May )] TJ ET BT 26.250 518.429 Td /F1 9.8 Tf [(1;183\(9\):1200-6. PubMed PMID:21471082.)] TJ ET BT 26.250 495.485 Td /F1 9.8 Tf [(58.)] TJ ET BT 45.502 495.485 Td /F1 9.8 Tf [(Han K, Ma H, An X, Su Y, Chen J, Lian Z, Zhao J, Zhu BP, Fontaine RE, Feng Z, Zeng G. Early use of )] TJ ET BT 26.250 480.041 Td /F1 9.8 Tf [(glucocorticoids was a risk factor for critical disease and death from pH1N1 infection. Clin Infect Dis. 2011 )] TJ ET BT 26.250 464.597 Td /F1 9.8 Tf [(Aug;53\(4\):326-33. PubMed PMID:21810744.)] TJ ET BT 26.250 441.653 Td /F1 9.8 Tf [(59.)] TJ ET BT 45.502 441.653 Td /F1 9.8 Tf [(Kim SH, Hong SB, Yun SC, Choi WI, Ahn JJ, Lee YJ, Lee HB, Lim CM, Koh Y. Corticosteroid treatment in )] TJ ET BT 26.250 426.209 Td /F1 9.8 Tf [(critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. )] TJ ET BT 26.250 410.765 Td /F1 9.8 Tf [(Am J Respir Crit Care Med. 2011 May 1;183\(9\):1207-14. PubMed PMID:21471084.)] TJ ET BT 26.250 387.821 Td /F1 9.8 Tf [(60.)] TJ ET BT 45.502 387.821 Td /F1 9.8 Tf [(Martin-Loeches I, Lisboa T, Rhodes A, Moreno RP, Silva E, Sprung C, Chiche JD, Barahona D, Villabon M, )] TJ ET BT 26.250 372.377 Td /F1 9.8 Tf [(Balasini C, Pearse RM, Matos R, Rello J. Use of early corticosteroid therapy on ICU admission in patients affected )] TJ ET BT 26.250 356.933 Td /F1 9.8 Tf [(by severe pandemic \(H1N1\)v influenza A infection. Intensive Care Med. 2011 Feb;37\(2\):272-83. PubMed )] TJ ET BT 26.250 341.489 Td /F1 9.8 Tf [(PMID:21107529.)] TJ ET BT 26.250 318.545 Td /F1 9.8 Tf [(61.)] TJ ET BT 45.502 318.545 Td /F1 9.8 Tf [(Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, )] TJ ET BT 26.250 303.101 Td /F1 9.8 Tf [(Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, )] TJ ET BT 26.250 287.657 Td /F1 9.8 Tf [(Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R. Surviving Sepsis Campaign: international )] TJ ET BT 26.250 272.213 Td /F1 9.8 Tf [(guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39\(2\):165-)] TJ ET BT 26.250 256.769 Td /F1 9.8 Tf [(228. PubMed PMID:23361625.)] TJ ET BT 26.250 233.825 Td /F1 9.8 Tf [(62.)] TJ ET BT 45.502 233.825 Td /F1 9.8 Tf [(International Severe Acute Respiratory and Emerging Infection Consortium \(ISARIC\) \(2013\) ISARIC and WHO )] TJ ET BT 26.250 218.381 Td /F1 9.8 Tf [(SARI and Natural History Protocols. Available at: http://isaric.tghn.org/articles/isaric-and-who-sari-and-natural-)] TJ ET BT 26.250 202.937 Td /F1 9.8 Tf [(history-protocols/. Last accessed 22 October 2013.)] TJ ET BT 26.250 179.993 Td /F1 9.8 Tf [(63.)] TJ ET BT 45.502 179.993 Td /F1 9.8 Tf [(World Health Organization \(2013\) Infection prevention and control during health care for probable or )] TJ ET BT 26.250 164.549 Td /F1 9.8 Tf [(confirmed cases of novel coronavirus \(nCoV\) infection. WHO, 2013 )] TJ ET BT 26.250 149.105 Td /F1 9.8 Tf [(\(http://www.who.int/csr/disease/coronavirus_infections/IPCnCoVguidance_06May13.pdf\). Last Accessed 22 )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(64.)] TJ ET BT 45.502 110.717 Td /F1 9.8 Tf [(Omrani AS, Matin MA, Haddad Q, Al-Nakhli D, Memish ZA, Albarrak AM. A family cluster of Middle East )] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(Infect Dis. 2013 Sep;17\(9\):e668-72. PubMed PMID:23916548.)] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(65.)] TJ ET BT 45.502 56.885 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro )] TJ ET Q q 15.000 38.352 577.500 738.648 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(East Respiratory Syndrome Coronavirus \(MERS-CoV\) July 2013. Avaiable at: )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_investigation_guideline_Jul13.pdf. Last )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(accessed 22 October 2013.)] TJ ET BT 26.250 710.813 Td /F1 9.8 Tf [(54.)] TJ ET BT 45.502 710.813 Td /F1 9.8 Tf [(Consortium for the Standardization of Influenza Seroepidemiology \(CONSISE\) \(2013\) CONSISE and Novel )] TJ ET BT 26.250 695.369 Td /F1 9.8 Tf [(Coronavirus Resources. Available at: http://consise.tghn.org/articles/novel-coronavirus-ncov/. Last accessed 22 )] TJ ET BT 26.250 679.925 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 656.981 Td /F1 9.8 Tf [(55.)] TJ ET BT 45.502 656.981 Td /F1 9.8 Tf [(Leung GM, Lim WW, Ho LM, Lam TH, Ghani AC, Donnelly CA, Fraser C, Riley S, Ferguson NM, Anderson RM, )] TJ ET BT 26.250 641.537 Td /F1 9.8 Tf [(Hedley AJ. 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Last Accessed 22 )] TJ ET BT 26.250 133.661 Td /F1 9.8 Tf [(October 2013.)] TJ ET BT 26.250 110.717 Td /F1 9.8 Tf [(64.)] TJ ET BT 45.502 110.717 Td /F1 9.8 Tf [(Omrani AS, Matin MA, Haddad Q, Al-Nakhli D, Memish ZA, Albarrak AM. A family cluster of Middle East )] TJ ET BT 26.250 95.273 Td /F1 9.8 Tf [(Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J )] TJ ET BT 26.250 79.829 Td /F1 9.8 Tf [(Infect Dis. 2013 Sep;17\(9\):e668-72. PubMed PMID:23916548.)] TJ ET BT 26.250 56.885 Td /F1 9.8 Tf [(65.)] TJ ET BT 45.502 56.885 Td /F1 9.8 Tf [(Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 18.032 Td /F5 11.0 Tf [(29)] TJ ET BT 25.000 18.032 Td /F5 11.0 Tf [(PLOS Currents Outbreaks)] TJ ET Q endstream endobj 1358 0 obj << /Type /Page /Parent 3 0 R /Contents 1359 0 R >> endobj 1359 0 obj << /Length 2052 >> stream 0.271 0.267 0.267 rg q 15.000 715.668 577.500 61.332 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. Treatment with interferon-2b and ribavirin )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013 Oct;19\(10\):1313-7. PubMed )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(PMID:24013700.)] TJ ET Q q 15.000 715.668 577.500 61.332 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. Treatment with interferon-2b and ribavirin )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013 Oct;19\(10\):1313-7. PubMed )] TJ ET BT 26.250 733.757 Td /F1 9.8 Tf [(PMID:24013700.)] TJ ET Q q 15.000 715.668 577.500 61.332 re W n 0.271 0.267 0.267 rg BT 26.250 764.645 Td /F1 9.8 Tf [(C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. Treatment with interferon-2b and ribavirin )] TJ ET BT 26.250 749.201 Td /F1 9.8 Tf [(improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013 Oct;19\(10\):1313-7. 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