Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 34 Records) |
Query Trace: Chong M [original query] |
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The third international hackathon for applying insights into large-scale genomic composition to use cases in a wide range of organisms.
Walker K , Kalra D , Lowdon R , Chen G , Molik D , Soto DC , Dabbaghie F , Khleifat AA , Mahmoud M , Paulin LF , Raza MS , Pfeifer SP , Agustinho DP , Aliyev E , Avdeyev P , Barrozo ER , Behera S , Billingsley K , Chong LC , Choubey D , De Coster W , Fu Y , Gener AR , Hefferon T , Henke DM , Höps W , Illarionova A , Jochum MD , Jose M , Kesharwani RK , Kolora SRR , Kubica J , Lakra P , Lattimer D , Liew CS , Lo BW , Lo C , Lötter A , Majidian S , Mendem SK , Mondal R , Ohmiya H , Parvin N , Peralta C , Poon CL , Prabhakaran R , Saitou M , Sammi A , Sanio P , Sapoval N , Syed N , Treangen T , Wang G , Xu T , Yang J , Zhang S , Zhou W , Sedlazeck FJ , Busby B . F1000Res 2022 11 530 In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics. |
Impact of SARS-CoV-2 infection on the association between laboratory tests and severe outcomes among hospitalized children
Xie J , Kuppermann N , Florin TA , Tancredi DJ , Funk AL , Kim K , Salvadori MI , Yock-Corrales A , Shah NP , Breslin KA , Chaudhari PP , Bergmann KR , Ahmad FA , Nebhrajani JR , Mintegi S , Gangoiti I , Plint AC , Avva UR , Gardiner MA , Malley R , Finkelstein Y , Dalziel SR , Bhatt M , Kannikeswaran N , Caperell K , Campos C , Sabhaney VJ , Chong SL , Lunoe MM , Rogers AJ , Becker SM , Borland ML , Sartori LF , Pavlicich V , Rino PB , Morrison AK , Neuman MI , Poonai N , Simon NE , Kam AJ , Kwok MY , Morris CR , Palumbo L , Ambroggio L , Navanandan N , Eckerle M , Klassen TP , Payne DC , Cherry JC , Waseem M , Dixon AC , Ferre IB , Freedman SB . Open Forum Infect Dis 2023 10 (10) ofad485 BACKGROUND: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations. METHODS: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations. RESULTS: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 10(9)/L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 10(9)/L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts. CONCLUSIONS: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative. |
Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome
Blue EE , White JJ , Dush MK , Gordon WW , Wyatt BH , White P , Marvin CT , Helle E , Ojala T , Priest JR , Jenkins MM , Almli LM , Reefhuis J , Pangilinan F , Brody LC , McBride KL , Garg V , Shaw GM , Romitti PA , Nembhard WN , Browne ML , Werler MM , Kay DM , Mital S , Chong JX , Nascone-Yoder NM , Bamshad MJ . HGG Adv 2023 4 (4) 100232 Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10(-5)), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2(707C>T) and CAPN2(1112C>T) variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis. |
Understanding COVID-19 vaccine hesitancy among K-12 staff, parents, and students: District of Columbia, February to April, 2022
Mark-Carew M , van Zyl A , Tatti KM , Chong M , Rose C , Sifre K , Jarris D , Still W , Aynalem G , Welton M , Thomas ES , Hall L , Samson ME . J Sch Health 2023 93 (12) 1079-1090 OBJECTIVE: Despite widespread availability of COVID-19 vaccines, millions of Americans have not received the recommended vaccine doses. In the District of Columbia (DC), COVID-19 vaccination rates are lowest among residents who are Non-Hispanic (NH) Black and among school-aged children. We assessed COVID-19 vaccine hesitancy among staff and parents of students in DC K-12 public and public charter schools. METHODS: We conducted a telephone-based survey from February 6 to April 16, 2022 to staff, students, and parents of students who participated in school-based COVID-19 screening testing. COVID-19-related survey items included: vaccination status, reasons for not getting vaccinated, perceived vaccine access, and trusted COVID-19 information sources. Utilizing time-to-event analyses, we evaluated differences across demographic groups. RESULTS: The interview response rate was 25.8% (308/1193). Most unvaccinated participants were NH Black and ages 5 to 11 years. Median time from vaccine eligibility to uptake was 236 days for NH Black participants vs. 10 days for NH White participants. Vaccine safety was the top concern among unvaccinated participants. Government and healthcare providers were the most trusted COVID-19 information sources. CONCLUSIONS: Differences in timing of vaccine uptake among respondents and greater vaccine hesitancy among NH Black participants compared to other racial/ethnic groups highlight a need for continued tailored outreach and communication using trusted sources to convey the importance, benefits, and safety of COVID-19 vaccination. |
Positive predictive value of International Classification of Diseases, Ninth Revision, Clinical Modification, and International Classification of Diseases, Tenth Revision, Clinical Modification, codes for identification of congenital heart defects
Ivey LC , Rodriguez FH 3rd , Shi H , Chong C , Chen J , Raskind-Hood CL , Downing KF , Farr SL , Book WM . J Am Heart Assoc 2023 12 (16) e030821 Background Administrative data permit analysis of large cohorts but rely on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes that may not reflect true congenital heart defects (CHDs). Methods and Results CHDs in 1497 cases with at least 1 encounter between January 1, 2010 and December 31, 2019 in 2 health care systems, identified by at least 1 of 87 ICD-9-CM/ICD-10-CM CHD codes were validated through medical record review for the presence of CHD and CHD native anatomy. Interobserver and intraobserver reliability averaged >95%. Positive predictive value (PPV) of ICD-9-CM/ICD-10-CM codes for CHD was 68.1% (1020/1497) overall, 94.6% (123/130) for cases identified in both health care systems, 95.8% (249/260) for severe codes, 52.6% (370/703) for shunt codes, 75.9% (243/320) for valve codes, 73.5% (119/162) for shunt and valve codes, and 75.0% (39/52) for "other CHD" (7 ICD-9-CM/ICD-10-CM codes). PPV for cases with >1 unique CHD code was 85.4% (503/589) versus 56.3% (498/884) for 1 CHD code. Of cases with secundum atrial septal defect ICD-9-CM/ICD-10-CM codes 745.5/Q21.1 in isolation, PPV was 30.9% (123/398). Patent foramen ovale was present in 66.2% (316/477) of false positives. True positives had younger mean age at first encounter with a CHD code than false positives (22.4 versus 26.3 years; P=0.0017). Conclusions CHD ICD-9-CM/ICD-10-CM codes have modest PPV and may not represent true CHD cases. PPV was improved by selecting certain features, but most true cases did not have these characteristics. The development of algorithms to improve accuracy may improve accuracy of electronic health records for CHD surveillance. |
International Classification of Diseases (ICD) Codes for Congenital Heart Defects (CHD) Have Variable and Limited Accuracy for Detecting CHD Cases (preprint)
Ivey LC , Rodriguez FH , Shi H , Chong C , Chen J , Raskind-Hood C , Downing KF , Farr SL , Book WM . medRxiv 2023 24 Background: Administrative data permits analysis of large cohorts but relies on International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification (ICD) codes that may not reflect true congenital heart defects (CHD). Method(s): 1497 cases with at least one encounter between 1/1/2010 - 12/31/2019 in two healthcare systems (one adult, one pediatric) identified by at least one of 87 ICD CHD codes were validated through chart review for the presence of CHD and CHD anatomic group. Result(s): Inter- and intra-observer reliability averaged > 95%. Positive predictive value (PPV) of ICD codes for CHD was 68.1% (1020/1497) overall, 94.6% (123/130) for cases identified in both healthcare systems, 95.8% (249/260) for severe codes, 52.6% (370/703) for shunt codes, 75.9% (243/320) for valve codes, 73.5% (119/162) for shunt and valve codes, and 75.0% (39/52) for "Other CHD" (7 ICD codes). PPV for cases with >1 unique CHD code was 85.4% (503/589) vs. 56.3% (498/884) for one CHD code. Of cases with secundum atrial septal defect ICD codes 745.5/Q21.1 in isolation, 30.9% (123/398) had a confirmed CHD. Patent foramen ovale was present in 66.2% (316/477) of false positives (FP). The median number of unique CHD-coded encounters was higher for true positives (TP) than FP (2.0; interquartile range [IQR]: 1.0-3.0 vs 1.0; IQR:1.0-1.0, respectively, p<0.0001). TP had younger mean age at first encounter with a CHD code than FP (22.4 years vs 26.3 years, p=0.0017). Conclusion(s): PPV of CHD ICD codes varies by characteristics for detection of CHD by ICD code and anatomic grouping. While an ICD code for severe CHD and/or the presence of a case in more than one data source, regardless of anatomic group, is associated with higher PPV for CHD, most TP cases did not have these characteristics. The development of algorithms to improve accuracy may improve administrative data for CHD surveillance. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.
Sok P , Sabo A , Almli LM , Jenkins MM , Nembhard WN , Agopian AJ , Bamshad MJ , Blue EE , Brody LC , Brown AL , Browne ML , Canfield MA , Carmichael SL , Chong JX , Dugan-Perez S , Feldkamp ML , Finnell RH , Gibbs RA , Kay DM , Lei Y , Meng Q , Moore CA , Mullikin JC , Muzny D , Olshan AF , Pangilinan F , Reefhuis J , Romitti PA , Schraw JM , Shaw GM , Werler MM , Harpavat S , Lupo PJ . Am J Med Genet A 2023 191 (6) 1546-1556 The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex. |
The National Clinical Care Commission Report to Congress: Recommendations to better leverage federal policies and programs to prevent and control diabetes
Herman WH , Schillinger D , Bolen S , Boltri JM , Bullock A , Chong W , Conlin PR , Cook JW , Dokun A , Fukagawa N , Gonzalvo J , Greenlee MC , Hawkins M , Idzik S , Leake E , Linder B , Lopata AM , Schumacher P , Shell D , Strogatz D , Towne J , Tracer H , Wu S . Diabetes Care 2023 46 (2) 255-261 The National Clinical Care Commission (NCCC) was established by Congress to make recommendations to leverage federal policies and programs to more effectively prevent and treat diabetes and its complications. The NCCC developed a guiding framework that incorporated elements of the Socioecological and Chronic Care Models. It surveyed federal agencies and conducted follow-up meetings with representatives from 10 health-related and 11 non-health-related federal agencies. It held 12 public meetings, solicited public comments, met with numerous interested parties and key informants, and performed comprehensive literature reviews. The final report, transmitted to Congress in January 2022, contained 39 specific recommendations, including 3 foundational recommendations that addressed the necessity of an all-of-government approach to diabetes, health equity, and access to health care. At the general population level, the NCCC recommended that the federal government adopt a health-in-all-policies approach so that the activities of non-health-related federal agencies that address agriculture, food, housing, transportation, commerce, and the environment be coordinated with those of health-related federal agencies to affirmatively address the social and environmental conditions that contribute to diabetes and its complications. For individuals at risk for type 2 diabetes, including those with prediabetes, the NCCC recommended that federal policies and programs be strengthened to increase awareness of prediabetes and the availability of, referral to, and insurance coverage for intensive lifestyle interventions for diabetes prevention and that data be assembled to seek approval of metformin for diabetes prevention. For people with diabetes and its complications, the NCCC recommended that barriers to proven effective treatments for diabetes and its complications be removed, the size and competence of the workforce to treat diabetes and its complications be increased, and new payment models be implemented to support access to lifesaving medications and proven effective treatments for diabetes and its complications. The NCCC also outlined an ambitious research agenda. The NCCC strongly encourages the public to support these recommendations and Congress to take swift action. |
Symptoms of depression, anxiety, and post-traumatic stress disorder, and suicidal ideation among school nurses in prekindergarten through grade 12 schools - United States, March 2022
Merkle SL , Welton M , van Zyl A , Chong M , Tanner A , Rose CE , Hertz M , Hill L , Leroy ZC , Sifre K , Thomas ES . J Sch Nurs 2022 39 (2) 10598405221131048 School nurses are integral to creating safe environments in U.S. schools. Many experienced increased work burden and stress during the COVID-19 pandemic. CDC collaborated with the National Association of School Nurses and the National Association of State School Nurse Consultants to distribute a 121-item online, anonymous survey to school nurses nationwide during March 7-30, 2022. Among the 7,971 respondents, symptoms of depression, anxiety and PTSD, and suicidal ideation were measured, and prevalence ratios were used to identify associations with demographics, workplace characteristics, and support. Results found high levels of work-related stressors and indicated that employment characteristics, COVID-19-related job duties, and other workplace stressors and supports affected school nurse mental health. The survey findings underscore the mental health challenges many school nurses experienced during the 2021/2022 school year. The findings can inform supportive policies and practices to reduce workplace stressors and increase workplace supports for school nurses. |
Post-COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection.
Funk AL , Kuppermann N , Florin TA , Tancredi DJ , Xie J , Kim K , Finkelstein Y , Neuman MI , Salvadori MI , Yock-Corrales A , Breslin KA , Ambroggio L , Chaudhari PP , Bergmann KR , Gardiner MA , Nebhrajani JR , Campos C , Ahmad FA , Sartori LF , Navanandan N , Kannikeswaran N , Caperell K , Morris CR , Mintegi S , Gangoiti I , Sabhaney VJ , Plint AC , Klassen TP , Avva UR , Shah NP , Dixon AC , Lunoe MM , Becker SM , Rogers AJ , Pavlicich V , Dalziel SR , Payne DC , Malley R , Borland ML , Morrison AK , Bhatt M , Rino PB , Beneyto Ferre I , Eckerle M , Kam AJ , Chong SL , Palumbo L , Kwok MY , Cherry JC , Poonai N , Wassem M , Simon NJ , Freedman SB . JAMA Netw Open 2022 5 (7) e2223253 IMPORTANCE: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. OBJECTIVES: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. EXPOSURE: SARS-CoV-2 detected via nucleic acid testing. MAIN OUTCOMES AND MEASURES: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. RESULTS: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). CONCLUSIONS AND RELEVANCE: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older. |
Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.
Li J , Yang W , Wang YJ , Ma C , Curry CJ , McGoldrick D , Nickerson DA , Chong JX , Blue EE , Mullikin JC , Reefhuis J , Nembhard WN , Romitti PA , Werler MM , Browne ML , Olshan AF , Finnell RH , Feldkamp ML , Pangilinan F , Almli LM , Bamshad MJ , Brody LC , Jenkins MM , Shaw GM . Am J Med Genet A 2022 188 (8) 2376-2388 Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease. |
Outcomes of SARS-CoV-2-Positive Youths Tested in Emergency Departments: The Global PERN-COVID-19 Study.
Funk AL , Florin TA , Kuppermann N , Tancredi DJ , Xie J , Kim K , Neuman MI , Ambroggio L , Plint AC , Mintegi S , Klassen TP , Salvadori MI , Malley R , Payne DC , Simon NJ , Yock-Corrales A , Nebhrajani JR , Chaudhari PP , Breslin KA , Finkelstein Y , Campos C , Bergmann KR , Bhatt M , Ahmad FA , Gardiner MA , Avva UR , Shah NP , Sartori LF , Sabhaney VJ , Caperell K , Navanandan N , Borland ML , Morris CR , Gangoiti I , Pavlicich V , Kannikeswaran N , Lunoe MM , Rino PB , Kam AJ , Cherry JC , Rogers AJ , Chong SL , Palumbo L , Angelats CM , Morrison AK , Kwok MY , Becker SM , Dixon AC , Poonai N , Eckerle M , Wassem M , Dalziel SR , Freedman SB . JAMA Netw Open 2022 5 (1) e2142322 IMPORTANCE: Severe outcomes among youths with SARS-CoV-2 infections are poorly characterized. OBJECTIVE: To estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED). DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study with 14-day follow-up enrolled participants between March 2020 and June 2021. Participants were youths aged younger than 18 years who were tested for SARS-CoV-2 infection at one of 41 EDs across 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States. Statistical analysis was performed from September to October 2021. EXPOSURES: Acute SARS-CoV-2 infection was determined by nucleic acid (eg, polymerase chain reaction) testing. MAIN OUTCOMES AND MEASURES: Severe outcomes, a composite measure defined as intensive interventions during hospitalization (eg, inotropic support, positive pressure ventilation), diagnoses indicating severe organ impairment, or death. RESULTS: Among 3222 enrolled youths who tested positive for SARS-CoV-2 infection, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years. After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died. Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]). Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes. Compared with hospitalized SARS-CoV-2-negative youths, the risk of severe outcomes was higher among hospitalized SARS-CoV-2-positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%). CONCLUSIONS AND RELEVANCE: In this study, approximately 3% of SARS-CoV-2-positive youths tested in EDs experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower. Risk factors such as age, underlying chronic illness, and symptom duration may be useful to consider when making clinical care decisions. |
Enterovirus D68 infection among hospitalized children with severe acute respiratory illness in El Salvador and Panama, 2012-2013.
Biggs HM , Nix WA , Zhang J , Rogers S , Clara W , Jara JH , Gonzalez R , Luciani K , Brizuela YS , Estripeaut D , Castillo JM , De Leon T , Corro M , Vergara O , Rauda R , Chong EG , Watson JT , Azziz-Baumgartner E , Gerber SI , Tong S , Dawood FS . Influenza Other Respir Viruses 2020 15 (2) 181-187 We assessed EV-D68 epidemiology and phylogenetics among children aged ≤9 years hospitalized with severe acute respiratory illnesses at five sites in Panama and El Salvador during 2012-2013. Respiratory specimens positive for enterovirus or rhinovirus were tested by real-time RT-PCR for EV-D68, and partial VP1 gene sequences were determined. Of 715 enrolled children, 17 from sites in both countries were EV-D68-positive and commonly had a history of asthma or wheezing. Phylogenetically, 15 of 16 sequences fell into Clade B1, and one into Clade A2. The Central American EV-D68s were closely related genetically to contemporaneous strains from North America, South America, and the Caribbean. |
Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.
Jenkins MM , Almli LM , Pangilinan F , Chong JX , Blue EE , Shapira SK , White J , McGoldrick D , Smith JD , Mullikin JC , Bean CJ , Nembhard WN , Lou XY , Shaw GM , Romitti PA , Keppler-Noreuil K , Yazdy MM , Kay DM , Carter TC , Olshan AF , Moore KJ , Nascone-Yoder N , Finnell RH , Lupo PJ , Feldkamp ML , Nickerson DA , Bamshad MJ , Brody LC , Reefhuis J . Birth Defects Res 2019 111 (20) 1618-1632 BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers. |
Surveillance for respiratory and diarrheal pathogens at the human-pig interface in Sarawak, Malaysia
Borkenhagen LK , Mallinson KA , Tsao RW , Ha SJ , Lim WH , Toh TH , Anderson BD , Fieldhouse JK , Philo SE , Chong KS , Lindsley WG , Ramirez A , Lowe JF , Coleman KK , Gray GC . PLoS One 2018 13 (7) e0201295 BACKGROUND: The large livestock operations and dense human population of Southeast Asia are considered a hot-spot for emerging viruses. OBJECTIVES: To determine if the pathogens adenovirus (ADV), coronavirus (CoV), encephalomyocarditis virus (EMCV), enterovirus (EV), influenza A-D (IAV, IBV, ICV, and IDV), porcine circovirus 2 (PCV2), and porcine rotaviruses A and C (RVA and RVC), are aerosolized at the animal-interface, and if humans working in these environments are carrying these viruses in their nasal airways. STUDY: This cross-sectional study took place in Sarawak, Malaysia among 11 pig farms, 2 abattoirs, and 3 animal markets in June and July of 2017. Pig feces, pig oral secretions, bioaerosols, and worker nasal wash samples were collected and analyzed via rPCR and rRT-PCR for respiratory and diarrheal viruses. RESULTS: In all, 55 pig fecal, 49 pig oral or water, 45 bioaerosol, and 78 worker nasal wash samples were collected across 16 sites. PCV2 was detected in 21 pig fecal, 43 pig oral or water, 3 bioaerosol, and 4 worker nasal wash samples. In addition, one or more bioaerosol or pig samples were positive for EV, IAV, and RVC, and one or more worker samples were positive for ADV, CoV, IBV, and IDV. CONCLUSIONS: This study demonstrates that nucleic acids from a number of targeted viruses were present in pig oral secretions and pig fecal samples, and that several viruses were detected in bioaerosol samples or in the nasal passages of humans with occupational exposure to pigs. These results demonstrate the need for future research in strengthening viral surveillance at the human-animal interface, specifically through expanded bioaerosol sampling efforts and a seroepidemiological study of individuals with exposure to pigs in this region for PCV2 infection. |
Francisella-Like Endosymbiont Detected in Haemaphysalis Ticks (Acari: Ixodidae) From the Republic of Korea.
Takhampunya R , Kim HC , Chong ST , Korkusol A , Tippayachai B , Davidson SA , Petersen JM , Klein TA . J Med Entomol 2017 54 (6) 1735-1742 A total of 6,255 ticks belonging to three genera and six species (Haemaphysalis flava Neumann, Haemaphysalis longicornis Neumann, Haemaphysalis phasiana Saito, Ixodes nipponensis Kitaoka & Saito, Ixodes persulcatus Schulze, and Amblyomma testudinarium Koch) collected from May-August, 2013, at four southwestern provinces in the Republic of Korea (ROK) were submitted to the Armed Forces Research Institute of Medical Sciences and assayed for selected tick-borne pathogens. One pool each of H. flava and H. phasiana was positive by PCR and sequencing for a Francisella-like endosymbiont, while all pools were negative for Francisella tularensis, the causative agent of tularemia. |
Risk Factors Associated with Blood Exposure for Sporadic Hepatitis E in Dhaka, Bangladesh.
Sazzad HMS , Luby SP , Labrique AB , Kamili S , Hayden TM , Kamili NA , Teo CG , Gurley ES . Am J Trop Med Hyg 2017 97 (5) 1437-1444 Fecal contamination of drinking water is associated with large hepatitis E virus (HEV) outbreaks of genotypes 1 and 2 in endemic areas. Sporadic transmission of HEV genotypes 3 and 4 in high-income countries has been associated with exposure to blood and animal contact. The objective of the study was to identify the risk factors for hepatitis E and the genotype(s) causing sporadic hepatitis E in Dhaka, Bangladesh. We selected, from a diagnostic center in Dhaka between November 2008 and November 2009, cases presenting with jaundice and anti-HEV IgM antibodies and age-matched controls were defined as those with no history of jaundice and normal blood test results. Serum samples were tested for HEV RNA using real-time reverse transcriptase polymerase chain reaction followed by a sequencing and phylogenetic analysis. A total of 109 cases and 109 controls were enrolled. The cases were more likely to be male (adjusted matched odds ratios [mOR] 2.2, 95% CI: 1.2-3.9; P = 0.01), or have reported contact with another person's blood or blood product, or contact with blood-contaminated sharp instruments (adjusted mOR 2.1, 95% CI: 1.1-4.1; P = 0.03) than controls. There were no significant differences between the cases and the controls in terms of reported high-risk sexual intercourse, consumption of undercooked meat, or contact or drinking fecally-contaminated water. The sera from three cases carried HEV RNA, all belonging to genotype 1. Findings from this study suggest that contact with human blood and sharing sharp instruments may transmit sporadic hepatitis E in Dhaka, Bangladesh. Efforts to prevent the transmission of blood-borne pathogens may also prevent sporadic HEV transmission in this endemic setting. |
Permissive, in vitro replication of hepatitis B virus genotype E.
Ji X , Zafrullah M , Wiese N , Hayden-Mixon T , Forbi JC , Teo CG , Purdy MA . J Virol Methods 2017 243 20-24 A cloned stable cell line, HepG2-HBVE6, was established following transfection of HepG2 cells with a retroviral plasmid into which a 1.1-fold genomic construct of hepatitis B virus (HBV) belonging to genotype E (HBV/E) was inserted. The cell line retains the entire HBV/E insert, and produces episomal HBV DNA. It expresses HBV pregenomic, preS1 and preS2/S transcripts, and sheds hepatitis B surface and e antigens as well as structures resembling HBV-subviral and Dane particles. The HepG2-HBVE6 cell line, in permitting recapitulation of the HBV life cycle, may be used for studying viral characteristics, therapeutic and preventative outcomes and for preparing reagents specific to HBV genotype E. |
Hepatitis E in Singapore: A Case-Series and Viral Phylodynamics Study.
Teo EC , Tan BH , Purdy MA , Wong PS , Ting PJ , Chang PJ , Oon LL , Sue A , Teo CG , Tan CK . Am J Trop Med Hyg 2017 96 (4) 922-928 The incidence of hepatitis E in Singapore appears to be increasing. A retrospective case-series study of patients diagnosed with hepatitis E in a tertiary hospital from 2009 to 2013 was conducted. Of 16 cases, eight (50%) were solid-organ transplant recipients (SOTRs), and 14 (88%) were found infected by genotype 3 hepatitis E virus (HEV-3). Bayesian inferences based on HEV subgenomic sequences from seven cases suggest that HEV-3 strains were introduced to Singapore as two principal lineages. Within limitations of the study, it can be inferred that one lineage, in the 3efg clade, emerged about 83 years ago, probably originating from Japan, whereas the other, in the 3abchij clade, emerged about 40 years ago, from the United States. Establishment and subsequent transmissions of strains from these two lineages likely contribute to the current endemicity of hepatitis E in Singapore. |
Vaginal and Rectal Clostridium sordellii and Clostridium perfringens Presence Among Women in the United States
Chong E , Winikoff B , Charles D , Agnew K , Prentice JL , Limbago BM , Platais I , Louie K , Jones HE , Shannon C , NCT01283828 Study Team , Avillan J , Kitchel B , Hubbard A , MacCannell D , Rasheed JK , Callaghan WM , McDonald LC . Obstet Gynecol 2016 127 (2) 360-8 OBJECTIVE: To characterize the presence of Clostridium sordellii and Clostridium perfringens in the vagina and rectum, identify correlates of presence, and describe strain diversity and presence of key toxins. METHODS: We conducted an observational cohort study in which we screened a diverse cohort of reproductive-aged women in the United States up to three times using vaginal and rectal swabs analyzed by molecular and culture methods. We used multivariate regression models to explore predictors of presence. Strains were characterized by pulsed-field gel electrophoresis and tested for known virulence factors by polymerase chain reaction assays. RESULTS: Of 4,152 participants enrolled between 2010 and 2013, 3.4% (95% confidence interval [CI] 2.9-4.0) were positive for C sordellii and 10.4% (95% CI 9.5-11.3) were positive for C perfringens at baseline. Among the 66% with follow-up data, 94.7% (95% CI 88.0-98.3) of those positive for C sordellii and 74.4% (95% CI 69.0-79.3) of those positive for C perfringens at baseline were negative at follow-up. At baseline, recent gynecologic surgery was associated with C sordellii presence, whereas a high body mass index was associated with C perfringens presence in adjusted models. Two of 238 C sordellii isolates contained the lethal toxin gene, and none contained the hemorrhagic toxin gene. Substantial strain diversity was observed in both species with few clusters and no dominant clones identified. CONCLUSION: The relatively rare and transient nature of C sordellii and C perfringens presence in the vagina and rectum makes it inadvisable to use any screening or prophylactic approach to try to prevent clostridial infection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01283828. |
Chronic Infection With Camelid Hepatitis E Virus in a Liver-transplant Recipient Who Regularly Consumes Camel Meat and Milk.
Lee GH , Tan BH , Teo EC , Lim SG , Dan YY , Wee A , Aw PP , Zhu Y , Hibberd ML , Tan CK , Purdy MA , Teo CG . Gastroenterology 2015 150 (2) 355-7 e3 There have been increasing reports of food-borne zoonotic transmission of hepatitis E virus (HEV) genotype 3, which causes chronic infections in immunosuppressed patients. We performed phylogenetic analyses of the HEV sequence (partial and full-length) from 1 patient from the Middle East who underwent liver transplantation, and compared these with other orthohepevirus A sequences. We found the patient to be infected by camelid HEV. This patient regularly consumed camel meat and milk, so camelid HEV, which is genotype 7, might infect humans. Our finding links consumption of camel-derived food products to post-transplantation hepatitis E, which, if detected at early stages, can be cured with antiviral therapy and reduced administration of immunosuppressive agents. |
Fatal Accelerated Cirrhosis after Imported HEV Genotype 4 Infection.
Perumpail RB , Ahmed A , Higgins JP , So SK , Cochran JL , Drobeniuc J , Mixson-Hayden TR , Teo CG . Emerg Infect Dis 2015 21 (9) 1679-81 Hepatitis E is a viral hepatitide that is endemic in many developing countries. In its classic form, it results from ingesting fecally contaminated water that carries hepatitis E virus (HEV), and it frequently resolves without treatment. When hepatitis E is imported to the United States, it originates mainly from persons who have acquired HEV genotype 1 infection from South Asia (1). We report imported HEV genotype 4 infection (Technical Appendix Figure, panel A) in a patient during which cirrhosis and fatal hepatic decompensation ensued. | The patient was a 68-year-old man of Chinese ethnicity who had been a California resident since 1985. He sought treatment for mild jaundice in April 2013 in Hong Kong, where he had been staying for 7 weeks. Sixteen years before, he had undergone orthotopic liver transplantation at Stanford University Medical Center (Palo Alto, California, USA) for hepatitis B cirrhosis. Since then, he had received entecavir and tacrolimus for maintenance and had been vaccinated against hepatitis A virus. Until his current illness, routine liver function tests had not indicated hepatic dysfunction (values in November 2012: alanine aminotransferase 2 IU/L, aspartate aminotransferase 24 IU/L, alkaline phosphatase 67 IU/L, total bilirubin 0.5 mg/dL). |
Re-evaluation of an Acanthamoeba Molecular Diagnostic Algorithm following an Atypical Case of Amoebic Keratitis.
Lau R , Cunanan M , Jackson J , Ali IK , Chong-Kit A , Gasgas J , Tian J , Ralevski F , Boggild AK . J Clin Microbiol 2015 BACKGROUND: Amoebic keratitis (AK) is a potentially blinding infection, the prompt diagnosis of which is essential to limiting ocular morbidity. We undertook a quality improvement initiative around the molecular detection of Acanthamoebae in our laboratory due to an unusual case of discordance. METHODS: Nine ATCC strains of Acanthamoeba and 40 delinked, biobanked surplus corneal scrapings were retrieved and analyzed for the presence of Acanthamoebae by 4 separate real time PCR assays. The assay used by the Free Living and Intestinal Amebas laboratory of the CDC was considered the reference standard, and performance characteristics of each individual assay, and pairs of assays were calculated. Outcome measures were sensitivity, specificity, and positive predictive value (PPV) and negative (NPV) predictive value. RESULTS: Of 49 included specimens, 14 (28.6%) were positive by the gold standard assay, and 35 (71.4%) were negative. Sensitivity of the individual test assays ranged from 64.3% to 92.9% compared to the gold standard, while specificity ranged from 88.6% to 91.4%. PPV and NPV ranged from 69.2% to 78.6%, and 86.1% to 96.9%, respectively. Combinations of assay pairs led to improved performance with sensitivities ranging from 92.9% to 100%, and specificity from 97.1% to 100%. ATCC and clinical strains of Acanthamoeba that failed detection by certain individual assays included A. castellani, A. culbertsoni, and A. lenticulata. In 3 clinical specimens, false negativity of the gold standard assay could not be excluded. CONCLUSIONS: Molecular diagnostic approaches, especially combinations of both highly sensitive and specific assays, offer a reasonably performing, operator independent, and rapid strategy for the detection of Acanthamoebae from clinical specimens, and are likely more practical than either culture or direct microscopic detection. |
Apolipoprotein E and protection against hepatitis E virus infection in American, non-Hispanic blacks.
Zhang L , Yesupriya A , Chang MH , Teshale E , Teo CG . Hepatology 2015 62 (5) 1346-52 Hepatitis E virus (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks address environmental and host behavioral/lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between anti-HEV IgG seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non-Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms (SNPs) across 190 genes (particularly those associated with lipid metabolism). Genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV IgG (15.3%; 95% confidence interval [CI], 12.3%-19.0%), compared with non-Hispanic whites (22.3%; 95% CI, 19.1%-25.7%), and Mexican Americans (21.8%; 95% CI, 19.0%-25.3%) (P < 0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional epsilon3 and epsilon4 alleles of apolipoprotein E (APOE) gene, encoding apolipoprotein E protein that mediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE epsilon4 (odds ratio [OR], 0.5; 95%CI, 0.4-0.7; P = 0.00004) and epsilon3 (OR, 0.6; 95%CI, 0.4-0.8; P = 0.001) compared to those carrying APOE epsilon2. No significant associations were observed between other SNPs and anti-HEV seropositivity in non-Hispanic blacks or between any SNPs and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans. CONCLUSION: APOE epsilon3 and epsilon4 are significantly associated with protection against HEV infection in non-Hispanic blacks. Additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons. |
Recent population expansions of hepatitis B virus in the United States.
Ramachandran S , Purdy MA , Xia GL , Campo DS , Dimitrova ZE , Teshale EH , Teo CG , Khudyakov YE . J Virol 2014 88 (24) 13971-80 The recent epidemic history of hepatitis B virus (HBV) infections in the United States is complex, as indicated by current disparity in HBV genotype distribution between acute and chronic hepatitis B cases and rapid decline in hepatitis B incidence since the 1990s. We report temporal changes in genetic composition of the HBV population using whole-genome sequences (n=179) from acute hepatitis B cases (n=1206) identified through the Sentinel County Surveillance for Acute Hepatitis (1998-2006). HBV belonged mainly to subtypes A2 (75%) and D3 (18%), with times of their most recent common ancestors being, respectively, 1979 and 1987, respectively. A2 underwent rapid population expansions in ca. 1995 and ca. 2002, coinciding with transient rises in acute hepatitis B notification rates among adults; D3 underwent expansion in ca. 1998. A2 strains from cases identified after 2002, compared to those before 2002, tended to cluster phylogenetically, indicating selective expansion of specific strains, and were significantly reduced in genetic diversity (p = 0.001) and frequency of drug-resistance mutations (p = 0.001). The expansion of genetically close HBV A2 strains was associated with risk of infection among male homosexuals (p = 0.03). Incident HBV strains circulating in the US were recent in origin, and restricted in genetic diversity. Disparate transmission dynamics among phylogenetic lineages affected the genetic composition of HBV populations and their capacity to maintain drug-resistance mutations. The tendency of selectively expanding HBV strains to be transmitted among male homosexuals highlights the need to improve hepatitis B vaccination coverage among at-risk adults. IMPORTANCE: Hepatitis B virus (HBV) remains an important cause of acute and chronic liver disease globally, and in the United States. Genetic analysis of HBV whole genomes from cases of acute hepatitis B identified from 1998-2006 in the United States showed dominance of genotype A2 (75%), followed by D3 (18%). Strains of both subtypes were recent in origin and underwent rapid population expansions from 1995-2000, indicating increase in transmission rate for certain HBV strains during a period of decline in the reported incidence of acute hepatitis B in the US. HBV A2 strains from a particular cluster that experienced the most recent population expansion were more commonly detected among men who have sex with men. Vaccination needs to be stepped up to protect persons who remain at risk of HBV infection. |
Next-generation sequencing reveals large connected networks of intra-host HCV variants.
Campo DS , Dimitrova Z , Yamasaki L , Skums P , Lau DT , Vaughan G , Forbi JC , Teo CG , Khudyakov Y . BMC Genomics 2014 15 Suppl 5 S4 BACKGROUND: Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host. RESULTS: Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient. CONCLUSIONS: Most intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance. |
Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Wang Z , Zhu B , Zhang M , Parikh H , Jia J , Chung CC , Sampson JN , Hoskins JW , Hutchinson A , Burdette L , Ibrahim A , Hautman C , Raj PS , Abnet CC , Adjei AA , Ahlbom A , Albanes D , Allen NE , Ambrosone CB , Aldrich M , Amiano P , Amos C , Andersson U , Andriole G Jr , Andrulis IL , Arici C , Arslan AA , Austin MA , Baris D , Barkauskas DA , Bassig BA , Beane Freeman LE , Berg CD , Berndt SI , Bertazzi PA , Biritwum RB , Black A , Blot W , Boeing H , Boffetta P , Bolton K , Boutron-Ruault MC , Bracci PM , Brennan P , Brinton LA , Brotzman M , Bueno-de-Mesquita HB , Buring JE , Butler MA , Cai Q , Cancel-Tassin G , Canzian F , Cao G , Caporaso NE , Carrato A , Carreon T , Carta A , Chang GC , Chang IS , Chang-Claude J , Che X , Chen CJ , Chen CY , Chen CH , Chen C , Chen KY , Chen YM , Chokkalingam AP , Chu LW , Clavel-Chapelon F , Colditz GA , Colt JS , Conti D , Cook MB , Cortessis VK , Crawford ED , Cussenot O , Davis FG , De Vivo I , Deng X , Ding T , Dinney CP , Di Stefano AL , Diver WR , Duell EJ , Elena JW , Fan JH , Feigelson HS , Feychting M , Figueroa JD , Flanagan AM , Fraumeni JF Jr , Freedman ND , Fridley BL , Fuchs CS , Gago-Dominguez M , Gallinger S , Gao YT , Gapstur SM , Garcia-Closas M , Garcia-Closas R , Gastier-Foster JM , Gaziano JM , Gerhard DS , Giffen CA , Giles GG , Gillanders EM , Giovannucci EL , Goggins M , Gokgoz N , Goldstein AM , Gonzalez C , Gorlick R , Greene MH , Gross M , Grossman HB , Grubb R 3rd , Gu J , Guan P , Haiman CA , Hallmans G , Hankinson SE , Harris CC , Hartge P , Hattinger C , Hayes RB , He Q , Helman L , Henderson BE , Henriksson R , Hoffman-Bolton J , Hohensee C , Holly EA , Hong YC , Hoover RN , Hosgood HD 3rd , Hsiao CF , Hsing AW , Hsiung CA , Hu N , Hu W , Hu Z , Huang MS , Hunter DJ , Inskip PD , Ito H , Jacobs EJ , Jacobs KB , Jenab M , Ji BT , Johansen C , Johansson M , Johnson A , Kaaks R , Kamat AM , Kamineni A , Karagas M , Khanna C , Khaw KT , Kim C , Kim IS , Kim YH , Kim YC , Kim YT , Kang CH , Jung YJ , Kitahara CM , Klein AP , Klein R , Kogevinas M , Koh WP , Kohno T , Kolonel LN , Kooperberg C , Kratz CP , Krogh V , Kunitoh H , Kurtz RC , Kurucu N , Lan Q , Lathrop M , Lau CC , Lecanda F , Lee KM , Lee MP , Le Marchand L , Lerner SP , Li D , Liao LM , Lim WY , Lin D , Lin J , Lindstrom S , Linet MS , Lissowska J , Liu J , Ljungberg B , Lloreta J , Lu D , Ma J , Malats N , Mannisto S , Marina N , Mastrangelo G , Matsuo K , McGlynn KA , McKean-Cowdin R , McNeill LH , McWilliams RR , Melin BS , Meltzer PS , Mensah JE , Miao X , Michaud DS , Mondul AM , Moore LE , Muir K , Niwa S , Olson SH , Orr N , Panico S , Park JY , Patel AV , Patino-Garcia A , Pavanello S , Peeters PH , Peplonska B , Peters U , Petersen GM , Picci P , Pike MC , Porru S , Prescott J , Pu X , Purdue MP , Qiao YL , Rajaraman P , Riboli E , Risch HA , Rodabough RJ , Rothman N , Ruder AM , Ryu JS , Sanson M , Schned A , Schumacher FR , Schwartz AG , Schwartz KL , Schwenn M , Scotlandi K , Seow A , Serra C , Serra M , Sesso HD , Severi G , Shen H , Shen M , Shete S , Shiraishi K , Shu XO , Siddiq A , Sierrasesumaga L , Sierri S , Sihoe AD , Silverman DT , Simon M , Southey MC , Spector L , Spitz M , Stampfer M , Stattin P , Stern MC , Stevens VL , Stolzenberg-Solomon RZ , Stram DO , Strom SS , Su WC , Sund M , Sung SW , Swerdlow A , Tan W , Tanaka H , Tang W , Tang ZZ , Tardon A , Tay E , Taylor PR , Tettey Y , Thomas DM , Tirabosco R , Tjonneland A , Tobias GS , Toro JR , Travis RC , Trichopoulos D , Troisi R , Truelove A , Tsai YH , Tucker MA , Tumino R , Van Den Berg D , Van Den Eeden SK , Vermeulen R , Vineis P , Visvanathan K , Vogel U , Wang C , Wang C , Wang J , Wang SS , Weiderpass E , Weinstein SJ , Wentzensen N , Wheeler W , White E , Wiencke JK , Wolk A , Wolpin BM , Wong MP , Wrensch M , Wu C , Wu T , Wu X , Wu YL , Wunder JS , Xiang YB , Xu J , Yang HP , Yang PC , Yatabe Y , Ye Y , Yeboah ED , Yin Z , Ying C , Yu CJ , Yu K , Yuan JM , Zanetti KA , Zeleniuch-Jacquotte A , Zheng W , Zhou B , Mirabello L , Savage SA , Kraft P , Chanock SJ , Yeager M , Landi MT , Shi J , Chatterjee N , Amundadottir LT . Hum Mol Genet 2014 23 (24) 6616-33 Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. |
Neurovirulence and immunogenicity of attenuated recombinant vesicular stomatitis viruses in nonhuman primates
Clarke DK , Nasar F , Chong S , Johnson JE , Coleman JW , Lee M , Witko SE , Kotash CS , Abdullah R , Megati S , Luckay A , Nowak B , Lackner A , Price RE , Little P , Kalyan N , Randolf V , Javadian A , Zamb TJ , Parks CL , Egan MA , Eldridge J , Hendry M , Udem SA . J Virol 2014 88 (12) 6690-6701 In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE: The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans. |
Influenza seasonality and vaccination timing in tropical and subtropical areas of southern and south-eastern Asia
Saha S , Chadha M , Al Mamun A , Rahman M , Sturm-Ramirez K , Chittaganpitch M , Pattamadilok S , Olsen SJ , Dwi Sampurno O , Setiawaty V , Nur Andriana Pangesti K , Samaan G , Archkhawongs S , Vongphrachanh P , Phonekeo D , Corwin A , Sok T , Buchy P , Chea N , Kitsutani P , Le Quynh M , Vu Dinh T , Lin R , Low C , Chong Chee K , Ismail N , Apandi Yusof M , Tandoc Iii A , Roque Jr V , Mishra A , Moen AC , Widdowson M-C , Partridge J , Lal RB . Bull World Health Organ 2014 92 (5) 318-330 OBJECTIVE: To characterize influenza seasonality and identify the best time of the year for vaccination against influenza in tropical and subtropical countries of southern and south-eastern Asia that lie north of the equator. METHODS: Weekly influenza surveillance data for 2006 to 2011 were obtained from Bangladesh, Cambodia, India, Indonesia, the Lao People's Democratic Republic, Malaysia, the Philippines, Singapore, Thailand and Viet Nam. Weekly rates of influenza activity were based on the percentage of all nasopharyngeal samples collected during the year that tested positive for influenza virus or viral nucleic acid on any given week. Monthly positivity rates were then calculated to define annual peaks of influenza activity in each country and across countries. FINDINGS: Influenza activity peaked between June/July and October in seven countries, three of which showed a second peak in December to February. Countries closer to the equator had year-round circulation without discrete peaks. Viral types and subtypes varied from year to year but not across countries in a given year. The cumulative proportion of specimens that tested positive from June to November was > 60% in Bangladesh, Cambodia, India, the Lao People's Democratic Republic, the Philippines, Thailand and Viet Nam. Thus, these tropical and subtropical countries exhibited earlier influenza activity peaks than temperate climate countries north of the equator. CONCLUSION: Most southern and south-eastern Asian countries lying north of the equator should consider vaccinating against influenza from April to June; countries near the equator without a distinct peak in influenza activity can base vaccination timing on local factors. |
Impact of immunosuppression on recall immune responses to influenza vaccination in stable renal transplant recipients
Cowan M , Chon WJ , Desai A , Andrews S , Bai Y , Veguilla V , Katz JM , Josephson MA , Wilson PC , Sciammas R , Chong AS . Transplantation 2013 97 (8) 846-53 BACKGROUND: The recommendation by the American Society of Transplantation for annual trivalent inactivated influenza vaccination greater than 3 to 6 months post-kidney transplantation provides a unique opportunity to test the in vivo impact of immunosuppression on recall T- and B-cell responses to influenza vaccination. METHODS: This study took advantage of recent breakthroughs in the single-cell quantification of human peripheral blood B-cell responses to prospectively evaluate both B- and T-cell responses to the seasonal (2010 and 2011) influenza vaccine in 23 stable renal transplant recipients and 22 healthy controls. RESULTS AND CONCLUSION: The results demonstrate that the early B-cell response to influenza vaccination, quantified by the frequency of influenza-specific antibody-secreting cells (ASC) in peripheral blood, was significantly reduced in stable transplant recipients compared to healthy controls. The magnitude of the seroresponse and the rate of seroconversion were also blunted. The influenza-specific interferon-gamma (IFNgamma) T-cell response was significantly reduced in transplant recipients; however, there was no correlation between the magnitude of the influenza-specific IgG ASC and IFNgamma responses. The induction of memory T- and B-cell responses to influenza vaccination supports the recommendation to vaccinate while the blunted responses demonstrate the efficacy of immunosuppression in controlling memory responses individual transplant recipients. |
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