Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-30 (of 37 Records) |
Query Trace: Hoffmann D[original query] |
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TMEM41B is a pan-flavivirus host factor (preprint)
Hoffmann HH , Schneider WM , Rozen-Gagnon K , Miles LA , Schuster F , Razooky B , Jacobson E , Wu X , Yi S , Rudin CM , MacDonald MR , McMullan LK , Poirier JT , Rice CM . bioRxiv 2020 11 11 Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. | HIGHLIGHTS: TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection. |
SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility (preprint)
Zhou B , Thao TTN , Hoffmann D , Taddeo A , Ebert N , Labroussaa F , Pohlmann A , King J , Portmann J , Halwe NJ , Ulrich L , Trüeb BS , Kelly JN , Fan X , Hoffmann B , Steiner S , Wang L , Thomann L , Lin X , Stalder H , Pozzi B , de Brot S , Jiang N , Cui D , Hossain J , Wilson M , Keller M , Stark TJ , Barnes JR , Dijkman R , Jores J , Benarafa C , Wentworth DE , Thiel V , Beer M . bioRxiv 2020 During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic (1) . However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro , it provides a real competitive advantage in vivo , particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating. |
Fatal case of heartland virus disease acquired in the Mid-Atlantic Region, United States
Liu S , Kannan S , Meeks M , Sanchez S , Girone KW , Broyhill JC , Martines RB , Bernick J , Flammia L , Murphy J , Hills SL , Burkhalter KL , Laven JJ , Gaines D , Hoffmann CJ . Emerg Infect Dis 2023 29 (5) 992-996 Heartland virus (HRTV) disease is an emerging tickborne illness in the midwestern and southern United States. We describe a reported fatal case of HRTV infection in the Maryland and Virginia region, states not widely recognized to have human HRTV disease cases. The range of HRTV could be expanding in the United States. |
SHEA/IDSA/APIC Practice Recommendation: Strategies to prevent healthcare-associated infections through hand hygiene: 2022 Update
Glowicz JB , Landon E , Sickbert-Bennett EE , Aiello AE , deKay K , Hoffmann KK , Maragakis L , Olmsted RN , Polgreen PM , Trexler PA , VanAmringe MA , Wood AR , Yokoe D , Ellingson KD . Infect Control Hosp Epidemiol 2023 44 (3) 1-22 The purpose of this document is to highlight practical recommendations to assist acute-care hospitals in prioritization and implementation of strategies to prevent healthcare-associated infections through hand hygiene. This document updates the Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals through Hand Hygiene, published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America, the Association for Professionals in Infection Control and Epidemiology, the American Hospital Association, and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise. |
Direct outpatient health care costs among commercially insured persons for common foodborne pathogens and acute gastroenteritis, 2012-2015
Whitham HK , Gilliland AE , Collier SA , ScallanWalter E , Hoffmann S . Foodborne Pathog Dis 2022 19 (8) 558-568 Foodborne illness is common in the United States with most, but not all, foodborne pathogens causing symptoms of acute gastroenteritis (AGI). Outpatient care is the most frequent type of medical care sought; however, more accurate estimates of outpatient costs are needed to inform food safety policy decision. Using the U.S. MarketScan Commercial Claims and Encounters database, we quantified the per-visit cost of outpatient visits with any AGI-related diagnosis (including pathogen-specific and nonspecific or symptom-based diagnoses) and for those with a pathogen-specific diagnosis for 1 of 29 pathogens commonly transmitted through food (including pathogens that cause AGI and some that do not). Our estimates included the per-case cost of office visits and associated laboratory tests and procedures as well as the conservative estimates of prescription cost. Most AGI outpatient visits were coded using nonspecific codes (e.g., infectious gastroenteritis), rather than pathogen-specific codes (e.g., Salmonella). From 2012 to 2015, we identified more than 3.4 million initial outpatient visits with any AGI diagnosis and 45,077 with a foodborne pathogen-specific diagnosis. As is typical of treatment cost data, severe cases of illness drove mean costs above median. The mean cost of an outpatient visit with any AGI was $696 compared with the median of $162. The mean costs of visits with pathogen-specific diagnoses ranged from $254 (median $131; interquartile range [IQR]: $98-184) for Streptococcus spp. Group A (n=22,059) to $1761 (median $161; IQR: $104-$1101) for Clostridium perfringens (n=30). Visits with two of the most common causes of foodborne illness, nontyphoidal Salmonella and norovirus, listed as a diagnosis, had mean costs of $841 and $509, respectively. Overall, the median per-case costs of outpatient visits increased with age, with some variation by pathogen. More empirically based estimates of outpatient costs for AGI and specific pathogens can enhance estimates of the economic cost of foodborne illness used to guide food policy and focus prevention efforts. |
Public Health Response to Multistate Salmonella Typhimurium Outbreak Associated with Prepackaged Chicken Salad, United States, 2018.
Greening BJr , Whitham HK , Aldous WK , Hall N , Garvey A , Mandernach S , Kahn EB , Nonnenmacher P , Snow J , Meltzer MI , Hoffmann S . Emerg Infect Dis 2022 28 (6) 1254-1256 Quantifying the effect of public health actions on population health is essential when justifying sustained public health investment. Using modeling, we conservatively estimated that rapid response to a multistate foodborne outbreak of Salmonella Typhimurium in the United States in 2018 potentially averted 94 reported cases and $633,181 in medical costs and productivity losses. |
The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis
Walker TM , Fowler PW , Knaggs J , Hunt M , Peto TE , Walker AS , Crook DW , Walker TM , Miotto P , Cirillo DM , Kser CU , Knaggs J , Iqbal Z , Hunt M , Chindelevitch L , Farhat MR , Comas I , Comas I , Posey J , Omar SV , Peto TE , Walker AS , Crook DW , Suresh A , Uplekar S , Laurent S , Colman RE , Rodwell TC , Nathanson CM , Zignol M , Ismail N , Rodwell TC , Walker AS , Steyn AJC , Lalvani A , Baulard A , Christoffels A , Mendoza-Ticona A , Trovato A , Skrahina A , Lachapelle AS , Brankin A , Piatek A , GibertoniCruz A , Koch A , Cabibbe AM , Spitaleri A , Brandao AP , Chaiprasert A , Suresh A , Barbova A , VanRie A , Ghodousi A , Bainomugisa A , Mandal A , Roohi A , Javid B , Zhu B , Letcher B , Rodrigues C , Nimmo C , Nathanson CM , Duncan C , Coulter C , Utpatel C , Liu C , Grazian C , Kong C , Kser CU , Wilson DJ , Cirillo DM , Matias D , Jorgensen D , Zimenkov D , Chetty D , Moore DA , Clifton DA , Crook DW , vanSoolingen D , Liu D , Kohlerschmidt D , Barreira D , Ngcamu D , SantosLazaro ED , Kelly E , Borroni E , Roycroft E , Andre E , Bttger EC , Robinson E , Menardo F , Mendes FF , Jamieson FB , Coll F , Gao GF , Kasule GW , Rossolini GM , Rodger G , Smith EG , Meintjes G , Thwaites G , Hoffmann H , Albert H , Cox H , Laurenson IF , Comas I , Arandjelovic I , Barilar I , Robledo J , Millard J , Johnston J , Posey J , Andrews JR , Knaggs J , Gardy J , Guthrie J , Taylor J , Werngren J , Metcalfe J , Coronel J , Shea J , Carter J , Pinhata JM , Kus JV , Todt K , Holt K , Nilgiriwala KS , Ghisi KT , Malone KM , Faksri K , Musser KA , Joseph L , Rigouts L , Chindelevitch L , Jarrett L , Grandjean L , Ferrazoli L , Rodrigues M , Farhat M , Schito M , Fitzgibbon MM , Loemb MM , Wijkander M , Ballif M , Rabodoarivelo MS , Mihalic M , Wilcox M , Hunt M , Zignol M , Merker M , Egger M , O'Donnell M , Caws M , Wu MH , Whitfield MG , Inouye M , Mansj M , DangThi MH , Joloba M , Kamal SM , Okozi N , Ismail N , Mistry N , Hoang NN , Rakotosamimanana N , Paton NI , Rancoita PMV , Miotto P , Lapierre P , Hall PJ , Tang P , Claxton P , Wintringer P , Keller PM , Thai PVK , Fowler PW , Supply P , Srilohasin P , Suriyaphol P , Rathod P , Kambli P , Groenheit R , Colman RE , Ong RTH , Warren RM , Wilkinson RJ , Diel R , Oliveira RS , Khot R , Jou R , Tahseen S , Laurent S , Gharbia S , Kouchaki S , Shah S , Plesnik S , Earle SG , Dunstan S , Hoosdally SJ , Mitarai S , Gagneux S , Omar SV , Yao SY , GrandjeanLapierre S , Battaglia S , Niemann S , Pandey S , Uplekar S , Halse TA , Cohen T , Cortes T , Prammananan T , Kohl TA , Thuong NTT , Teo TY , Peto TEA , Rodwell TC , William T , Walker TM , Rogers TR , Surve U , Mathys V , Furi V , Cook V , Vijay S , Escuyer V , Dreyer V , Sintchenko V , Saphonn V , Solano W , Lin WH , vanGemert W , He W , Yang Y , Zhao Y , Qin Y , Xiao YX , Hasan Z , Iqbal Z , Puyen ZM , CryPticConsortium theSeq , Treat Consortium . Lancet Microbe 2022 3 (4) e265-e273 Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (73%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (07%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (914%), moxifloxacin (916%) and ethambutol (933%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation. 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license |
The Use of Whole-Genome Sequencing by the Federal Interagency Collaboration for Genomics for Food and Feed Safety in the United States.
Stevens EL , Carleton HA , Beal J , Tillman GE , Lindsey RL , Lauer AC , Pightling A , Jarvis KG , Ottesen A , Ramachandran P , Hintz L , Katz LS , Folster JP , Whichard JM , Trees E , Timme RE , McDermott P , Wolpert B , Bazaco M , Zhao S , Lindley S , Bruce BB , Griffin PM , Brown E , Allard M , Tallent S , Irvin K , Hoffmann M , Wise M , Tauxe R , Gerner-Smidt P , Simmons M , Kissler B , Defibaugh-Chavez S , Klimke W , Agarwala R , Lindsay J , Cook K , Austerman SR , Goldman D , McGarry S , Hale KR , Dessai U , Musser SM , Braden C . J Food Prot 2022 85 (5) 755-772 This multi-agency report developed under the Interagency Collaboration for Genomics for Food and Feed Safety (Gen-FS) provides an overview of the use of and transition to Whole-Genome Sequencing (WGS) technology to detect and characterize pathogens transmitted commonly by food and identify their sources. We describe foodborne pathogen analysis, investigation, and harmonization efforts among federal agencies, including the National Institutes of Health (NIH); the Department of Health and Human Services' Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA); and the U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS), Agricultural Research Service (ARS), and Animal and Plant Health Inspection Service (APHIS). We describe single nucleotide polymorphism (SNP), core-genome (cg) and whole-genome multi-locus sequence typing (wgMLST) data analysis methods as used in CDC's PulseNet and FDA's GenomeTrakr networks, underscoring the complementary nature of the results for linking genetically related foodborne pathogens during outbreak investigations while allowing flexibility to meet the specific needs of Gen-FS agency partners. We highlight how we apply WGS to pathogen characterization (virulence and antimicrobial resistance profiles), source attribution efforts, and increasing transparency by making the sequences and other data publicly available through the National Center for Biotechnology Information (NCBI). Finally, we highlight the impact of current trends in the use of culture-independent diagnostics tests (CIDT) for human diagnostic testing on analytical approaches related to food safety. Lastly, we highlight what is next for WGS in food safety. |
Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.
Ulrich L , Halwe NJ , Taddeo A , Ebert N , Schön J , Devisme C , Trüeb BS , Hoffmann B , Wider M , Fan X , Bekliz M , Essaidi-Laziosi M , Schmidt ML , Niemeyer D , Corman VM , Kraft A , Godel A , Laloli L , Kelly JN , Calderon BM , Breithaupt A , Wylezich C , Veiga IB , Gultom M , Osman S , Zhou B , Adea K , Meyer B , Eberhardt C , Thomann L , Gsell M , Labroussaa F , Jores J , Summerfield A , Drosten C , Eckerle IA , Wentworth DE , Dijkman R , Hoffmann D , Thiel V , Beer M , Benarafa C . Nature 2021 602 (7896) 307-313 Emerging variants of concern (VOC) drive the SARS-CoV-2 pandemic(1,2). Experimental assessment of replication and transmission of major VOC compared to progenitors are needed to understand successful emerging mechanisms of VOC(3). Here, we show that Alpha and Beta spike (S) proteins have a greater affinity to human angiotensin converting enzyme 2 (hACE2) receptor over the progenitor variant (wt-S(614G)) in vitro. Yet Alpha and wt-S(614G) had similar replication kinetics in human nasal airway epithelial cultures, whereas Beta was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over the progenitor variant (wt-S(614G)) in ferrets and two mouse models, where the substitutions in S were major drivers for fitness advantage. In hamsters, supporting high replication levels, Alpha and wt-S(614G) had comparable fitness. In contrast, Beta was outcompeted by Alpha and wt-S(614G) in hamsters and hACE2-expressing mice. Our study highlights the importance of using multiple models for complete fitness characterization of VOC and demonstrates adaptation of Alpha towards increased upper respiratory tract replication and enhanced transmission in vivo in restrictive models, whereas Beta fails to overcome contemporary strains in naïve animals. |
Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.
Dhana A , Hamada Y , Kengne AP , Kerkhoff AD , Rangaka MX , Kredo T , Baddeley A , Miller C , Singh S , Hanifa Y , Grant AD , Fielding K , Affolabi D , Merle CS , Wachinou AP , Yoon C , Cattamanchi A , Hoffmann CJ , Martinson N , Mbu ET , Sander MS , Balcha TT , Skogmar S , Reeve BWP , Theron G , Ndlangalavu G , Modi S , Cavanaugh J , Swindells S , Chaisson RE , Ahmad Khan F , Howard AA , Wood R , Thit SS , Kyi MM , Hanson J , Drain PK , Shapiro AE , Kufa T , Churchyard G , Nguyen DT , Graviss EA , Bjerrum S , Johansen IS , Gersh JK , Horne DJ , LaCourse SM , Al-Darraji HAA , Kamarulzaman A , Kempker RR , Tukvadze N , Barr DA , Meintjes G , Maartens G . Lancet Infect Dis 2021 22 (4) 507-518 BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m(2)), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization. |
SARS-CoV-2 spike D614G change enhances replication and transmission.
Zhou B , Thi Nhu Thao T , Hoffmann D , Taddeo A , Ebert N , Labroussaa F , Pohlmann A , King J , Steiner S , Kelly JN , Portmann J , Halwe NJ , Ulrich L , Trüeb BS , Fan X , Hoffmann B , Wang L , Thomann L , Lin X , Stalder H , Pozzi B , de Brot S , Jiang N , Cui D , Hossain J , Wilson M , Keller M , Stark TJ , Barnes JR , Dijkman R , Jores J , Benarafa C , Wentworth DE , Thiel V , Beer M . Nature 2021 592 (7852) 122-127 During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic(1). However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human host cell surface receptor angiotensin-converting enzyme 2 (ACE2), (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro, it provides a real competitive advantage in vivo, particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating. |
Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.
Bastard P , Michailidis E , Hoffmann HH , Chbihi M , Le Voyer T , Rosain J , Philippot Q , Seeleuthner Y , Gervais A , Materna M , de Oliveira PMN , Maia MLS , Dinis Ano Bom AP , Azamor T , Araújo da Conceição D , Goudouris E , Homma A , Slesak G , Schäfer J , Pulendran B , Miller JD , Huits R , Yang R , Rosen LB , Bizien L , Lorenzo L , Chrabieh M , Erazo LV , Rozenberg F , Jeljeli MM , Béziat V , Holland SM , Cobat A , Notarangelo LD , Su HC , Ahmed R , Puel A , Zhang SY , Abel L , Seligman SJ , Zhang Q , MacDonald MR , Jouanguy E , Rice CM , Casanova JL . J Exp Med 2021 218 (4) Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination. |
Genomic Drivers of Multidrug-Resistant Shigella Affecting Vulnerable Patient Populations in the United States and Abroad.
Worley JN , Javkar K , Hoffmann M , Hysell K , Garcia-Williams A , Tagg K , Kanjilal S , Strain E , Pop M , Allard M , Francois Watkins L , Bry L . mBio 2021 12 (1) Multidrug-resistant (MDR) Shigella infections have been identified globally among men who have sex with men (MSM). The highly drug-resistant phenotype often confounds initial antimicrobial therapy, placing patients at risk for adverse outcomes, the development of more drug-resistant strains, and additional treatment failures. New macrolide-resistant Shigella strains complicate treatment further as azithromycin is a next-in-line antibiotic for MDR strains, and an antibiotic-strain combination confounded by gaps in validated clinical breakpoints for clinical laboratories to interpret macrolide resistance in Shigella We present the first high-resolution genomic analyses of 2,097 U.S. Shigella isolates, including those from MDR outbreaks. A sentinel shigellosis case in an MSM patient revealed a strain carrying 12 plasmids, of which two carried known resistance genes, the pKSR100-related plasmid pMHMC-004 and spA-related plasmid pMHMC-012. Genomic-epidemiologic analyses of isolates revealed high carriage rates of pMHMC-004 predominantly in U.S. isolates from men and not in other demographic groups. Isolates genetically related to the sentinel case further harbored elevated numbers of unique replicons, showing the receptivity of this Shigella lineage to plasmid acquisition. Findings from integrated genomic-epidemiologic analyses were leveraged to direct targeted clinical actions to improve rapid diagnosis and patient care and for public health efforts to further reduce spread.IMPORTANCE Multidrug-resistant Shigella isolates with resistance to macrolides are an emerging public health threat. We define a plasmid/pathogen complex behind infections seen in the United States and globally in vulnerable patient populations and identify multiple outbreaks in the United States and evidence of intercontinental transmission. Using new tools and sequence information, we experimentally identify the drivers of antibiotic resistance that complicate patient treatment to facilitate improvements to clinical microbiologic testing for their detection. We illustrate the use of these methods to support multiagency efforts to combat multidrug-resistant Shigella using publicly available tools, existing genomic data, and resources in clinical microbiology and public health laboratories to inform credible actions to reduce spread. |
TMEM41B Is a Pan-flavivirus Host Factor.
Hoffmann HH , Schneider WM , Rozen-Gagnon K , Miles LA , Schuster F , Razooky B , Jacobson E , Wu X , Yi S , Rudin CM , MacDonald MR , McMullan LK , Poirier JT , Rice CM . Cell 2020 184 (1) 133-148 e20 Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. |
Gen-FS coordinated proficiency test data for genomic foodborne pathogen surveillance, 2017 and 2018 exercises.
Timme RE , Lafon PC , Balkey M , Adams JK , Wagner D , Carleton H , Strain E , Hoffmann M , Sabol A , Rand H , Lindsey R , Sheehan D , Baugher JD , Trees E . Sci Data 2020 7 (1) 402 The US PulseNet and GenomeTrakr laboratory networks work together within the Genomics for Food Safety (Gen-FS) consortium to collect and analyze genomic data for foodborne pathogen surveillance (species include Salmonella enterica, Listeria monocytogenes, Escherichia coli (STECs), and Campylobactor). In 2017 these two laboratory networks started harmonizing their respective proficiency test exercises, agreeing on distributing a single strain-set and following the same standard operating procedure (SOP) for genomic data collection, running a jointly coordinated annual proficiency test exercise. In this data release we are publishing the reference genomes and raw data submissions for the 2017 and 2018 proficiency test exercises. |
2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.
Kuhn JH , Adkins S , Alioto D , Alkhovsky SV , Amarasinghe GK , Anthony SJ , Avšič-Županc T , Ayllón MA , Bahl J , Balkema-Buschmann A , Ballinger MJ , Bartonička T , Basler C , Bavari S , Beer M , Bente DA , Bergeron É , Bird BH , Blair C , Blasdell KR , Bradfute SB , Breyta R , Briese T , Brown PA , Buchholz UJ , Buchmeier MJ , Bukreyev A , Burt F , Buzkan N , Calisher CH , Cao M , Casas I , Chamberlain J , Chandran K , Charrel RN , Chen B , Chiumenti M , Choi IR , Clegg JCS , Crozier I , da Graça JV , Dal Bó E , Dávila AMR , de la Torre JC , de Lamballerie X , de Swart RL , Di Bello PL , Di Paola N , Di Serio F , Dietzgen RG , Digiaro M , Dolja VV , Dolnik O , Drebot MA , Drexler JF , Dürrwald R , Dufkova L , Dundon WG , Duprex WP , Dye JM , Easton AJ , Ebihara H , Elbeaino T , Ergünay K , Fernandes J , Fooks AR , Formenty PBH , Forth LF , Fouchier RAM , Freitas-Astúa J , Gago-Zachert S , Gāo GF , García ML , García-Sastre A , Garrison AR , Gbakima A , Goldstein T , Gonzalez JJ , Griffiths A , Groschup MH , Günther S , Guterres A , Hall RA , Hammond J , Hassan M , Hepojoki J , Hepojoki S , Hetzel U , Hewson R , Hoffmann B , Hongo S , Höper D , Horie M , Hughes HR , Hyndman TH , Jambai A , Jardim R , Jiāng D , Jin Q , Jonson GB , Junglen S , Karadağ S , Keller KE , Klempa B , Klingström J , Kobinger G , Kondō H , Koonin EV , Krupovic M , Kurath G , Kuzmin IV , Laenen L , Lamb RA , Lambert AJ , Langevin SL , Lee B , Lemos ERS , Leroy EM , Li D , Lǐ J , Liang M , Liú W , Liú Y , Lukashevich IS , Maes P , Marciel de Souza W , Marklewitz M , Marshall SH , Martelli GP , Martin RR , Marzano SL , Massart S , McCauley JW , Mielke-Ehret N , Minafra A , Minutolo M , Mirazimi A , Mühlbach HP , Mühlberger E , Naidu R , Natsuaki T , Navarro B , Navarro JA , Netesov SV , Neumann G , Nowotny N , Nunes MRT , Nylund A , Økland AL , Oliveira RC , Palacios G , Pallas V , Pályi B , Papa A , Parrish CR , Pauvolid-Corrêa A , Pawęska JT , Payne S , Pérez DR , Pfaff F , Radoshitzky SR , Rahman AU , Ramos-González PL , Resende RO , Reyes CA , Rima BK , Romanowski V , Robles Luna G , Rota P , Rubbenstroth D , Runstadler JA , Ruzek D , Sabanadzovic S , Salát J , Sall AA , Salvato MS , Sarpkaya K , Sasaya T , Schwemmle M , Shabbir MZ , Shí X , Shí Z , Shirako Y , Simmonds P , Širmarová J , Sironi M , Smither S , Smura T , Song JW , Spann KM , Spengler JR , Stenglein MD , Stone DM , Straková P , Takada A , Tesh RB , Thornburg NJ , Tomonaga K , Tordo N , Towner JS , Turina M , Tzanetakis I , Ulrich RG , Vaira AM , van den Hoogen B , Varsani A , Vasilakis N , Verbeek M , Wahl V , Walker PJ , Wang H , Wang J , Wang X , Wang LF , Wèi T , Wells H , Whitfield AE , Williams JV , Wolf YI , Wú Z , Yang X , Yáng X , Yu X , Yutin N , Zerbini FM , Zhang T , Zhang YZ , Zhou G , Zhou X . Arch Virol 2020 165 (12) 3023-3072 In March 2020, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. At the genus rank, 20 new genera were added, two were deleted, one was moved, and three were renamed. At the species rank, 160 species were added, four were deleted, ten were moved and renamed, and 30 species were renamed. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV. |
Racial differences in sleep duration intersect with sex, socioeconomic status, and U.S. geographic region: The REGARDS study
Petrov ME , Long DL , Grandner MA , MacDonald LA , Cribbet MR , Robbins R , Cundiff JM , Molano JR , Hoffmann CM , Wang X , Howard G , Howard VJ . Sleep Health 2020 6 (4) 442-450 OBJECTIVES: Short and long sleep duration are associated with poor health outcomes and are most prevalent among racial/ethnic minorities. Few studies have investigated the intersection of other sociodemographic characteristics with race/ethnicity on sleep duration prevalence. DESIGN: Longitudinal retrospective analysis of continental U.S. cohort, the REasons for Geographic And Racial Differences in Stroke (REGARDS) PARTICIPANTS: Black (n = 7,547) and white (n = 12,341) adults, 56% women, >/=45 years MEASUREMENTS: At baseline (2003-07), participants reported age, sex, race, education, income, marital status, U.S. region, and employment status. The weighted average of reported sleep duration on weekdays and weekends, assessed at follow-up (2008-10), was categorized as <6, 6.0-6.99, 7.0-7.99 [reference], 8.0-8.99, and >/=9 h. Multinomial logistic regression models examined the independent and multivariable associations of sociodemographic factors with sleep duration. Interactions terms between race with education, income, region, and sex were examined. RESULTS: Average sleep duration was 7.0 h (SD=1.3). Prevalence of short (<6 h) and long (>/=9 h) sleep duration was 11.4% (n = 2,260) and 7.0% (n = 1,395), respectively. In the multivariable model, interactions terms race*income, race*sex, and race*region were significant (P < .05). Relative to white adults, black adults, were most likely to have short sleep duration. The magnitude of that likelihood increased across greater levels of household income, but with greatest odds among black adults living outside of the Southeast and Appalachian United States, particularly for men (>/=$75k; black men OR = 5.47, 95%CI: 3.94,7.54; black women OR = 4.28, 95%CI: 3.08, 5.96). CONCLUSIONS: Race in the context of socioeconomic, sex, and regional factors should be examined as key modifiers of sleep duration. |
Immunological methods for diagnosis and monitoring of IgE-mediated allergy caused by industrial sensitizing agents (IMExAllergy)
Baur X , Akdis CA , Budnik LT , Cruz MJ , Fischer A , Forster-Ruhrmann U , Goen T , Goksel O , Heutelbeck AR , Jones M , Lux H , Maestrelli P , Munoz X , Nemery B , Schlunssen V , Sigsgaard T , Traidl-Hoffmann C , Siegel P . Allergy 2019 74 (10) 1885-1897 Industrial sensitizing agents (allergens) in living and working environments play an important role in eliciting type I allergic disorders including asthma and allergic rhinitis. Successful management of allergic diseases necessitates identifying their specific causes (i.e. identify the causative agent(s) and the route of contact to allergen: airborne, or skin contact) to avoid further exposure. Identification of sensitization by a sensitive and validated measurement of specific-IgE is an important step in the diagnosis. However, only a limited number of environmental and occupational allergens are available on the market for use in sIgE testing. Accordingly, specific in-house testing by individual diagnostic and laboratory centers is often required. Currently, different immunological tests are in use at various diagnostic centers that often produce considerably divergent results, mostly due to lack of standardized allergen preparation and standardized procedures as well as inadequate quality control. Our review and meta-analysis exhibited satisfactory performance of s IgE detection test for most high molecular weight (HMW) allergens with a pooled sensitivity of 0.74 and specificity of 0.71. However, for low molecular weight (LMW) allergens, pooled sensitivity is generally lower (0.28) and specificity higher (0.89) than for HMW tests. Major recommendations based on the presented data include diagnostic use of sIgE to HMW allergens. A negative sIgE results for LMW agents does not exclude sensitization. In addition, the requirements for full transparency of the content of allergen preparations with details on standardization and quality control is underlined. Development of standard operating procedures for in-house sIgE assays, and clinical validation, centralized quality control and audits are emphasized. There is also a need for specialized laboratories to provide a custom service for the development of tests for the measurement of putative novel occupational allergens that are not commercially available. This article is protected by copyright. All rights reserved. |
Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation
Hoffmann S , Devleesschauwer B , Aspinall W , Cooke R , Corrigan T , Havelaar A , Angulo F , Gibb H , Kirk M , Lake R , Speybroeck N , Torgerson P , Hald T . PLoS One 2017 12 (9) e0183641 BACKGROUND: Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. METHODS AND FINDINGS: We used Cooke's Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. CONCLUSIONS: We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in many parts of the world, providing guidance for policy actions to control FBDs. |
Comparative Analysis of Extended Spectrum Beta- Lactamase CTX-M-65-Producing Salmonella Infantis Isolates from Humans, Food Animals, and Retail Chickens in the United States.
Tate H , Folster JP , Hsu CH , Chen J , Hoffmann M , Li C , Morales C , Tyson GH , Mukerjee S , Brown AC , Green A , Wilson W , Dessai U , Abbott J , Joseph L , Haro J , Ayers S , McDermott PF , Zhao S . Antimicrob Agents Chemother 2017 61 (7) We sequenced the genomes of ten Salmonella enterica serovar Infantis containing blaCTX-M-65 isolated from chicken, cattle, and human sources collected between 2012 and 2015 in the United States through routine NARMS surveillance and product sampling programs. We also completely assembled the plasmids from four of the isolates. All isolates had a D87Y mutation in the gyrA gene and harbored between 7 and 10 resistance genes (aph (4)-Ia, aac (3)-IVa, aph(3' )-Ic, blaCTX-M-65, fosA3, floR, dfrA14, sul1, tetA, aadA1) located in two distinct sites of a megaplasmid ( approximately 316-323kb) similar to that described in a blaCTX-M-65-positive S. Infantis isolated from a patient in Italy. High-quality single nucleotide polymorphism (hqSNP) analysis revealed that all U.S. isolates were closely related, separated by only 1 to 38 pairwise high quality SNPs, indicating a high likelihood that strains from humans, chicken, and cattle recently evolved from a common ancestor. The U.S. isolates were genetically similar to the blaCTX-M-65-positive S. Infantis isolate from Italy, with a separation of 34 to 47 SNPs. This is the first report of the blaCTX-M-65 gene and the pESI-like megaplasmid from S. Infantis in the United States, and illustrates the importance of applying a global One Health, human and animal perspective to combat antimicrobial resistance. |
Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.
Rhee SY , Varghese V , Holmes SP , Van Zyl GU , Steegen K , Boyd MA , Cooper DA , Nsanzimana S , Saravanan S , Charpentier C , de Oliveira T , Etiebet MA , Garcia F , Goedhals D , Gomes P , Gunthard HF , Hamers RL , Hoffmann CJ , Hunt G , Jiamsakul A , Kaleebu P , Kanki P , Kantor R , Kerschberger B , Marconi VC , D'Amour Ndahimana J , Ndembi N , Ngo-Giang-Huong N , Rokx C , Santoro MM , Schapiro JM , Schmidt D , Seu L , Sigaloff KC , Sirivichayakul S , Skhosana L , Sunpath H , Tang M , Yang C , Carmona S , Gupta RK , Shafer RW . EBioMedicine 2017 18 225-235 Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naive individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen. |
Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub Saharan Africa: A retrospective multi-centre cohort study
Gregson J , Kaleebu P , Marconi VC , van Vuuren C , Ndembi N , Hamers RL , Kanki P , Hoffmann CJ , Lockman S , Pillay D , de Oliveira T , Clumeck N , Hunt G , Kerschberger B , Shafer RW , Yang C , Raizes E , Kantor R , Gupta RK . Lancet Infect Dis 2016 17 (3) 296-304 BACKGROUND: HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART. METHODS: We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs. FINDINGS: Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60.5 cells per muL [IQR 21.0-128.0] in patients with TAMS vs 95.0 cells per muL [37.0-177.0] in patients without TAMs; p=0.007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0.0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0.0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0.0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0.64 (p<0.0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1.29 (1.13-1.47; p<0.0001) INTERPRETATION: TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains. FUNDING: The Wellcome Trust. |
Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study
null , Carlo DD , Bester PA , Reyes-Teran G , Romero K , Avila-Rios S , Gregson J , Tang M , Rhee SY , Shafer RW , Ndembi N , Hamers RL , de Wit TFR , Marconi VC , Diero L , Brooks K , Theys K , Camacho R , Kantor R , Arruda M , Garcia F , Monge S , Gunthard HF , Hoffmann CJ , Kanki PJ , Kumarasamy N , Kerschberger B , Mor O , Charpentier C , Todesco E , Rokx C , Gras L , Halvas EK , Sunpath H , Di Carlo D , Santoro MM , Antinori A , Andreoni M , Latini A , Mussini C , Aghokeng A , Sonnerborg A , Neogi U , Fessel WJ , Agolory S , Raizes E , Yang C , Blanco JL , Juma JM , Smit E , Schmidt D , Watera C , Asio J , Kirungi W , Tostevin A , Dunn D , El-Hay T , Clumeck N , Goedhals D , van Vuuren C , Sabin C , Mukui I , Perno CF , Hunt G , Morris L , de Oliveira T , Pillay D , Gupta RK , Schulter E , Murakami-Ogasawara A , Sirivichayakul S , Ruxrungtham K , Mekprasan S , Kaleebu P . Lancet Infect Dis 2016 16 (5) 565-575 BACKGROUND: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. METHODS: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. FINDINGS: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1.50, 95% CI 1.27-1.77 for CD4 cell count <100 cells per muL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1.48, 95% CI 1.20-1.82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0.626]). INTERPRETATION: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. FUNDING: The Wellcome Trust. |
World Health Organization estimates of the relative contributions of food to the burden of disease due to selected foodborne hazards: a structured expert elicitation
Hald T , Aspinall W , Devleesschauwer B , Cooke R , Corrigan T , Havelaar AH , Gibb HJ , Torgerson PR , Kirk MD , Angulo FJ , Lake RJ , Speybroeck N , Hoffmann S . PLoS One 2016 11 (1) e0145839 BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization (WHO) to estimate the global burden of foodborne diseases (FBDs). This estimation is complicated because most of the hazards causing FBD are not transmitted solely by food; most have several potential exposure routes consisting of transmission from animals, by humans, and via environmental routes including water. This paper describes an expert elicitation study conducted by the FERG Source Attribution Task Force to estimate the relative contribution of food to the global burden of diseases commonly transmitted through the consumption of food. METHODS AND FINDINGS: We applied structured expert judgment using Cooke's Classical Model to obtain estimates for 14 subregions for the relative contributions of different transmission pathways for eleven diarrheal diseases, seven other infectious diseases and one chemical (lead). Experts were identified through international networks followed by social network sampling. Final selection of experts was based on their experience including international working experience. Enrolled experts were scored on their ability to judge uncertainty accurately and informatively using a series of subject-matter specific 'seed' questions whose answers are unknown to the experts at the time they are interviewed. Trained facilitators elicited the 5th, and 50th and 95th percentile responses to seed questions through telephone interviews. Cooke's Classical Model uses responses to the seed questions to weigh and aggregate expert responses. After this interview, the experts were asked to provide 5th, 50th, and 95th percentile estimates for the 'target' questions regarding disease transmission routes. A total of 72 experts were enrolled in the study. Ten panels were global, meaning that the experts should provide estimates for all 14 subregions, whereas the nine panels were subregional, with experts providing estimates for one or more subregions, depending on their experience in the region. The size of the 19 hazard-specific panels ranged from 6 to 15 persons with several experts serving on more than one panel. Pathogens with animal reservoirs (e.g. non-typhoidal Salmonella spp. and Toxoplasma gondii) were in general assessed by the experts to have a higher proportion of illnesses attributable to food than pathogens with mainly a human reservoir, where human-to-human transmission (e.g. Shigella spp. and Norovirus) or waterborne transmission (e.g. Salmonella Typhi and Vibrio cholerae) were judged to dominate. For many pathogens, the foodborne route was assessed relatively more important in developed subregions than in developing subregions. The main exposure routes for lead varied across subregions, with the foodborne route being assessed most important only in two subregions of the European region. CONCLUSIONS: For the first time, we present worldwide estimates of the proportion of specific diseases attributable to food and other major transmission routes. These findings are essential for global burden of FBD estimates. While gaps exist, we believe the estimates presented here are the best current source of guidance to support decision makers when allocating resources for control and intervention, and for future research initiatives. |
No virological evidence for an influenza A - like virus in European bats
Fereidouni S , Kwasnitschka L , Balkema Buschmann A , Müller T , Freuling C , Schatz J , Pikula J , Bandouchova H , Hoffmann R , Ohlendorf B , Kerth G , Tong S , Donis R , Beer M , Harder T . Zoonoses Public Health 2015 62 (3) 187-9 New members of the influenza A virus genus have been detected recently in bats from South America. By molecular investigations, using a generic real-time RT-PCR (RT-qPCR) that detects all previously known influenza A virus subtypes (H1-H16) and a newly developed RT-qPCR specific for the South American bat influenza-like virus of subtype H17, a total of 1571 samples obtained from 1369 individual bats of 26 species from Central Europe were examined. No evidence for the occurrence of such influenza viruses was found. Further attempts towards a more comprehensive evaluation of the role of bats in the ecology and epidemiology of influenza viruses should be based on more intense monitoring efforts. However, given the protected status of bats, not only in Europe, such activities need to be embedded into existing pathogen-monitoring programs. |
Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an IPD meta-analysis
Muthuri SG , Venkatesan S , Myles PR , Leonardi-Bee J , Lim WS , Mamun AA , Anovadiya AP , Araujo WN , Azziz-Baumgartner E , Baez C , Bantar C , Barhoush MM , Bassetti M , Beovic B , Bingisser R , Bonmarin I , Borja-Aburto VH , Cao B , Carratala J , Cuezzo MR , Denholm JT , Dominguez SR , Duarte PA , Dubnov-Raz G , Echavarria M , Fanella S , Fraser J , Gao Z , Gerardin P , Giannella M , Gubbels S , Herberg J , Iglesias AL , Hoeger PH , Hoffmann M , Hu X , Islam QT , Jimenez MF , Kandeel A , Keijzers G , Khalili H , Khandaker G , Knight M , Kusznierz G , Kuzman I , Kwan AM , Amine IL , Langenegger E , Lankarani KB , Leo YS , Linko R , Liu P , Madanat F , Manabe T , Mayo-Montero E , McGeer A , Memish ZA , Metan G , Mikic D , Mohn KG , Moradi A , Nymadawa P , Ozbay B , Ozkan M , Parekh D , Paul M , Poeppl W , Polack FP , Rath BA , Rodriguez AH , Siqueira MM , Skret-Magierlo J , Talarek E , Tang JW , Torres A , Torun SH , Tran D , Uyeki TM , van Zwol A , Vaudry W , Velyvyte D , Vidmar T , Zarogoulidis P , Nguyen-Van-Tam JS . Influenza Other Respir Viruses 2015 10 (3) 192-204 BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on Influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta-analysis of individual participant data (IPD) from 20,634 hospitalised patients with laboratory confirmed A(H1N1)pdm09 (n=20,021) or clinically diagnosed (n=613) 'pandemic influenza'. The primary outcome was radiologically confirmed influenza-related pneumonia (IRP). Odds ratios (OR) were estimated using generalized linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Among 20,634 included participants, 5,978 (29.0%) had IRP; conversely, 3,349 (16.2%) had confirmed absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0.83 (95%CI 0.64 - 1.06; p=0.136)]. Among the 5,978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR=0.72 (0.44-1.17; p=0.180)] or likelihood of requiring ventilatory support [adj. OR=1.17 (0.71-1.92; p=0.537)]; but early treatment versus later significantly reduced mortality [adj. OR=0.70 (0.55-0.88; p=0.003)] and likelihood of requiring ventilatory support [adj. OR=0.68 (0.54-0.85; p=0.001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support. |
Influenza virus surveillance by the Instituto Adolfo Lutz, influenza season 2014: antiviral resistance
Santos KC , Silva DB , Benega MA , Paulino Rde S , ESilva ER Jr , Pereira Ddos S , Mussi AD , Silva VC , Gubareva L V , Paiva TM . Rev Inst Med Trop Sao Paulo 2015 57 (1) 92 Neuraminidase (NA) inhibitors (NAIs) are the only antivirals that are effective for prophylaxis and the treatment of seasonal influenza A and B infections. There are currently two NAIs approved in most countries: oseltamivir (Tamiflu; F. Hoffmann - La Roche) and zanamivir (Relenza; GlaxoSmithKline plc.). The development of drug resistance is a major drawback for any antiviral therapy, and these specific anti-influenza drugs are not excluded from this rule. Thus, the proper use of NAIs and worldwide monitoring for the presence and spread of drug resistant influenza viruses are of the utmost importance. The existence of a global surveillance network for influenza, underpinning vaccine strain selection, is a valuable asset when seeking to track the emergence of antiviral resistance. | The Instituto Adolfo Lutz, São Paulo, SP, Brazil, plays a role in national and global influenza surveillance. The objective of the present study was to monitor antiviral resistance to assist public health authorities with decisions regarding prophylaxis and treatment strategies. | Using the real time polymerase chain reaction assay (rRT-PCR), influenza viruses of type A, subtype H1N1pdm09 and H3N2, as well as type B viruses, were identified and antiviral resistance testing was conducted using pyrosequencing2 and Sanger dideoxy sequence analysis5. | Prior to the emergence of the pandemic virus in 2009, the presence of the oseltamivir resistance-conferring marker, H275Y, was identified in seasonal influenza A (H1N1). In 2014, influenza virus surveillance identified the same marker, H275Y, in an influenza A (H1N1) pdm09 strain isolated from a 20 year-old pregnant woman living in Mato Grosso/Cuiabá, the Midwest region of Brazil. The virus was collected in March 2014. In addition, two permissive secondary NA mutations; V241I and N369K were detected in the virus isolated in the Midwest region of Brazil1. These mutations are known to negate the impact of the NA H275Y oseltamivir resistance mutation on viral replicative fitness. This patient was treated with oseltamivir, rocephin, azithromycin and made a full recovery from the respiratory disease. | The choice of assay for assessing the susceptibility of the influenza virus to NAIs depends on factors pertaining to appropriateness of the setting, cost, sustainability, speed in obtaining valid results, reliability in terms of predictive values, and accessibility. The high sensitivity of genotypic assays allows for testing of clinical specimens, thus eliminating the need for virus propagation in cell culture. In addition, rapid genotypic testing facilitates more appropriate patient management and can significantly advance and assist in large-scale epidemiological studies of drug-resistant variants4. | |
Comparative genomic analysis and virulence differences in closely related salmonella enterica serotype heidelberg isolates from humans, retail meats, and animals.
Hoffmann M , Zhao S , Pettengill J , Luo Y , Monday SR , Abbott J , Ayers SL , Cinar HN , Muruvanda T , Li C , Allard MW , Whichard J , Meng J , Brown EW , McDermott PF . Genome Biol Evol 2014 6 (5) 1046-68 Salmonella enterica subsp. enterica serovar Heidelberg (S. Heidelberg) is one of the top serovars causing human salmonellosis. Recently, an antibiotic-resistant strain of this serovar was implicated in a large 2011 multistate outbreak resulting from consumption of contaminated ground turkey that involved 136 confirmed cases, with one death. In this study, we assessed the evolutionary diversity of 44 S. Heidelberg isolates using whole-genome sequencing (WGS) generated by the 454 GS FLX (Roche) platform. The isolates, including 30 with nearly indistinguishable (one band difference) Xbal pulsed-field gel electrophoresis patterns (JF6X01.0032, JF6X01.0058), were collected from various sources between 1982 and 2011 and included nine isolates associated with the 2011 outbreak. Additionally, we determined the complete sequence for the chromosome and three plasmids from a clinical isolate associated with the 2011 outbreak using the Pacific Biosciences (PacBio) system. Using single-nucleotide polymorphism (SNP) analyses, we were able to distinguish highly clonal isolates, including strains isolated at different times in the same year. The isolates from the recent 2011 outbreak clustered together with a mean SNP variation of only 17 SNPs. The S. Heidelberg isolates carried a variety of phages, such as prophage P22, P4, lambda-like prophage Gifsy-2, and the P2-like phage which carries the sopE1 gene, virulence genes including 62 pathogenicity, and 13 fimbrial markers and resistance plasmids of the incompatibility (Inc)I1, IncA/C, and IncHI2 groups. Twenty-one strains contained an IncX plasmid carrying a type IV secretion system. On the basis of the recent and historical isolates used in this study, our results demonstrated that, in addition to providing detailed genetic information for the isolates, WGS can identify SNP targets that can be utilized for differentiating highly clonal S. Heidelberg isolates. |
Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences.
Nasser W , Beres SB , Olsen RJ , Dean MA , Rice KA , Long SW , Kristinsson KG , Gottfredsson M , Vuopio J , Raisanen K , Caugant DA , Steinbakk M , Low DE , McGeer A , Darenberg J , Henriques-Normark B , Van Beneden CA , Hoffmann S , Musser JM . Proc Natl Acad Sci U S A 2014 111 (17) E1768-76 We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD(+)-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide. |
Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data
Muthuri SG , Venkatesan S , Myles PR , Leonardi-Bee J , Al Khuwaitir TS , Al Mamun A , Anovadiya AP , Azziz-Baumgartner E , Baez C , Bassetti M , Beovic B , Bertisch B , Bonmarin I , Booy R , Borja-Aburto VH , Burgmann H , Cao B , Carratala J , Denholm JT , Dominguez SR , Duarte PA , Dubnov-Raz G , Echavarria M , Fanella S , Gao Z , Gerardin P , Giannella M , Gubbels S , Herberg J , Iglesias AL , Hoger PH , Hu X , Islam QT , Jimenez MF , Kandeel A , Keijzers G , Khalili H , Knight M , Kudo K , Kusznierz G , Kuzman I , Kwan AM , Amine IL , Langenegger E , Lankarani KB , Leo YS , Linko R , Liu P , Madanat F , Mayo-Montero E , McGeer A , Memish Z , Metan G , Mickiene A , Mikic D , Mohn KG , Moradi A , Nymadawa P , Oliva ME , Ozkan M , Parekh D , Paul M , Polack FP , Rath BA , Rodriguez AH , Sarrouf EB , Seale AC , Sertogullarindan B , Siqueira MM , Skret-Magierlo J , Stephan F , Talarek E , Tang JW , To KK , Torres A , Torun SH , Tran D , Uyeki TM , Van Zwol A , Vaudry W , Vidmar T , Yokota RT , Zarogoulidis P , Nguyen-Van-Tam JS . Lancet Respir Med 2014 2 (5) 395-404 BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29 234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0.81; 95% CI 0.70-0.93; p=0.0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0.48; 95% CI 0.41-0.56; p<0.0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0.50; 95% CI 0.37-0.67; p<0.0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1.23] [95% CI 1.18-1.28]; p<0.0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche. |
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