Mia Q Zhu,Guillermina Kuan,Hannah E Maier,Roger Lopez,Abigail Shotwell,Miguel Plazaola,Sergio Ojeda,Nery Sanchez,Angel Balmaseda,Aubree Gordon
The role of under-nutrition on influenza virus shedding is unclear. We assessed stunting, an indicator of chronic under-nutrition, as a predictor of shedding duration in children in the Household Influenza Cohort Study, in Managua, Nicaragua. Stunted children, aged 3-9 years, shed influenza longer than their non-stunted peers. In sub-group analysis, associations were driven by H3N2 and influenza B (IB) infections. Analysis of cycle threshold (Ct) values showed slower clearance of IB viruses in stunted children. These findings suggest under-nutrition may prolong influenza shedding, with implications for transmission dynamics and control strategies in low- and middle-income countries where stunting remains prevalent.
{"title":"Stunting Increases Influenza Virus Shedding Duration in Preschool/School-Aged Children.","authors":"Mia Q Zhu,Guillermina Kuan,Hannah E Maier,Roger Lopez,Abigail Shotwell,Miguel Plazaola,Sergio Ojeda,Nery Sanchez,Angel Balmaseda,Aubree Gordon","doi":"10.1093/infdis/jiaf641","DOIUrl":"https://doi.org/10.1093/infdis/jiaf641","url":null,"abstract":"The role of under-nutrition on influenza virus shedding is unclear. We assessed stunting, an indicator of chronic under-nutrition, as a predictor of shedding duration in children in the Household Influenza Cohort Study, in Managua, Nicaragua. Stunted children, aged 3-9 years, shed influenza longer than their non-stunted peers. In sub-group analysis, associations were driven by H3N2 and influenza B (IB) infections. Analysis of cycle threshold (Ct) values showed slower clearance of IB viruses in stunted children. These findings suggest under-nutrition may prolong influenza shedding, with implications for transmission dynamics and control strategies in low- and middle-income countries where stunting remains prevalent.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Camille Esneau,David Boettiger,Sarah Leask,Nathan E Bryant,Natalie Niessen,Jodie McVernon,Adrian Marcato,Sandra Carlson,Stuart Browne,Rejoy Thomas,Edward C Holmes,Krispin Hajkowicz,Lynelle Tilbrook,Nathan Moon,Craig Dalton,Nathan W Bartlett,Joshua S Davis
BACKGROUNDThe COVID-19 pandemic has underscored the importance of effective surveillance and early warning systems for respiratory viruses, but most current surveillance data focus on symptomatic individuals visiting healthcare facilities. Symptomatic and asymptomatic virus transmission in the community can both play major roles in the spread of respiratory outbreaks. We aimed to assess the feasibility of monitoring symptomatic and asymptomatic respiratory virus infection in a sample of community dwelling volunteers.METHODSThe Pandemic REspiratory Virus Epidemiological SurveillaNce Trial (PREVENT) was nested within the ongoing FluTracking platform, which involves community-dwelling adults filling in a weekly online respiratory symptom survey. We recruited 52 FluTracking participants living in one Australian city to self-collect weekly nasal swabs and return them via post for a 50-week period. All swabs were tested for the presence of respiratory viruses using a 16-plex PCR panel. Results were correlated with weekly symptom surveys.RESULTSA total of 2,068 nasal swabs were received, corresponding to an 84% swab collection and return rate. 55 samples (3.0%) were discarded due to delayed postage or sample leakage. At least one sample tested positive for virus in 231 of 2,013 participant-weeks (11.0%), with 24.2% of these detections being in asymptomatic individuals. Rhinovirus (57.6% of positive swabs) and SARS-COV-2 (20.3% of positive swabs) were the most frequently detected viruses.CONCLUSIONRegular self-collected nasal swabs for detecting respiratory viruses in a community setting is feasible in Australia and provides valuable information on asymptomatic infection.
{"title":"The Pandemic REspiratory Virus Epidemiological SurveillaNce Trial - A self-swab surveillance system for respiratory viruses nested within FluTracking.","authors":"Camille Esneau,David Boettiger,Sarah Leask,Nathan E Bryant,Natalie Niessen,Jodie McVernon,Adrian Marcato,Sandra Carlson,Stuart Browne,Rejoy Thomas,Edward C Holmes,Krispin Hajkowicz,Lynelle Tilbrook,Nathan Moon,Craig Dalton,Nathan W Bartlett,Joshua S Davis","doi":"10.1093/infdis/jiaf632","DOIUrl":"https://doi.org/10.1093/infdis/jiaf632","url":null,"abstract":"BACKGROUNDThe COVID-19 pandemic has underscored the importance of effective surveillance and early warning systems for respiratory viruses, but most current surveillance data focus on symptomatic individuals visiting healthcare facilities. Symptomatic and asymptomatic virus transmission in the community can both play major roles in the spread of respiratory outbreaks. We aimed to assess the feasibility of monitoring symptomatic and asymptomatic respiratory virus infection in a sample of community dwelling volunteers.METHODSThe Pandemic REspiratory Virus Epidemiological SurveillaNce Trial (PREVENT) was nested within the ongoing FluTracking platform, which involves community-dwelling adults filling in a weekly online respiratory symptom survey. We recruited 52 FluTracking participants living in one Australian city to self-collect weekly nasal swabs and return them via post for a 50-week period. All swabs were tested for the presence of respiratory viruses using a 16-plex PCR panel. Results were correlated with weekly symptom surveys.RESULTSA total of 2,068 nasal swabs were received, corresponding to an 84% swab collection and return rate. 55 samples (3.0%) were discarded due to delayed postage or sample leakage. At least one sample tested positive for virus in 231 of 2,013 participant-weeks (11.0%), with 24.2% of these detections being in asymptomatic individuals. Rhinovirus (57.6% of positive swabs) and SARS-COV-2 (20.3% of positive swabs) were the most frequently detected viruses.CONCLUSIONRegular self-collected nasal swabs for detecting respiratory viruses in a community setting is feasible in Australia and provides valuable information on asymptomatic infection.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christina S Thornton,Drake C Bouzek,Lindsay J Caverly
Cystic fibrosis (CF) lung disease is a result of defective CFTR-mediated ion transport, producing dehydrated mucus, impaired mucociliary clearance and an opportune environment for chronic airway infection. CF airway infections are polymicrobial airway ecosystems often dominated by CF pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia, Stenotrophomonas, Achromobacter, and nontuberculous mycobacteria that drive cycles of infection, inflammation, and bronchiectasis. Highly effective CFTR modulators, including elexacaftor/tezacaftor/ivacaftor, improve airway hydration and mucociliary clearance and reduce pathogen CF acquisition and density. However, even with CFTR modulator treatment, most individuals with established infection remain chronically infected, and long-term impacts of CFTR modulators on airway infection dynamics and associated clinical outcomes remain unclear. In this review, we address key gaps in understanding chronic infection in the CFTR modulator era, including changes in infection-related lung disease pathogenesis, airway-gut microbiome interactions, approaches to airway infection sampling, and implications for infection management.
{"title":"Microbiota, Mucus, and Modulators: CF Infection Pathogenesis in the CFTR Modulator Era.","authors":"Christina S Thornton,Drake C Bouzek,Lindsay J Caverly","doi":"10.1093/infdis/jiaf626","DOIUrl":"https://doi.org/10.1093/infdis/jiaf626","url":null,"abstract":"Cystic fibrosis (CF) lung disease is a result of defective CFTR-mediated ion transport, producing dehydrated mucus, impaired mucociliary clearance and an opportune environment for chronic airway infection. CF airway infections are polymicrobial airway ecosystems often dominated by CF pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia, Stenotrophomonas, Achromobacter, and nontuberculous mycobacteria that drive cycles of infection, inflammation, and bronchiectasis. Highly effective CFTR modulators, including elexacaftor/tezacaftor/ivacaftor, improve airway hydration and mucociliary clearance and reduce pathogen CF acquisition and density. However, even with CFTR modulator treatment, most individuals with established infection remain chronically infected, and long-term impacts of CFTR modulators on airway infection dynamics and associated clinical outcomes remain unclear. In this review, we address key gaps in understanding chronic infection in the CFTR modulator era, including changes in infection-related lung disease pathogenesis, airway-gut microbiome interactions, approaches to airway infection sampling, and implications for infection management.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brian M Schmidt,Piyush Ranjan,John Erb-Downward,Robert P Dickson
BACKGROUNDExisting tools to predict successful response to surgery for the treatment of diabetic foot osteomyelitis are lacking. Recent studies in non-bone infections have revealed that nanopore sequencing can provide real-time metagenomic identification of pathogens. In a cohort of patients with diabetic foot osteomyelitis, we tested the feasibility of generating interpretable metagenomic data from surgically-acquired osseous tissue, and compared bacterial community features (pathogen dominance) with clinical outcomes (resolution of infection). We hypothesized that nanopore-generated microbial data can be feasibly generated from surgically-acquired bone, aligns with conventional culture results, and is predictive of clinical response.METHODSWe performed a pilot feasibility study of ten consecutive patients hospitalized with diabetic foot osteomyelitis who underwent surgery for osteomyelitis. We performed metagenomic sequencing of surgical bone samples using the MinION (Oxford Nanopore). Our primary metagenomic index was community dominance (relative abundance of most abundant species). Our primary clinical endpoint was clinical response to surgery, adjudicated at one year.RESULTSWe successfully generated interpretable metagenomic data from all (10/10) specimens, including two specimens with negative culture growth. Among culture-positive specimens, the culture-identified pathogen was either the first or second most abundant organism in all cases. Patients with favorable clinical response exhibited greater pathogen dominance than patients with unfavorable response (p=0.002).CONCLUSIONSIn patients with surgically treated osteomyelitis, nanopore sequencing can generate interpretable metagenomic data from bone specimens that is culture-concordant and associated with clinical response. These findings support the feasibility and plausibility of using real-time metagenomic sequencing to improve the clinical management of osteomyelitis.
{"title":"Microbial Dominance in Diabetic Foot Osteomyelitis using Nanopore Sequencing Techniques Predicts Positive Response to Surgical Intervention.","authors":"Brian M Schmidt,Piyush Ranjan,John Erb-Downward,Robert P Dickson","doi":"10.1093/infdis/jiaf617","DOIUrl":"https://doi.org/10.1093/infdis/jiaf617","url":null,"abstract":"BACKGROUNDExisting tools to predict successful response to surgery for the treatment of diabetic foot osteomyelitis are lacking. Recent studies in non-bone infections have revealed that nanopore sequencing can provide real-time metagenomic identification of pathogens. In a cohort of patients with diabetic foot osteomyelitis, we tested the feasibility of generating interpretable metagenomic data from surgically-acquired osseous tissue, and compared bacterial community features (pathogen dominance) with clinical outcomes (resolution of infection). We hypothesized that nanopore-generated microbial data can be feasibly generated from surgically-acquired bone, aligns with conventional culture results, and is predictive of clinical response.METHODSWe performed a pilot feasibility study of ten consecutive patients hospitalized with diabetic foot osteomyelitis who underwent surgery for osteomyelitis. We performed metagenomic sequencing of surgical bone samples using the MinION (Oxford Nanopore). Our primary metagenomic index was community dominance (relative abundance of most abundant species). Our primary clinical endpoint was clinical response to surgery, adjudicated at one year.RESULTSWe successfully generated interpretable metagenomic data from all (10/10) specimens, including two specimens with negative culture growth. Among culture-positive specimens, the culture-identified pathogen was either the first or second most abundant organism in all cases. Patients with favorable clinical response exhibited greater pathogen dominance than patients with unfavorable response (p=0.002).CONCLUSIONSIn patients with surgically treated osteomyelitis, nanopore sequencing can generate interpretable metagenomic data from bone specimens that is culture-concordant and associated with clinical response. These findings support the feasibility and plausibility of using real-time metagenomic sequencing to improve the clinical management of osteomyelitis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziyi Wang, Nelly Amenyogbe, Rym Ben-Othman, Bing Cai, Mandy Lo, Olubukola T Idoko, Oludare A Odumade, Reza Falsafi, Travis M Blimkie, Andy An, Casey P Shannon, Sebastiano Montante, Bhavjinder K Dhillon, Joann Diray-Arce, Al Ozonoff, Kinga K Smolen, Ryan R Brinkman, Kerry McEnaney, Asimenia Angelidou, Peter Richmond, Scott J Tebbutt, Beate Kampmann, Robert E W Hancock, Amy H Y Lee, Ofer Levy, Tobias R Kollmann, David Martino
We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes and immune cell counts from the EPIC-HIPC newborn cohort, we report promoter methylation was negatively correlated (Pearson's r = -0.5, p < 2.2×10-16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early onset sepsis risk (OR = 0.26, p = 0.015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, FDR < 0.05).
我们研究了UBASH3A基因的遗传和表观遗传调控及其与早发性脓毒症的关系。通过对EPIC-HIPC新生儿队列的匹配全血DNA甲基化、基因表达、基因型和免疫细胞计数，我们报告启动子甲基化与UBASH3A基因表达和循环CD3+ t细胞数量的个体发生变化呈负相关（Pearson's r = -0.5, p < 2.2×10-16）。出生时较高的启动子甲基化与较低的UBASH3A表达和较低的早期脓毒症风险相关（OR = 0.26, p = 0.015）。遗传变异显著影响基线UBASH3A甲基化的变化（132顺式- meqtl， FDR < 0.05）。
{"title":"Higher promoter methylation of the Ubiquitin Associated and SH3 domain containing A ( UBASH3A ) gene is associated with T-lymphocyte ontogeny and reduced susceptibility to early-onset sepsis","authors":"Ziyi Wang, Nelly Amenyogbe, Rym Ben-Othman, Bing Cai, Mandy Lo, Olubukola T Idoko, Oludare A Odumade, Reza Falsafi, Travis M Blimkie, Andy An, Casey P Shannon, Sebastiano Montante, Bhavjinder K Dhillon, Joann Diray-Arce, Al Ozonoff, Kinga K Smolen, Ryan R Brinkman, Kerry McEnaney, Asimenia Angelidou, Peter Richmond, Scott J Tebbutt, Beate Kampmann, Robert E W Hancock, Amy H Y Lee, Ofer Levy, Tobias R Kollmann, David Martino","doi":"10.1093/infdis/jiaf636","DOIUrl":"https://doi.org/10.1093/infdis/jiaf636","url":null,"abstract":"We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes and immune cell counts from the EPIC-HIPC newborn cohort, we report promoter methylation was negatively correlated (Pearson's r = -0.5, p &lt; 2.2×10-16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early onset sepsis risk (OR = 0.26, p = 0.015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, FDR &lt; 0.05).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cara J Broshkevitch,Anna R Giuliano,Joel M Palefsky,Georges Nahhas,Stephen E Goldstone,Brady Dubin,Alfred Saah,Alain Luxembourg,Christine Velicer,Joseph E Tota
BACKGROUNDThe global prevalence of and risk factors associated with same-type HPV infection across multiple anogenital sites among men has not been quantified.METHODSMen aged 16-27 years participating in a multi-country 4-valent HPV vaccine trial (NCT00090285) were assessed at baseline for prevalent HPV infection at penile/scrotal and perineal/perianal sites (heterosexual men [HM] and men who have sex with men [MSM]) and additionally at intra-anal sites (MSM). Concordant infection with 9-valent HPV (9vHPV) vaccine types (6/11/16/18/31/33/45/52/58) was defined as same-type 9vHPV infection at 2 or 3 sites.RESULTS3363 HM and 595 MSM were included. Prevalence of concordant 9vHPV infection at 2 anogenital sites was 3.7% among HM and 9.1% among MSM, and 8.2% at 3 sites (including the intra-anal site) among MSM. HPV6 and HPV16 were most likely to occur at multiple anogenital sites in HM and MSM, with strong agreement observed between perineal/perianal and anal sites among MSM for HPV6 (Cohen's kappa, 0.78; 95% CI, .69-.87) and HPV16 (0.61; 95% CI, .50-.73).CONCLUSIONSConcordant anogenital 9vHPV infection was more common among MSM than HM, which is consistent with evidence that MSM are at increased risk of HPV-related cancer across multiple anogenital sites. Clinical Trial Registration: ClinicalTrials.gov, NCT00090285.
{"title":"Assessment of Concordant Human Papillomavirus Infection With 9-Valent Vaccine Types Across Anogenital Sites in Young Men.","authors":"Cara J Broshkevitch,Anna R Giuliano,Joel M Palefsky,Georges Nahhas,Stephen E Goldstone,Brady Dubin,Alfred Saah,Alain Luxembourg,Christine Velicer,Joseph E Tota","doi":"10.1093/infdis/jiaf564","DOIUrl":"https://doi.org/10.1093/infdis/jiaf564","url":null,"abstract":"BACKGROUNDThe global prevalence of and risk factors associated with same-type HPV infection across multiple anogenital sites among men has not been quantified.METHODSMen aged 16-27 years participating in a multi-country 4-valent HPV vaccine trial (NCT00090285) were assessed at baseline for prevalent HPV infection at penile/scrotal and perineal/perianal sites (heterosexual men [HM] and men who have sex with men [MSM]) and additionally at intra-anal sites (MSM). Concordant infection with 9-valent HPV (9vHPV) vaccine types (6/11/16/18/31/33/45/52/58) was defined as same-type 9vHPV infection at 2 or 3 sites.RESULTS3363 HM and 595 MSM were included. Prevalence of concordant 9vHPV infection at 2 anogenital sites was 3.7% among HM and 9.1% among MSM, and 8.2% at 3 sites (including the intra-anal site) among MSM. HPV6 and HPV16 were most likely to occur at multiple anogenital sites in HM and MSM, with strong agreement observed between perineal/perianal and anal sites among MSM for HPV6 (Cohen's kappa, 0.78; 95% CI, .69-.87) and HPV16 (0.61; 95% CI, .50-.73).CONCLUSIONSConcordant anogenital 9vHPV infection was more common among MSM than HM, which is consistent with evidence that MSM are at increased risk of HPV-related cancer across multiple anogenital sites. Clinical Trial Registration: ClinicalTrials.gov, NCT00090285.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tracy L Diamond,Yash Kapoor,Fangbiao Li,Bang-Lin Wan,Melissa A Boddicker,Jill W Maxwell,Winnie Ngo,Jane A Fontenot,Kelly A Soileau,Francois J Villinger,Jay A Grobler,Shubing Wang,Kerry L Fillgrove,Henry S Lange,Ernest Asante-Appiah
BACKGROUNDMK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor being evaluated for prevention of HIV-1 acquisition. MK-8527 is phosphorylated intracellularly to its active form, MK-8527-triphosphate, which inhibits HIV-1 replication. This study evaluated the efficacy of oral MK-8527 as pre-exposure prophylaxis in rhesus macaques challenged intrarectally with simian-human immunodeficiency virus (SHIV).METHODSTwo groups of male macaques (n = 8 per group) received weekly oral doses of MK-8527 for 12 weeks. Starting 1 week after treatment initiation, the macaques received weekly intrarectal challenge with SHIV162P3 for 10 weeks. Each group was treated in 3 dosing panels: Group 1 received MK-8527 6, 1, and 0 mg/kg (vehicle only), whereas Group 2 received MK-8527 2, 0.3, and 0.1 mg/kg. A washout period of ≥4 weeks followed each dosing panel. A control group (n = 8) was challenged without receiving MK-8527. Plasma viral loads were monitored weekly, with infection confirmed by 2 consecutive measurements of SHIV RNA >100 copies/mL. Concentrations of MK-8527 phosphorylated forms were quantified using liquid chromatography-tandem mass spectrometry.RESULTSOnce-weekly doses of MK-8527 ≥ 0.1 mg/kg for 12 weeks conferred complete protection against intrarectal SHIV acquisition, and 7/8 untreated control macaques and 5/8 vehicle-only macaques became infected. The rate of infection for macaques receiving MK-8527 was at least 11.1-fold (P = .009) lower compared with the control or vehicle group. MK-8527-triphosphate trough concentrations at 0.1 mg/kg resulted in a mean inhibitory quotient of 2.2.CONCLUSIONSProphylaxis with MK-8527 completely protected macaques from SHIV infection, supporting its further clinical development for prevention of HIV-1 acquisition.
{"title":"Weekly Oral Prophylaxis With MK-8527 Protects Rhesus Macaques From Intrarectal Challenge With Simian-Human Immunodeficiency Virus.","authors":"Tracy L Diamond,Yash Kapoor,Fangbiao Li,Bang-Lin Wan,Melissa A Boddicker,Jill W Maxwell,Winnie Ngo,Jane A Fontenot,Kelly A Soileau,Francois J Villinger,Jay A Grobler,Shubing Wang,Kerry L Fillgrove,Henry S Lange,Ernest Asante-Appiah","doi":"10.1093/infdis/jiaf610","DOIUrl":"https://doi.org/10.1093/infdis/jiaf610","url":null,"abstract":"BACKGROUNDMK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor being evaluated for prevention of HIV-1 acquisition. MK-8527 is phosphorylated intracellularly to its active form, MK-8527-triphosphate, which inhibits HIV-1 replication. This study evaluated the efficacy of oral MK-8527 as pre-exposure prophylaxis in rhesus macaques challenged intrarectally with simian-human immunodeficiency virus (SHIV).METHODSTwo groups of male macaques (n = 8 per group) received weekly oral doses of MK-8527 for 12 weeks. Starting 1 week after treatment initiation, the macaques received weekly intrarectal challenge with SHIV162P3 for 10 weeks. Each group was treated in 3 dosing panels: Group 1 received MK-8527 6, 1, and 0 mg/kg (vehicle only), whereas Group 2 received MK-8527 2, 0.3, and 0.1 mg/kg. A washout period of ≥4 weeks followed each dosing panel. A control group (n = 8) was challenged without receiving MK-8527. Plasma viral loads were monitored weekly, with infection confirmed by 2 consecutive measurements of SHIV RNA >100 copies/mL. Concentrations of MK-8527 phosphorylated forms were quantified using liquid chromatography-tandem mass spectrometry.RESULTSOnce-weekly doses of MK-8527 ≥ 0.1 mg/kg for 12 weeks conferred complete protection against intrarectal SHIV acquisition, and 7/8 untreated control macaques and 5/8 vehicle-only macaques became infected. The rate of infection for macaques receiving MK-8527 was at least 11.1-fold (P = .009) lower compared with the control or vehicle group. MK-8527-triphosphate trough concentrations at 0.1 mg/kg resulted in a mean inhibitory quotient of 2.2.CONCLUSIONSProphylaxis with MK-8527 completely protected macaques from SHIV infection, supporting its further clinical development for prevention of HIV-1 acquisition.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Avisha Chowdhury,Bianca Garcia Garcia,Muhammad Atif Zahoor,Nahla Fadl ElMawla,Alan R Davidson,Haley D M Wyatt,Karen L Maxwell,Ayoub Mahassine,Adam Gehring,Jordan J Feld
BACKGROUNDHepatitis C virus (HCV) diagnosis usually requires detection of antibody followed by HCV RNA. The requirement for two tests leads to major drop-offs in the cascade of care. Existing near-care HCV RNA tests have slow turnaround time and are expensive with limited availability. We aim to develop a cost-effective, rapid and sensitive test for detection of HCV RNA to enhance screening, particularly in marginalized and remote populations.METHODSAfter RNA extraction from plasma, HCV RNA is reverse transcribed and amplified using loop-mediated isothermal amplification (RT-LAMP) with HCV-specific primers. The amplified HCV DNA is then detected via CRISPR-Cas12b with a fluorescence readout.RESULTSHCV RNA from patient samples with genotypes 1a, 1b, 2, 3a and 4 was detected with high sensitivity and specificity. The lower limit of detection (LLOD) with HCV JFH1 plasmid (genotype 2) is 250 plasmid copies/ml (∼100 IU/ml). For clinical samples, we determined the LLOD for genotypes 1 and 3, the most common in North America. Using 500 μl plasma, genotype 1 RNA ≥100 IU/ml was detected within 40-45 min, while genotype 3 had an LLOD of 5,000 IU/ml. Clinical sensitivity was 100% in 72 HCV patient samples, including acute HCV and HCV/HBV co-infection. Specificity was 100%, with no false positives in 33 HCV-negative samples, including those with HBV or HIV/HBV co-infection.CONCLUSIONSOur assay shows high specificity and sensitivity to detect HCV RNA directly from plasma within 45 min, and hence could be utilized for efficient screening and diagnosis of HCV infection globally.
{"title":"A rapid assay for HCV RNA detection using RT-LAMP coupled CRISPR-Cas12b based strategy.","authors":"Avisha Chowdhury,Bianca Garcia Garcia,Muhammad Atif Zahoor,Nahla Fadl ElMawla,Alan R Davidson,Haley D M Wyatt,Karen L Maxwell,Ayoub Mahassine,Adam Gehring,Jordan J Feld","doi":"10.1093/infdis/jiaf609","DOIUrl":"https://doi.org/10.1093/infdis/jiaf609","url":null,"abstract":"BACKGROUNDHepatitis C virus (HCV) diagnosis usually requires detection of antibody followed by HCV RNA. The requirement for two tests leads to major drop-offs in the cascade of care. Existing near-care HCV RNA tests have slow turnaround time and are expensive with limited availability. We aim to develop a cost-effective, rapid and sensitive test for detection of HCV RNA to enhance screening, particularly in marginalized and remote populations.METHODSAfter RNA extraction from plasma, HCV RNA is reverse transcribed and amplified using loop-mediated isothermal amplification (RT-LAMP) with HCV-specific primers. The amplified HCV DNA is then detected via CRISPR-Cas12b with a fluorescence readout.RESULTSHCV RNA from patient samples with genotypes 1a, 1b, 2, 3a and 4 was detected with high sensitivity and specificity. The lower limit of detection (LLOD) with HCV JFH1 plasmid (genotype 2) is 250 plasmid copies/ml (∼100 IU/ml). For clinical samples, we determined the LLOD for genotypes 1 and 3, the most common in North America. Using 500 μl plasma, genotype 1 RNA ≥100 IU/ml was detected within 40-45 min, while genotype 3 had an LLOD of 5,000 IU/ml. Clinical sensitivity was 100% in 72 HCV patient samples, including acute HCV and HCV/HBV co-infection. Specificity was 100%, with no false positives in 33 HCV-negative samples, including those with HBV or HIV/HBV co-infection.CONCLUSIONSOur assay shows high specificity and sensitivity to detect HCV RNA directly from plasma within 45 min, and hence could be utilized for efficient screening and diagnosis of HCV infection globally.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nadine Rouphael,Ralph Tanios,Jessica Traenkner,Matthew D Pauly,Nishit Shetty,Meredith J Shephard,A J Campbell,Christelle Radi,Shamika Danzy,Jin Pan,Andrew P Catchpole,Alex Mann,Joshua F Detelich,Anice C Lowen,Linsey C Marr,Seema S Lakdawala,
BACKGROUNDControlled human infection models are widely used to study infectious diseases. Since the 1960s, these studies have primarily relied on intranasal inoculation, as earlier aerosol-based methods raised safety concerns and were largely abandoned despite better mimicking the natural route of infection.METHODSUtilizing modern advances in aerosol delivery, we conducted a dose-escalation study to evaluate the safety and feasibility of aerosol inoculation for human influenza challenge. Healthy adults aged 18-49 years were inoculated with influenza A/Perth/16/2009 (H3N2) using either a flow-focusing monodisperse aerosol generator (FMAG) delivering coarse particles or a medical nebulizer delivering fine particles. Participants were monitored in a controlled inpatient setting with symptom tracking, virologic sampling, and serology. Doses were escalated according to predefined safety and attack rate thresholds.RESULTSFourteen participants were enrolled. Flow-focusing monodisperse aerosol generator delivery at higher dose levels resulted in infection in 75% of participants (3/4), while nebulizer delivery produced infection in 50% (2/4). Illnesses were mild and self-limited. Viral shedding was detected at multiple respiratory sites, and adverse events were infrequent and generally mild. No serious adverse events occurred. Antibody responses were observed in a subset of infected participants.CONCLUSIONSIn this small pilot, aerosolized challenge using modern delivery systems was feasible under controlled conditions; no safety concerns were identified, and MMID was induced in a subset of participants. These data establish a methodological framework for future studies evaluating pathogenesis and mucosal immune responses to a variety of respiratory pathogens.
{"title":"Feasibility and Safety of Aerosolized Influenza Virus Challenge in Humans Using Two Modern Delivery Systems.","authors":"Nadine Rouphael,Ralph Tanios,Jessica Traenkner,Matthew D Pauly,Nishit Shetty,Meredith J Shephard,A J Campbell,Christelle Radi,Shamika Danzy,Jin Pan,Andrew P Catchpole,Alex Mann,Joshua F Detelich,Anice C Lowen,Linsey C Marr,Seema S Lakdawala, ","doi":"10.1093/infdis/jiaf603","DOIUrl":"https://doi.org/10.1093/infdis/jiaf603","url":null,"abstract":"BACKGROUNDControlled human infection models are widely used to study infectious diseases. Since the 1960s, these studies have primarily relied on intranasal inoculation, as earlier aerosol-based methods raised safety concerns and were largely abandoned despite better mimicking the natural route of infection.METHODSUtilizing modern advances in aerosol delivery, we conducted a dose-escalation study to evaluate the safety and feasibility of aerosol inoculation for human influenza challenge. Healthy adults aged 18-49 years were inoculated with influenza A/Perth/16/2009 (H3N2) using either a flow-focusing monodisperse aerosol generator (FMAG) delivering coarse particles or a medical nebulizer delivering fine particles. Participants were monitored in a controlled inpatient setting with symptom tracking, virologic sampling, and serology. Doses were escalated according to predefined safety and attack rate thresholds.RESULTSFourteen participants were enrolled. Flow-focusing monodisperse aerosol generator delivery at higher dose levels resulted in infection in 75% of participants (3/4), while nebulizer delivery produced infection in 50% (2/4). Illnesses were mild and self-limited. Viral shedding was detected at multiple respiratory sites, and adverse events were infrequent and generally mild. No serious adverse events occurred. Antibody responses were observed in a subset of infected participants.CONCLUSIONSIn this small pilot, aerosolized challenge using modern delivery systems was feasible under controlled conditions; no safety concerns were identified, and MMID was induced in a subset of participants. These data establish a methodological framework for future studies evaluating pathogenesis and mucosal immune responses to a variety of respiratory pathogens.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Our viewpoint summarizes key points of a recently published review on the evolution of our understanding of airway infections in the era of highly effective modulators. Herein we discuss how this will shape our current and future research and practice endeavors.
{"title":"Clearing the air: Rethinking airway infection with CFTR modulators","authors":"Edith T Zemanick, Ranjani Somayaji","doi":"10.1093/infdis/jiaf625","DOIUrl":"https://doi.org/10.1093/infdis/jiaf625","url":null,"abstract":"Our viewpoint summarizes key points of a recently published review on the evolution of our understanding of airway infections in the era of highly effective modulators. Herein we discuss how this will shape our current and future research and practice endeavors.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"157 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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