Madleen Orumaa, Elen Johanne Lahlum, Marie Gulla, Joseph Tota, M. Nygård, Ståle Nygård
In Norway, single cohort vaccination with quadrivalent HPV (qHPV) vaccine targeting 12-year-old girls took place from 2009-2016. In 2020, the oldest vaccinated cohort was 23 years old and had approached the age where risk of being diagnosed with cervical intraepithelial lesion grade 2 or worse (CIN2+) increases rapidly. The aim of this cohort study was to assess direct qHPV vaccine effectiveness (VE) against CIN2+ among Norwegian women aged 16-30 in 2007-2020. By using population-based health registries and individual-level data on vaccination status and potential subsequent CIN2+ incidence, we found 82% qHPV VE among women vaccinated before the age of 17.
{"title":"Quadrivalent HPV vaccine effectiveness against cervical intraepithelial lesion grade 2 or worse in Norway: A registry-based study of 0,9 million Norwegian women.","authors":"Madleen Orumaa, Elen Johanne Lahlum, Marie Gulla, Joseph Tota, M. Nygård, Ståle Nygård","doi":"10.1093/infdis/jiae209","DOIUrl":"https://doi.org/10.1093/infdis/jiae209","url":null,"abstract":"In Norway, single cohort vaccination with quadrivalent HPV (qHPV) vaccine targeting 12-year-old girls took place from 2009-2016. In 2020, the oldest vaccinated cohort was 23 years old and had approached the age where risk of being diagnosed with cervical intraepithelial lesion grade 2 or worse (CIN2+) increases rapidly. The aim of this cohort study was to assess direct qHPV vaccine effectiveness (VE) against CIN2+ among Norwegian women aged 16-30 in 2007-2020. By using population-based health registries and individual-level data on vaccination status and potential subsequent CIN2+ incidence, we found 82% qHPV VE among women vaccinated before the age of 17.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655678","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}
Sharon A Riddler, Clifton W Kelly, Craig J Hoesley, Ken S Ho, Jeanna M Piper, Stacey Edick, Faye Heard, Gustavo F Doncel, Sherri Johnson, Peter L Anderson, Rhonda M Brand, Ratiya Pamela Kunjara Na Ayudhya, José A Bauermeister, Sharon L Hillier, Craig W Hendrix
Background On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. Methods MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420 Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.
{"title":"A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention","authors":"Sharon A Riddler, Clifton W Kelly, Craig J Hoesley, Ken S Ho, Jeanna M Piper, Stacey Edick, Faye Heard, Gustavo F Doncel, Sherri Johnson, Peter L Anderson, Rhonda M Brand, Ratiya Pamela Kunjara Na Ayudhya, José A Bauermeister, Sharon L Hillier, Craig W Hendrix","doi":"10.1093/infdis/jiae211","DOIUrl":"https://doi.org/10.1093/infdis/jiae211","url":null,"abstract":"Background On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally. Methods MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420 Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high &gt;2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p&lt;0.065 and p&lt;0.039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642371","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}
Alyssa K W Maclean, Stacey Morrow, Fang Niu, Nancy D Hanson
Background K. pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance. Methods MICs to β-lactams and inhibitor combinations were determined by agar dilution or E-test. Outer membrane porin production was evaluated by western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by RT-qPCR. Results Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane/tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. ESβLs and pAmpCs in addition to porin loss were sufficient to confer resistance to the third generation cephalosporins, pipercillin/tazobactam, ceftolozane/tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to pipercillin/tazobactam. Discussion Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.
背景肺炎双球菌能够通过表达β-内酰胺酶(染色体和质粒编码)和下调外膜孔蛋白对β-内酰胺类抗生素产生耐药性。然而,这些机制在多大程度上相互作用产生耐药表型还不十分清楚。本研究旨在确定β-内酰胺酶和外膜孔蛋白对β-内酰胺耐药性的影响程度。方法 通过琼脂稀释法或 E 测试法确定β-内酰胺类药物和抑制剂组合的 MIC。外膜孔蛋白的生成通过外膜分馏物的 Western 印迹进行评估。通过全基因组测序确定β-内酰胺酶的携带情况,并通过 RT-qPCR 评估其表达情况。结果 质粒编码的β-内酰胺酶对头孢他啶和头孢唑肟的耐药性非常重要。染色体 SHV 的高表达对头孢羟氨苄/他唑巴坦的耐药性很重要。外膜孔蛋白的缺失可预测美罗培南的耐药性。ESβLs和pAmpCs以及孔蛋白缺失足以产生对第三代头孢菌素、哌西林/他唑巴坦、头孢唑烷/他唑巴坦和美罗培南的耐药性。讨论 通过全基因组测序检测耐药基因并不足以预测对所有测试抗生素的耐药性。某些 β-内酰胺耐药性取决于质粒编码和染色体 β-内酰胺酶的表达以及孔蛋白的缺失。
{"title":"What Contributes to the MIC? Beyond β-Lactamase Gene Detection in Klebsiella pneumoniae","authors":"Alyssa K W Maclean, Stacey Morrow, Fang Niu, Nancy D Hanson","doi":"10.1093/infdis/jiae204","DOIUrl":"https://doi.org/10.1093/infdis/jiae204","url":null,"abstract":"Background K. pneumoniae is capable of resistance to β-lactam antibiotics through expression of β-lactamases (both chromosomal and plasmid-encoded) and downregulation of outer membrane porins. However, the extent to which these mechanisms interplay in a resistant phenotype is not well understood. The purpose of this study was to determine the extent to which β-lactamases and outer membrane porins affected β-lactam resistance. Methods MICs to β-lactams and inhibitor combinations were determined by agar dilution or E-test. Outer membrane porin production was evaluated by western blot of outer membrane fractions. β-lactamase carriage was determined by whole genome sequencing and expression evaluated by RT-qPCR. Results Plasmid-encoded β-lactamases were important for cefotaxime and ceftazidime resistance. Elevated expression of chromosomal SHV was important for ceftolozane/tazobactam resistance. Loss of outer membrane porins was predictive of meropenem resistance. ESβLs and pAmpCs in addition to porin loss were sufficient to confer resistance to the third generation cephalosporins, pipercillin/tazobactam, ceftolozane/tazobactam, and meropenem. pAmpCs (CMY-2 and DHA) alone conferred resistance to pipercillin/tazobactam. Discussion Detection of a resistance gene by whole genome sequencing was not sufficient to predict resistance to all antibiotics tested. some β-lactam resistance was dependent on the expression of both plasmid-encoded and chromosomal β-lactamases and loss of porins.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642560","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}
Kanal Singh, Kevin Rubenstein, Viviane Callier, K. Shaw-Saliba, Adam W. Rupert, Robin L. Dewar, S. Laverdure, Helene Highbarger, P. Lallemand, Meei-Li W Huang, Keith R Jerome, R. Sampoleo, Margaret G. Mills, Alexander L. Greninger, K. Juneja, D. Porter, Constance A Benson, Walla Dempsey, Hana M. El Sahly, Chris Focht, N. Jilg, Catharine I. Paules, Rekha R Rapaka, T. Uyeki, H. C. Lane, J. Beigel, Lori E Dodd, Aneesh K Mehta, Nadine G Rouphael, Jessica J. Traenkner, V. Cantos, Ghina Alaaeddine, Barry S. Zingman, R. Grossberg, Paul F. Riska, Elizabeth Hohmann, Mariam Torres-Soto, N. Jilg, Helen Y Chu, Anna Wald, Margaret Green, Anne Luetkemeyer, Pierre-Cedric B. Crouch, Hannah Jang, Susan Kline, Joanne Billings, B. Noren, Diego López de Castilla, Jason W. Van Winkle, Francis X. Riedo, Robert W. Finberg, Jennifer P. Wang, Mireya Wessolossky, Kerry Dierberg, Benjamin Eckhardt, Henry J. Neumann, Victor F. Tapson, Jonathan Grein, F. Sutterwala, L. Hsieh, Alpesh N Amin, Thomas F. Patterson, H. Javeri, Trung Vu, R
BACKGROUND Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.
{"title":"SARS-CoV-2 RNA and nucleocapsid antigen are blood biomarkers associated with severe disease outcomes that improve in response to remdesivir.","authors":"Kanal Singh, Kevin Rubenstein, Viviane Callier, K. Shaw-Saliba, Adam W. Rupert, Robin L. Dewar, S. Laverdure, Helene Highbarger, P. Lallemand, Meei-Li W Huang, Keith R Jerome, R. Sampoleo, Margaret G. Mills, Alexander L. Greninger, K. Juneja, D. Porter, Constance A Benson, Walla Dempsey, Hana M. El Sahly, Chris Focht, N. Jilg, Catharine I. Paules, Rekha R Rapaka, T. Uyeki, H. C. Lane, J. Beigel, Lori E Dodd, Aneesh K Mehta, Nadine G Rouphael, Jessica J. Traenkner, V. Cantos, Ghina Alaaeddine, Barry S. Zingman, R. Grossberg, Paul F. Riska, Elizabeth Hohmann, Mariam Torres-Soto, N. Jilg, Helen Y Chu, Anna Wald, Margaret Green, Anne Luetkemeyer, Pierre-Cedric B. Crouch, Hannah Jang, Susan Kline, Joanne Billings, B. Noren, Diego López de Castilla, Jason W. Van Winkle, Francis X. Riedo, Robert W. Finberg, Jennifer P. Wang, Mireya Wessolossky, Kerry Dierberg, Benjamin Eckhardt, Henry J. Neumann, Victor F. Tapson, Jonathan Grein, F. Sutterwala, L. Hsieh, Alpesh N Amin, Thomas F. Patterson, H. Javeri, Trung Vu, R","doi":"10.1093/infdis/jiae198","DOIUrl":"https://doi.org/10.1093/infdis/jiae198","url":null,"abstract":"BACKGROUND\u0000Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo.\u0000\u0000\u0000METHODS\u0000Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.\u0000\u0000\u0000RESULTS\u0000Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.\u0000\u0000\u0000CONCLUSIONS\u0000Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140664767","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}
Eun Kyo Ha, Ju Hee Kim, Bo Eun Han, Jeewon Shin, Eun Lee, Seonkyeong Rhie, Won Seok Lee, Soonchul Lee, Man Yong Han
Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1,420,941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. At age 6, we assessed neurodevelopmental outcomes using the validated Korean Developmental Test, covering six major domains. Utilizing propensity score-based Inverse Probability Weighting to ensure covariates including considering covariates including sex, birth weight, changes in body weight from birth to 4–6 months of age, head circumference at 4–6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5,451 children with rotavirus hospitalization and 310,874 unexposed individuals reveled heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6-year-olds.
{"title":"Rotavirus hospitalization in early childhood: fine motor skills and cognition at six years old—Population-based cohort study","authors":"Eun Kyo Ha, Ju Hee Kim, Bo Eun Han, Jeewon Shin, Eun Lee, Seonkyeong Rhie, Won Seok Lee, Soonchul Lee, Man Yong Han","doi":"10.1093/infdis/jiae218","DOIUrl":"https://doi.org/10.1093/infdis/jiae218","url":null,"abstract":"Rotavirus is linked to severe childhood gastroenteritis and neurological complications, but its impact on neurodevelopment remains uncertain. We examined data from 1,420,941 Korean children born between 2009 and 2011, using the Korean National Health Insurance System. At age 6, we assessed neurodevelopmental outcomes using the validated Korean Developmental Test, covering six major domains. Utilizing propensity score-based Inverse Probability Weighting to ensure covariates including considering covariates including sex, birth weight, changes in body weight from birth to 4–6 months of age, head circumference at 4–6 months of age, residence at birth, economic status, infant feeding types, and birth year. The main analysis that encompassed 5,451 children with rotavirus hospitalization and 310,874 unexposed individuals reveled heightened odds of suspected delays in fine motor skills and cognition among exposed children. Our results suggest an association between rotavirus-related hospitalization in infancy and suspected delays in fine motor function and cognition in 6-year-olds.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808250","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}
Background Understanding the association between the immune response and the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has implications for forthcoming prevention strategies. We evaluated the association between antibody titers and the risk of infection for the general population during the Omicron-dominant phase. Methods This was a prospective cohort study of residents or people affiliated with institutions in Bizen City, which included 1,899 participants. We measured the titers of antibodies against SARS-CoV-2 repeatedly every 2 months from June 2022 to March 2023. Infection status was obtained from self-reported questionnaires and the official registry. We estimated risk ratios (RRs) for infection within 2 months of the date of each antibody measurement with 95% confidence intervals (CIs) based on antibody titer categories and spline functions. Results Compared with the <2,500 arbitrary unit (AU)/mL category, the 2,500–5,000, 5,000–10,000, and ≥10,000 AU/mL categories had adjusted RRs (95% CI) of 0.81 (0.61–1.08), 0.51 (0.36–0.72), and 0.41 (0.31–0.54), respectively. The spline function showed a non-linear relationship between antibody titer and risk. Conclusions Higher antibody titers were associated with a lower risk. We demonstrate the usefulness of measuring an antibody titers to determine the appropriate timing for future vaccination.
{"title":"Antibody titers and the risk of infection during the SARS-CoV-2 Omicron phase in Bizen City, Japan","authors":"Tomoka Kadowaki, Ayako Sasaki, Naomi Matsumoto, Toshiharu Mitsuhashi, Hideharu Hagiya, Soshi Takao, Takashi Yorifuji","doi":"10.1093/infdis/jiae207","DOIUrl":"https://doi.org/10.1093/infdis/jiae207","url":null,"abstract":"Background Understanding the association between the immune response and the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has implications for forthcoming prevention strategies. We evaluated the association between antibody titers and the risk of infection for the general population during the Omicron-dominant phase. Methods This was a prospective cohort study of residents or people affiliated with institutions in Bizen City, which included 1,899 participants. We measured the titers of antibodies against SARS-CoV-2 repeatedly every 2 months from June 2022 to March 2023. Infection status was obtained from self-reported questionnaires and the official registry. We estimated risk ratios (RRs) for infection within 2 months of the date of each antibody measurement with 95% confidence intervals (CIs) based on antibody titer categories and spline functions. Results Compared with the &lt;2,500 arbitrary unit (AU)/mL category, the 2,500–5,000, 5,000–10,000, and ≥10,000 AU/mL categories had adjusted RRs (95% CI) of 0.81 (0.61–1.08), 0.51 (0.36–0.72), and 0.41 (0.31–0.54), respectively. The spline function showed a non-linear relationship between antibody titer and risk. Conclusions Higher antibody titers were associated with a lower risk. We demonstrate the usefulness of measuring an antibody titers to determine the appropriate timing for future vaccination.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642701","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}
Sakthi Priya Selvamani, Anis Khan, Enoch S E Tay, Matthew Garvey, Harout Ajoyan, Eve Diefenbach, Brian S Gloss, Thomas Tu, Jacob George, Mark W Douglas
Background Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function. Methods Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot. Results Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation. Conclusions HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.
背景丙型肝炎病毒(HCV)和乙型肝炎病毒(HBV)引起的慢性肝炎在临床上有很大的不同。丙型肝炎病毒(HCV)会导致肝脂肪变性和胰岛素抵抗,而乙型肝炎病毒(HBV)则会增加罹患肝癌的风险。我们假设这些差异可能是由于病毒对线粒体功能的特异性影响。方法 利用海马技术研究病毒感染对线粒体功能的影响。采用基于细胞的检测方法测量线粒体膜电位,并对丙酮酸和乳酸进行量化。对从表达 HBV、感染 HCV 和用同位素标记氨基酸培养的对照细胞中分离出来的线粒体进行了质谱分析,以确定不同丰度的蛋白质。通过实时 PCR 和 Western 印迹证实了关键线粒体蛋白表达的改变。结果 观察到线粒体功能和 ATP 生成随着 HCV 感染和 HBV 表达而降低。HCV 会损害糖酵解,减少调节脂肪酸氧化基因的表达,促进脂质积累。HBV 通过增加将丙酮酸转化为乳酸的乳酸脱氢酶 A 的表达,导致乳酸积累。在表达 HBV 的细胞中,丙酮酸脱氢酶激酶的表达明显增加,抑制了丙酮酸向乙酰-CoA 的转化,从而减少了乙酰-CoA 在线粒体氧化磷酸化中的可用性。结论 HCV 和 HBV 会损害线粒体功能并减少 ATP 的产生。HCV 通过损害脂肪酸氧化减少了乙酰-CoA 在能量生成中的可用性,导致脂质积累和肝脏脂肪变性。HBV 不影响脂肪氧化,但会通过破坏丙酮酸代谢减少乙酰-CoA 的供应。这会促进乳酸酸中毒和氧化应激,增加疾病恶化和肝癌的风险。
{"title":"Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis","authors":"Sakthi Priya Selvamani, Anis Khan, Enoch S E Tay, Matthew Garvey, Harout Ajoyan, Eve Diefenbach, Brian S Gloss, Thomas Tu, Jacob George, Mark W Douglas","doi":"10.1093/infdis/jiae210","DOIUrl":"https://doi.org/10.1093/infdis/jiae210","url":null,"abstract":"Background Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function. Methods Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot. Results Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation. Conclusions HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642370","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}
Nancy Gillis, Brittney L Dickey, Christelle Colin-Leitzinger, Yi-Han Tang, Ryan M Putney, Tania E Mesa, Sean J Yoder, Gita Suneja, Adam M Spivak, Ami B Patel, Martine Extermann, Anna R Giuliano, Mingxiang Teng, Jacob Kresovich, Anders Berglund, Anna E Coghill
Background Cancer-related deaths for people living with HIV (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. Methods We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. Results In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, p=0.07). After adjusting for patient characteristics, PWH were four-times more likely to have CH than PWoH (OR 4.1, 95% CI 1.3-13.9, p=0.02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). Conclusion This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.
背景 艾滋病毒感染者(PWH)与癌症相关的死亡人数正在增加,原因是他们的预期寿命更长,而与癌症相关的结果却不尽相同。我们假设,晚期生物衰老会导致艾滋病病毒感染者和癌症患者的癌症相关发病率和死亡率。我们试图确定克隆性造血(CH)对威尔士人癌症差异的影响。方法 我们进行了一项回顾性研究,以比较克隆性造血在感染艾滋病病毒(PWH)和未感染艾滋病病毒(PWoH)的人群中的发病率和临床结果。根据肿瘤部位、年龄、肿瘤序列和癌症治疗状况,研究对象包括艾滋病感染者和类似的艾滋病感染者。此外,还使用表观遗传甲基化钟测量了生物老化。结果 在136名癌症患者中,PWH的CH发生率是相似PWoH的两倍(23% vs 11%,P=0.07)。在对患者特征进行调整后,PWH 患 CH 的几率是 PWoH 的四倍(OR 4.1,95% CI 1.3-13.9,P=0.02)。CH对存活率的影响在PWH中最为明显,与PWoH相比,如果患有CH,PWH的5年存活率为38%(如果没有CH,则为59%),而如果患有CH,PWoH的5年存活率为75%(如果没有CH,则为83%)。结论 本研究首次证明,与罹患相同癌症的 PWoH 相比,PWH 的 CH 患病率可能更高。CH可能是导致威尔士族癌症患者生存率较低的一个独立的生物老化风险因素。
{"title":"Clonal hematopoiesis in patients with HIV and cancer","authors":"Nancy Gillis, Brittney L Dickey, Christelle Colin-Leitzinger, Yi-Han Tang, Ryan M Putney, Tania E Mesa, Sean J Yoder, Gita Suneja, Adam M Spivak, Ami B Patel, Martine Extermann, Anna R Giuliano, Mingxiang Teng, Jacob Kresovich, Anders Berglund, Anna E Coghill","doi":"10.1093/infdis/jiae212","DOIUrl":"https://doi.org/10.1093/infdis/jiae212","url":null,"abstract":"Background Cancer-related deaths for people living with HIV (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. Methods We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. Results In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, p=0.07). After adjusting for patient characteristics, PWH were four-times more likely to have CH than PWoH (OR 4.1, 95% CI 1.3-13.9, p=0.02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). Conclusion This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642629","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}
Mary Bridget Waters, Kevin Hybiske, Ren Ikeda, Bernhard Kaltenboeck, Lisa E Manhart, Kristen M Kreisel, Christine M Khosropour
Chlamydia trachomatis (CT) is a sexually transmitted infection that can lead to adverse reproductive health outcomes. CT prevalence estimates are primarily derived from screening using nucleic acid amplification tests (NAATs). However, screening guidelines in the United States only include particular subpopulations, and NAATs only detect current infections. In contrast, seroassays identify past CT infections which are important for understanding the public health impacts of CT, including pelvic inflammatory disease and tubal factor infertility. Older seroassays have been plagued by low sensitivity and specificity and have not been validated using a consistent reference measure, making it challenging to compare studies, define the epidemiology of CT and determine the effectiveness of control programs. Newer seroassays have better performance characteristics. This narrative review summarizes the “state of the science” for CT seroassays that have been applied in epidemiologic studies and provides practical considerations for interpreting the literature and employing seroassays in future research.
{"title":"Chlamydia trachomatis seroassays used in epidemiologic research: a narrative review and practical considerations","authors":"Mary Bridget Waters, Kevin Hybiske, Ren Ikeda, Bernhard Kaltenboeck, Lisa E Manhart, Kristen M Kreisel, Christine M Khosropour","doi":"10.1093/infdis/jiae199","DOIUrl":"https://doi.org/10.1093/infdis/jiae199","url":null,"abstract":"Chlamydia trachomatis (CT) is a sexually transmitted infection that can lead to adverse reproductive health outcomes. CT prevalence estimates are primarily derived from screening using nucleic acid amplification tests (NAATs). However, screening guidelines in the United States only include particular subpopulations, and NAATs only detect current infections. In contrast, seroassays identify past CT infections which are important for understanding the public health impacts of CT, including pelvic inflammatory disease and tubal factor infertility. Older seroassays have been plagued by low sensitivity and specificity and have not been validated using a consistent reference measure, making it challenging to compare studies, define the epidemiology of CT and determine the effectiveness of control programs. Newer seroassays have better performance characteristics. This narrative review summarizes the “state of the science” for CT seroassays that have been applied in epidemiologic studies and provides practical considerations for interpreting the literature and employing seroassays in future research.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621445","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}
Ruth N Moro, Carolina Mehaffy, Prithwiraj De, Elizabeth Phillips, Andrey S Borisov, Timothy R Sterling, Karen M Dobos
Background Flu-like reactions can occur after exposure to rifampin, rifapentine, or isoniazid. Prior studies have reported the presence of antibodies to rifampin, but associations with underlying pathogenesis are unclear. Methods We evaluated PREVENT TB study participants who received weekly isoniazid + rifapentine for 3 months (3HP) or daily isoniazid for 9 months (9H) as treatment for M. tuberculosis infection. Flu-like reaction was defined as a grade ≥2 of any of flu-like symptoms. Controls (3HP or 9H) did not report flu-like reactions. We developed a competitive enzyme-linked immunosorbent assays (ELISA) to detect antibodies against rifapentine, isoniazid, rifampin, and rifapentine metabolite. Results Among 128 participants, 69 received 3HP (22 with flu-like reactions; 47 controls) and 59 received 9H (12 with flu-like reactions; 47 controls). In participants receiving 3HP, anti-rifapentine IgG was identified in 2/22 (9%) participants with flu-like reactions and 6/47 (13%) controls (P = 0.7), anti-isoniazid IgG in 2/22 (9%) participants with flu-like reactions and 4/47 (9%) controls (P = 0.9), and anti-rifapentine metabolite IgG in 2/47 (4%) controls (P = 0.9). Among participants receiving 9H, IgG and IgM anti-isoniazid antibodies were each present in 4/47 (9%) controls, respectively, but none among participants with flu-like reactions; anti-rifapentine IgG antibodies were not present in any participants with flu-like reactions or controls. Conclusions We detected anti-rifapentine, anti-isoniazid, and anti-rifapentine metabolite antibodies, but the proportions of participants with antibodies were low, and did not differ between participants with flu-like reactions and those without such reactions. This suggests that flu-like reactions associated with 3HP and 9H were not antibody-mediated.
{"title":"Assessment for Antibodies to Rifapentine and Isoniazid in Persons Developing Flu-like Reactions During Treatment of Latent Tuberculosis Infection","authors":"Ruth N Moro, Carolina Mehaffy, Prithwiraj De, Elizabeth Phillips, Andrey S Borisov, Timothy R Sterling, Karen M Dobos","doi":"10.1093/infdis/jiae180","DOIUrl":"https://doi.org/10.1093/infdis/jiae180","url":null,"abstract":"Background Flu-like reactions can occur after exposure to rifampin, rifapentine, or isoniazid. Prior studies have reported the presence of antibodies to rifampin, but associations with underlying pathogenesis are unclear. Methods We evaluated PREVENT TB study participants who received weekly isoniazid + rifapentine for 3 months (3HP) or daily isoniazid for 9 months (9H) as treatment for M. tuberculosis infection. Flu-like reaction was defined as a grade ≥2 of any of flu-like symptoms. Controls (3HP or 9H) did not report flu-like reactions. We developed a competitive enzyme-linked immunosorbent assays (ELISA) to detect antibodies against rifapentine, isoniazid, rifampin, and rifapentine metabolite. Results Among 128 participants, 69 received 3HP (22 with flu-like reactions; 47 controls) and 59 received 9H (12 with flu-like reactions; 47 controls). In participants receiving 3HP, anti-rifapentine IgG was identified in 2/22 (9%) participants with flu-like reactions and 6/47 (13%) controls (P = 0.7), anti-isoniazid IgG in 2/22 (9%) participants with flu-like reactions and 4/47 (9%) controls (P = 0.9), and anti-rifapentine metabolite IgG in 2/47 (4%) controls (P = 0.9). Among participants receiving 9H, IgG and IgM anti-isoniazid antibodies were each present in 4/47 (9%) controls, respectively, but none among participants with flu-like reactions; anti-rifapentine IgG antibodies were not present in any participants with flu-like reactions or controls. Conclusions We detected anti-rifapentine, anti-isoniazid, and anti-rifapentine metabolite antibodies, but the proportions of participants with antibodies were low, and did not differ between participants with flu-like reactions and those without such reactions. This suggests that flu-like reactions associated with 3HP and 9H were not antibody-mediated.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621661","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}