Background Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.
背景：抗逆转录病毒治疗（ART）导致骨质疏松和骨折，增加艾滋病毒感染者（PLH）的发病率和死亡率。ART诱导免疫重建骨质流失（IRBL），一种与免疫系统再激活相关的炎症反应。女性占PLH的50%，其中许多人现在正处于更年期，这是绝经后骨质疏松症的主要原因，也增加了骨折的风险。然而，IRBL与绝经后骨质流失之间的相互作用尚不清楚，本研究对此进行了调查。方法采用小鼠IRBL模型，与卵巢切除术（Ovx）同时或先后应用，这是一种绝经后骨质疏松小鼠模型。采用微计算机断层扫描（µCT）评估椎骨和股骨的皮质骨和小梁骨，通过ELISA测定骨吸收和形成的血清标志物量化骨转换。流式细胞术分析T细胞生成破骨细胞因子。结果虽然Ovx和IRBL同时发生没有累加效应，但Ovx和IRBL相继发生可引起累积性骨质流失。抗炎剂Abatacept （Δ=-13.9 vs. Control: p=不显著）和益生菌鼠李糖乳杆菌GG （Δ=-8.6 vs. Control: p=不显著）显著减少Ovx和IRBL联合导致的椎体骨丢失（Δ=-42.6 vs. Control: p=不显著）。两种治疗均可减少骨吸收，刺激骨形成，抑制CD4+ T细胞产生破骨细胞因子TNF-α和IL-17A。结论序贯IRBL和绝经后骨质流失是累积性的。如果在人类中得到验证，早期筛查和预防可以降低绝经后感染艾滋病毒（WLH）的妇女骨折风险。益生菌疗法可能提供一种有益的替代药物治疗。
{"title":"Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models","authors":"Sadaf Dabeer, Ashish Kumar Tripathi, Daiana Weiss, Tatyana Vikulina, Ighovwerha Ofotokun, M Neale Weitzmann","doi":"10.1093/infdis/jiae643","DOIUrl":"https://doi.org/10.1093/infdis/jiae643","url":null,"abstract":"Background Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent &gt;50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p&lt;0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887693","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}
Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle
Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA <200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p<0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope<0). Higher NfL (β=-0.08, p<0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).
{"title":"Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People Living with HIV","authors":"Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle","doi":"10.1093/infdis/jiae623","DOIUrl":"https://doi.org/10.1093/infdis/jiae623","url":null,"abstract":"Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA &lt;200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p&lt;0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope&lt;0). Higher NfL (β=-0.08, p&lt;0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887690","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}
Tosin E Omole, Huong Mai Nguyen, Agata Marcinow, Myo Minn Oo, Naima Jahan, Aloysious Ssemaganda, Giulia Severini, Katherine K Thomas, Connie Celum, Nelly Mugo, Andrew Mujugira, James Kublin, Lawrence Corey, Aida Sivro, Jairam R Lingappa, Glenda Gray, Lyle R McKinnon
Background CD4+ T cells expressing α4β7 are optimal targets for HIV infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men (MSM) or people who inject drugs (PWID) in the Americas, indicating need for further research. Methods This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network; HVTN 503) and East Africa (Partners Pre-Exposure Prophylaxis/Couples’ Observational Study; PP/COS), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses. Results Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T cell decline, similar to what was observed previously in South Africa. Conclusions These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.
{"title":"Pre-HIV α4β7hi CD4+ T cells and HIV risk among heterosexual individuals in Africa","authors":"Tosin E Omole, Huong Mai Nguyen, Agata Marcinow, Myo Minn Oo, Naima Jahan, Aloysious Ssemaganda, Giulia Severini, Katherine K Thomas, Connie Celum, Nelly Mugo, Andrew Mujugira, James Kublin, Lawrence Corey, Aida Sivro, Jairam R Lingappa, Glenda Gray, Lyle R McKinnon","doi":"10.1093/infdis/jiae638","DOIUrl":"https://doi.org/10.1093/infdis/jiae638","url":null,"abstract":"Background CD4+ T cells expressing α4β7 are optimal targets for HIV infections, with higher pre-HIV α4β7hi expression linked to increased HIV acquisition and progression in South African women. However, similar associations were not observed in men who have sex with men (MSM) or people who inject drugs (PWID) in the Americas, indicating need for further research. Methods This retrospective case-control study enrolled heterosexual men and women from South Africa (HIV Vaccine Trials Network; HVTN 503) and East Africa (Partners Pre-Exposure Prophylaxis/Couples’ Observational Study; PP/COS), quantifying α4β7 expression on CD4+ T cells as a predictor of subsequent HIV risk using flow cytometry analyses. Results Associations between α4β7hi expression and HIV acquisition varied across cohorts. In HVTN 503, women had a higher risk estimate compared to men, but this was not significant. In PP/COS, α4β7hi expression was generally protective, particularly in Ugandans. Additionally, α4β7hi expression inversely correlated with peak viral load in PP/COS but not in HVTN 503; in the latter cohort, α4β7hi expression was inversely correlated with the CD4/CD8 ratio and predicted rapid CD4+ T cell decline, similar to what was observed previously in South Africa. Conclusions These findings suggest that α4β7hi expression on CD4+ T cells may not predict HIV acquisition and progression in all contexts, which may be due to cohort effects, modes of transmission, viral clade, or other factors.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884137","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}
Prabha Chandrasekaran, Irina Maljkovic Berry, Viviane Callier, Scott M Anthony, Krystle Hensley, Jens H Kuhn, Kathryn Shaw-Saliba, Stephen B Kennedy, Mark Kieh, Sarah M Browne, Ian Crozier, Richard T Davey, H Clifford Lane, Lisa E Hensley, Dean A Follmann
Background The robustness and persistence of vaccine antigen-induced antibodies are often used as proxy indicators of vaccine efficacy, but immune responses to vaccine vectors are typically less well-defined. Our study considered the kinetics of immunoglobulin (IgG) responses against the vector (vesicular stomatitis Indiana virus [VSIV]) nucleoprotein (N) and the inserted antigen (Ebola virus [EBOV]) glycoprotein (GP1,2) components of the rVSVΔG-ZEBOV-GP (rVSV-ZEBOV) vaccine and evaluated their use as biomarkers to confirm self-reported vaccination status. Methods From the Partnership for Research on Ebola Virus in Liberia (PREVAIL) I clinical trial (NCT02344407), we randomly selected 212 participants who received rVSV-ZEBOV (n=107) or placebo (n=105). Levels of IgG antibodies to EBOV GP1,2 or VSIV N were measured using the Filovirus Animal Non-Clinical Group (FANG) ELISA and a newly developed single-molecule array (Simoa) immunoassay, respectively. Results Anti-EBOV GP1,2 IgG and anti-VSIV N IgG were first detected 10–14 d post-vaccination, further increased at 28 d, and remained stable through 360 d. Antibody titers were significantly higher in women compared to men. Anti-EBOV GP1,2 and anti-VSIV N IgG titers were significantly correlated (p<0.001) at 28 d (r=0.47), 180 d (r=0.45), and 360 d (r=0.59). At 28 d, the area under the curve (AUC) of receiver operating characteristic (ROC) curves discriminated vaccinated from unvaccinated patients with high accuracy (AUC=0.965 for anti-VSIV N IgG; AUC=0.945 for anti-EBOV GP1,2 IgG [p<0.001]). Conclusions We report a reliable assay to measure vector-induced humoral responses after rVSV-ZEBOV vaccination and demonstrate the assay’s utility to confirm vaccination status.
疫苗抗原诱导抗体的稳健性和持久性通常被用作疫苗效力的代理指标，但对疫苗载体的免疫反应通常不太明确。我们的研究考虑了免疫球蛋白（IgG）对载体（水疱性口炎印第安纳病毒[VSIV]）核蛋白(N)和插入抗原（埃博拉病毒[EBOV]）糖蛋白（GP1,2）成分rVSVΔG-ZEBOV-GP （rVSV-ZEBOV）疫苗的反应动力学，并评估了它们作为生物标志物的用途，以确认自我报告的疫苗接种状态。方法从利比里亚埃博拉病毒研究伙伴关系（PREVAIL） I临床试验（NCT02344407）中随机选择212名接受rVSV-ZEBOV （n=107）或安慰剂（n=105）的参与者。分别采用丝状病毒动物非临床组（FANG） ELISA和新开发的单分子阵列（Simoa）免疫分析法检测EBOV GP1、2或VSIV N的IgG抗体水平。结果接种后10 ~ 14 d首次检测到ebov抗体GP1、2 IgG和vsiv抗体N IgG，接种后28 d进一步升高，接种后360 d保持稳定，女性抗体滴度明显高于男性。抗ebov GP1,2和抗vsiv N IgG滴度在28 d (r=0.47), 180 d （r=0.45）和360 d （r=0.59）时显著相关（p<0.001）。28 d时，受试者工作特征曲线（ROC）曲线下面积（AUC）区分接种者与未接种者准确率较高(抗vsv N IgG AUC=0.965；抗ebov GP1,2 IgG的AUC=0.945 [p<0.001])。我们报告了一种可靠的方法来测量rVSV-ZEBOV疫苗接种后载体诱导的体液反应，并证明了该方法在确认疫苗接种状态方面的实用性。
{"title":"Vector induced humoral responses after rVSVΔG-ZEBOV-GP immunization identify vaccinated individuals and correlate with Ebola virus glycoprotein antibodies","authors":"Prabha Chandrasekaran, Irina Maljkovic Berry, Viviane Callier, Scott M Anthony, Krystle Hensley, Jens H Kuhn, Kathryn Shaw-Saliba, Stephen B Kennedy, Mark Kieh, Sarah M Browne, Ian Crozier, Richard T Davey, H Clifford Lane, Lisa E Hensley, Dean A Follmann","doi":"10.1093/infdis/jiae632","DOIUrl":"https://doi.org/10.1093/infdis/jiae632","url":null,"abstract":"Background The robustness and persistence of vaccine antigen-induced antibodies are often used as proxy indicators of vaccine efficacy, but immune responses to vaccine vectors are typically less well-defined. Our study considered the kinetics of immunoglobulin (IgG) responses against the vector (vesicular stomatitis Indiana virus [VSIV]) nucleoprotein (N) and the inserted antigen (Ebola virus [EBOV]) glycoprotein (GP1,2) components of the rVSVΔG-ZEBOV-GP (rVSV-ZEBOV) vaccine and evaluated their use as biomarkers to confirm self-reported vaccination status. Methods From the Partnership for Research on Ebola Virus in Liberia (PREVAIL) I clinical trial (NCT02344407), we randomly selected 212 participants who received rVSV-ZEBOV (n=107) or placebo (n=105). Levels of IgG antibodies to EBOV GP1,2 or VSIV N were measured using the Filovirus Animal Non-Clinical Group (FANG) ELISA and a newly developed single-molecule array (Simoa) immunoassay, respectively. Results Anti-EBOV GP1,2 IgG and anti-VSIV N IgG were first detected 10–14 d post-vaccination, further increased at 28 d, and remained stable through 360 d. Antibody titers were significantly higher in women compared to men. Anti-EBOV GP1,2 and anti-VSIV N IgG titers were significantly correlated (p&lt;0.001) at 28 d (r=0.47), 180 d (r=0.45), and 360 d (r=0.59). At 28 d, the area under the curve (AUC) of receiver operating characteristic (ROC) curves discriminated vaccinated from unvaccinated patients with high accuracy (AUC=0.965 for anti-VSIV N IgG; AUC=0.945 for anti-EBOV GP1,2 IgG [p&lt;0.001]). Conclusions We report a reliable assay to measure vector-induced humoral responses after rVSV-ZEBOV vaccination and demonstrate the assay’s utility to confirm vaccination status.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884139","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}
Fernando Dias Gonçalves Lima, Kirsten Rozemeijer, Ramon P van der Zee, Stèfanie Dick, Timo J ter Braak, Debby E Geijsen, Philip Meijnen, Birgit I Lissenberg-Witte, Carel J M van Noesel, Henry J C de Vries, Jan M Prins, Renske D M Steenbergen
Introduction High-resolution anoscopy (HRA) to prevent anal cancer is complex and screening capacity is limited. Previously, we showed that DNA methylation analysis of anal high-grade squamous intraepithelial lesions (HSIL) biopsies can distinguish between HSIL with an increased cancer risk, and HSIL with a low cancer risk, in which treatment may be safely withheld. Here, we assessed the performance of methylation analysis in anal swabs to identify patients with underlying HSIL with an increased cancer risk. Methods A cross-sectional series of paired anal swabs and biopsies of 215 persons with HIV and swabs of 19 anal cancer patients were tested for 6 methylation markers. Data were analysed by logistic regression analysis. The primary endpoint was methylation-positive biopsy HSIL (M+HSIL), indicating increased cancer risk. Test performance on swabs of methylation markers, HPV and/or cytology, as well as cancer detection and HRA referral rates were calculated. Results Anal cancer swabs had the highest methylation levels. ZNF582, and marker panels ASCL1/ZNF582 and LHX8/ZNF582 yielded an area-under-the-curve of 0.68 to 0.70 to detect underlying M+HSIL. LHX8/ZNF582 methylation at 80% sensitivity corresponded to 43% fewer patients requiring HRA, without missing any anal cancers and detecting 79% of HPV16-positive HSIL-anal intraepithelial neoplasia grade 3. Methylation and HPV co-testing performed similarly to cytology and HPV co-testing. Conclusion DNA methylation levels in anal swabs reflect underlying anal disease. Methylation analysis could reduce HRA referrals substantially, while maintaining a high sensitivity for M+HSIL and detecting all cancers. These results encourage screening on anal swabs to preselect patients that require HRA.
{"title":"DNA methylation analysis on anal swabs for anal cancer screening in people living with HIV","authors":"Fernando Dias Gonçalves Lima, Kirsten Rozemeijer, Ramon P van der Zee, Stèfanie Dick, Timo J ter Braak, Debby E Geijsen, Philip Meijnen, Birgit I Lissenberg-Witte, Carel J M van Noesel, Henry J C de Vries, Jan M Prins, Renske D M Steenbergen","doi":"10.1093/infdis/jiae627","DOIUrl":"https://doi.org/10.1093/infdis/jiae627","url":null,"abstract":"Introduction High-resolution anoscopy (HRA) to prevent anal cancer is complex and screening capacity is limited. Previously, we showed that DNA methylation analysis of anal high-grade squamous intraepithelial lesions (HSIL) biopsies can distinguish between HSIL with an increased cancer risk, and HSIL with a low cancer risk, in which treatment may be safely withheld. Here, we assessed the performance of methylation analysis in anal swabs to identify patients with underlying HSIL with an increased cancer risk. Methods A cross-sectional series of paired anal swabs and biopsies of 215 persons with HIV and swabs of 19 anal cancer patients were tested for 6 methylation markers. Data were analysed by logistic regression analysis. The primary endpoint was methylation-positive biopsy HSIL (M+HSIL), indicating increased cancer risk. Test performance on swabs of methylation markers, HPV and/or cytology, as well as cancer detection and HRA referral rates were calculated. Results Anal cancer swabs had the highest methylation levels. ZNF582, and marker panels ASCL1/ZNF582 and LHX8/ZNF582 yielded an area-under-the-curve of 0.68 to 0.70 to detect underlying M+HSIL. LHX8/ZNF582 methylation at 80% sensitivity corresponded to 43% fewer patients requiring HRA, without missing any anal cancers and detecting 79% of HPV16-positive HSIL-anal intraepithelial neoplasia grade 3. Methylation and HPV co-testing performed similarly to cytology and HPV co-testing. Conclusion DNA methylation levels in anal swabs reflect underlying anal disease. Methylation analysis could reduce HRA referrals substantially, while maintaining a high sensitivity for M+HSIL and detecting all cancers. These results encourage screening on anal swabs to preselect patients that require HRA.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884140","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 Amino acid (AA) substitutions in the fusion protein of respiratory syncytial virus (RSV) and their effects remain unclear. We aimed to analyze AA substitutions in main neutralizing epitopes of the fusion (F) protein. Methods We analyzed F protein genes of 236 RSV strains isolated from children hospitalized with RSV infection in Fukushima, Japan (June 2008–February 2023). AA substitutions were detected at antigenic sites II, V, and Ø, the main neutralizing epitopes. We conducted neutralization assays using site-specific mAbs to investigate the relationship between AA substitutions and mAb susceptibility. Finally, we examined viral replicative ability. Results Site Ⅱ: RSV strains isolated from children receiving palivizumab treatment exhibited the K272M substitution in RSV-A and K272E substitution in RSV-B, showing reduced susceptibility to site Ⅱ-specific antibody. Site Ⅴ: In RSV-A, >50% of strains isolated since 2022 harbored the V178I substitution; however, this did not change susceptibility to site Ⅴ-specific antibody. In RSV-B, L172Q/S173L mutant strains became predominant around 2016, leading to reduced susceptibility to site Ⅴ-specific antibodies. Site Ø: No AA substitutions were detected in RSV-A. In RSV-B, the I206M/Q209R mutant strain became predominant around 2018, leading to improved site Ø-specific antibody susceptibility and replicative ability. However, none of the substitutions reduced susceptibility to site Ø-specific antibodies. Conclusions The RSV F protein in Fukushima has naturally undergone AA substitutions with corresponding changes in antibody susceptibility. In addition to substitutions similar to those observed globally, unique substitutions have been observed. Therefore, AA substitutions and antibody susceptibility in various regions must be monitored.
{"title":"Amino acid substitutions in the fusion protein of respiratory syncytial virus in Fukushima, Japan during 2008–2023 and their effects","authors":"Hisao Okabe, Koichi Hashimoto, Sakurako Norito, Yuichiro Asano, Masatoki Sato, Yohei Kume, Mina Chishiki, Hajime Maeda, Fumi Mashiyama, Aya Takeyama, Hiromichi Murai, Kenji Nemoto, Masaki Ito, Shigeo Suzuki, Hiroko Sakuma, Kazuya Shirato, Hayato Go, Mitsuaki Hosoya","doi":"10.1093/infdis/jiae636","DOIUrl":"https://doi.org/10.1093/infdis/jiae636","url":null,"abstract":"Background Amino acid (AA) substitutions in the fusion protein of respiratory syncytial virus (RSV) and their effects remain unclear. We aimed to analyze AA substitutions in main neutralizing epitopes of the fusion (F) protein. Methods We analyzed F protein genes of 236 RSV strains isolated from children hospitalized with RSV infection in Fukushima, Japan (June 2008–February 2023). AA substitutions were detected at antigenic sites II, V, and Ø, the main neutralizing epitopes. We conducted neutralization assays using site-specific mAbs to investigate the relationship between AA substitutions and mAb susceptibility. Finally, we examined viral replicative ability. Results Site Ⅱ: RSV strains isolated from children receiving palivizumab treatment exhibited the K272M substitution in RSV-A and K272E substitution in RSV-B, showing reduced susceptibility to site Ⅱ-specific antibody. Site Ⅴ: In RSV-A, &gt;50% of strains isolated since 2022 harbored the V178I substitution; however, this did not change susceptibility to site Ⅴ-specific antibody. In RSV-B, L172Q/S173L mutant strains became predominant around 2016, leading to reduced susceptibility to site Ⅴ-specific antibodies. Site Ø: No AA substitutions were detected in RSV-A. In RSV-B, the I206M/Q209R mutant strain became predominant around 2018, leading to improved site Ø-specific antibody susceptibility and replicative ability. However, none of the substitutions reduced susceptibility to site Ø-specific antibodies. Conclusions The RSV F protein in Fukushima has naturally undergone AA substitutions with corresponding changes in antibody susceptibility. In addition to substitutions similar to those observed globally, unique substitutions have been observed. Therefore, AA substitutions and antibody susceptibility in various regions must be monitored.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884144","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 Current guidelines recommend combining a macrolide with a β-lactam antibiotic for the empirical treatment of moderate-to-high severity community-acquired pneumonia (CAP); however macrolide use is associated with potential adverse events and antimicrobial resistance. Methods We analysed electronic health data from 8,872 adults in Oxfordshire, UK, hospitalised with CAP between 01-January-2016 and 19-March-2024, who received either amoxicillin or co-amoxiclav as initial treatment. We examined the effects of adjunctive macrolides on 30-day all-cause mortality, time to hospital discharge, and changes in Sequential Organ Failure Assessment (SOFA) score, using inverse probability treatment weighting to address confounding by baseline severity. Subgroup analyses by severity and sensitivity analyses with missing covariates imputed were performed. Results There was no evidence of an association between the use of additional macrolides and 30-day mortality, with marginal odds ratios of 1.05 (95%CI 0.75-1.47) for amoxicillin with vs. without macrolide, and 1.12 (0.93-1.34) for co-amoxiclav with vs. without macrolide. No evidence of difference was found in time to discharge from additional macrolides to amoxicillin (restricted mean days lost +1.76 [-1.66,+5.19]), or co-amoxiclav (+0.44 [-1.63,+2.51]). There was also no evidence that macrolide use was associated with SOFA score decreases. Results were consistent across stratified analyses by pneumonia severity, and remained broadly similar in sensitivity analyses with missing data imputed. Conclusions At a population level, the addition of macrolides was not associated with improved clinical outcomes for CAP patients. The potential advantages of combining macrolides with a β-lactam antibiotic in CAP treatment should be balanced against the risks of adverse effects and antimicrobial resistance.
{"title":"Addition of macrolide antibiotics for hospital treatment of community-acquired pneumonia","authors":"Jia Wei, A Sarah Walker, David W Eyre","doi":"10.1093/infdis/jiae639","DOIUrl":"https://doi.org/10.1093/infdis/jiae639","url":null,"abstract":"Background Current guidelines recommend combining a macrolide with a β-lactam antibiotic for the empirical treatment of moderate-to-high severity community-acquired pneumonia (CAP); however macrolide use is associated with potential adverse events and antimicrobial resistance. Methods We analysed electronic health data from 8,872 adults in Oxfordshire, UK, hospitalised with CAP between 01-January-2016 and 19-March-2024, who received either amoxicillin or co-amoxiclav as initial treatment. We examined the effects of adjunctive macrolides on 30-day all-cause mortality, time to hospital discharge, and changes in Sequential Organ Failure Assessment (SOFA) score, using inverse probability treatment weighting to address confounding by baseline severity. Subgroup analyses by severity and sensitivity analyses with missing covariates imputed were performed. Results There was no evidence of an association between the use of additional macrolides and 30-day mortality, with marginal odds ratios of 1.05 (95%CI 0.75-1.47) for amoxicillin with vs. without macrolide, and 1.12 (0.93-1.34) for co-amoxiclav with vs. without macrolide. No evidence of difference was found in time to discharge from additional macrolides to amoxicillin (restricted mean days lost +1.76 [-1.66,+5.19]), or co-amoxiclav (+0.44 [-1.63,+2.51]). There was also no evidence that macrolide use was associated with SOFA score decreases. Results were consistent across stratified analyses by pneumonia severity, and remained broadly similar in sensitivity analyses with missing data imputed. Conclusions At a population level, the addition of macrolides was not associated with improved clinical outcomes for CAP patients. The potential advantages of combining macrolides with a β-lactam antibiotic in CAP treatment should be balanced against the risks of adverse effects and antimicrobial resistance.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884141","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}
Jenna Alessandrini, Brendan T Smith, Tiffany Fitzpatrick, Sarah A Buchan
Background Socio-economic status (SES) is an important determinant of severe respiratory infections. Despite being a leading cause of hospitalization, limited attention has been given to social inequities in respiratory syncytial virus (RSV), particularly outside of childhood and beyond neighbourhood-level measures. This study aimed to quantify the burden of severe RSV disease across the age continuum by individual-level SES indicators. Methods We conducted a longitudinal descriptive study of Canadians (excluding Québec) ≥6 months of age using linked socio-demographic and hospitalization data from the 2016 Canadian Census Health and Environment Cohort (2016-2019). Crude and age-stratified International Classification of Diseases, 10th Revision, Canada (ICD-10-CA) coded RSV-related hospitalization rates, rate ratios (RRs), and rate differences (RDs) per 100,000 person-years were estimated across SES indicators using Poisson regression. Results Rates of RSV-related hospitalization were greatest among Canadians with lower compared to higher SES, as indicated through multiple measures including income (RD: 11.7 [95% confidence interval, 10.1-13.3]; RR: 2.8 [2.4-3.2]), education (RD: 18.7 [16.6-20.9]; RR: 3.3 [2.9-3.7]), and various indicators of poorer housing conditions including unaffordable housing and apartment-living. Inequities in RSV-related hospitalization varied by SES measure and age group; while rates were highest among 6-59-month- and ≥80-year-olds overall, some of the greatest relative SES inequities were among other age groups. Conclusions This work highlights novel individual-level social determinants influencing the burden of severe RSV disease. In addition to clinical characteristics, understanding SES factors role in age-specific RSV-related hospitalization risk is necessary to inform equitable prevention efforts, including delivery of emerging RSV immunizations.
{"title":"Socio-Economic Inequities in the Age-Specific Burden of Severe Respiratory Syncytial Virus (RSV) in Canada, 2016-2019","authors":"Jenna Alessandrini, Brendan T Smith, Tiffany Fitzpatrick, Sarah A Buchan","doi":"10.1093/infdis/jiae635","DOIUrl":"https://doi.org/10.1093/infdis/jiae635","url":null,"abstract":"Background Socio-economic status (SES) is an important determinant of severe respiratory infections. Despite being a leading cause of hospitalization, limited attention has been given to social inequities in respiratory syncytial virus (RSV), particularly outside of childhood and beyond neighbourhood-level measures. This study aimed to quantify the burden of severe RSV disease across the age continuum by individual-level SES indicators. Methods We conducted a longitudinal descriptive study of Canadians (excluding Québec) ≥6 months of age using linked socio-demographic and hospitalization data from the 2016 Canadian Census Health and Environment Cohort (2016-2019). Crude and age-stratified International Classification of Diseases, 10th Revision, Canada (ICD-10-CA) coded RSV-related hospitalization rates, rate ratios (RRs), and rate differences (RDs) per 100,000 person-years were estimated across SES indicators using Poisson regression. Results Rates of RSV-related hospitalization were greatest among Canadians with lower compared to higher SES, as indicated through multiple measures including income (RD: 11.7 [95% confidence interval, 10.1-13.3]; RR: 2.8 [2.4-3.2]), education (RD: 18.7 [16.6-20.9]; RR: 3.3 [2.9-3.7]), and various indicators of poorer housing conditions including unaffordable housing and apartment-living. Inequities in RSV-related hospitalization varied by SES measure and age group; while rates were highest among 6-59-month- and ≥80-year-olds overall, some of the greatest relative SES inequities were among other age groups. Conclusions This work highlights novel individual-level social determinants influencing the burden of severe RSV disease. In addition to clinical characteristics, understanding SES factors role in age-specific RSV-related hospitalization risk is necessary to inform equitable prevention efforts, including delivery of emerging RSV immunizations.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884143","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}
Rachel Mittelstaedt, Sanjat Kanjilal, David Helekal, Gregory K Robbins, Yonatan H Grad
Among doxycycline post-exposure prophylaxis (doxy-PEP) eligible men, Staphylococcus aureus tetracycline non-susceptibility is more prevalent than in the overall population and is associated with resistance to trimethoprim-sulfamethoxazole and clindamycin. Doxy-PEP may select for multi-drug-resistant S. aureus, underscoring the importance of surveillance.
{"title":"Staphylococcus aureus Tetracycline Resistance and Co-resistance in a Doxy-PEP-Eligible Population","authors":"Rachel Mittelstaedt, Sanjat Kanjilal, David Helekal, Gregory K Robbins, Yonatan H Grad","doi":"10.1093/infdis/jiae634","DOIUrl":"https://doi.org/10.1093/infdis/jiae634","url":null,"abstract":"Among doxycycline post-exposure prophylaxis (doxy-PEP) eligible men, Staphylococcus aureus tetracycline non-susceptibility is more prevalent than in the overall population and is associated with resistance to trimethoprim-sulfamethoxazole and clindamycin. Doxy-PEP may select for multi-drug-resistant S. aureus, underscoring the importance of surveillance.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"630 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884142","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}
Cheryl L Day, Irene N Njuguna, Lisa Marie Cranmer, Wendy E Whatney, Rachel A Pearson, Cecilia S Lindestam Arlehamn, Alessandro Sette, Sylvia M LaCourse, Jaclyn N Escudero, Loren E Sasser, Cyrus Mugo, Hellen Moraa Okinyi, Elizabeth Maleche-Obimbo, Dalton C Wamalwa, Grace C John-Stewart
Background Despite immune restoration after initiation of antiretroviral treatment (ART), the risk of tuberculosis (TB) persists in children living with HIV (CLHIV). We determined patterns of immune restoration of mycobacteria-specific T cells following ART in CLHIV. Methods CD4 and CD8 T cell activation and memory phenotype and functional profiles before and 6 months after ART were evaluated in peripheral blood mononuclear cells (PBMCs) from CLHIV enrolled in the PUSH study (NCT02063880) in Nairobi, Kenya. T cell expression of cytokines and activation induced markers (AIM) were measured following stimulation of PBMCs with a pool of 300 peptides from TB (MTB300) or staphylococcal enterotoxin B (SEB). Results Among 47 CLHIV of median age 1.5 years, SEB-induced Th1 cytokine+ and AIM+ CD4 cell frequencies increased significantly after 6 months ART. Although MTB300-specific CD4 and CD8 cell frequency did not increase after ART, polyfunctional capacity of MTB300-specific CD4 cells expressing combinations of Th1 cytokines with CD40L increased significantly after ART. Baseline age, immune activation, and effector memory CD4 levels were associated with less restoration of MTB300-specific polyfunctional CD4 cells, whereas CD4% and levels of naïve CD4 cells following ART were associated with improved MTB300-specific polyfunctional capacity. Conclusions Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 cells persisted 6 months after ART, with higher deficits in older CLHIV with more immunosuppression, higher immune activation, and lower proportion of naïve CD4 cells. These findings may explain persistent TB risk during early ART among CLHIV and identify those at highest risk.
{"title":"Patterns and cofactors of polyfunctional mycobacteria-specific T cell response restoration following 6-month antiretroviral treatment in children living with HIV","authors":"Cheryl L Day, Irene N Njuguna, Lisa Marie Cranmer, Wendy E Whatney, Rachel A Pearson, Cecilia S Lindestam Arlehamn, Alessandro Sette, Sylvia M LaCourse, Jaclyn N Escudero, Loren E Sasser, Cyrus Mugo, Hellen Moraa Okinyi, Elizabeth Maleche-Obimbo, Dalton C Wamalwa, Grace C John-Stewart","doi":"10.1093/infdis/jiae630","DOIUrl":"https://doi.org/10.1093/infdis/jiae630","url":null,"abstract":"Background Despite immune restoration after initiation of antiretroviral treatment (ART), the risk of tuberculosis (TB) persists in children living with HIV (CLHIV). We determined patterns of immune restoration of mycobacteria-specific T cells following ART in CLHIV. Methods CD4 and CD8 T cell activation and memory phenotype and functional profiles before and 6 months after ART were evaluated in peripheral blood mononuclear cells (PBMCs) from CLHIV enrolled in the PUSH study (NCT02063880) in Nairobi, Kenya. T cell expression of cytokines and activation induced markers (AIM) were measured following stimulation of PBMCs with a pool of 300 peptides from TB (MTB300) or staphylococcal enterotoxin B (SEB). Results Among 47 CLHIV of median age 1.5 years, SEB-induced Th1 cytokine+ and AIM+ CD4 cell frequencies increased significantly after 6 months ART. Although MTB300-specific CD4 and CD8 cell frequency did not increase after ART, polyfunctional capacity of MTB300-specific CD4 cells expressing combinations of Th1 cytokines with CD40L increased significantly after ART. Baseline age, immune activation, and effector memory CD4 levels were associated with less restoration of MTB300-specific polyfunctional CD4 cells, whereas CD4% and levels of naïve CD4 cells following ART were associated with improved MTB300-specific polyfunctional capacity. Conclusions Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 cells persisted 6 months after ART, with higher deficits in older CLHIV with more immunosuppression, higher immune activation, and lower proportion of naïve CD4 cells. These findings may explain persistent TB risk during early ART among CLHIV and identify those at highest risk.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848926","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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