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Objective: Evaluating the vascular function in HIV+ compared to HIV- with assessment of body composition, inflammation, and gut integrity markers.Design: A non-invasive test that measures the endothelial function.Methods: We included participants ≥18 years, with peripheral arterial tonometry testing (EndoPAT2000) between 2014-2022. Persons living with HIV (PLWH) had documented infection, a stable ART regimen, and a Viral Load…

Objective: To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHDs).Design: Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design.Methods: PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008 to 2018 based on ICD code mapping. Mental health (MH) multimorbidity was defined as having ≥2 MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥1 visit/year) and viral suppression (HIV RNA ≤200 copies/ml) by presence vs. absence of each MHD between 2016 and 2018.Results: Among 122 896 PWH, 67 643 (55.1%) were diagnosed with ≥1 MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008 and 2018, whereas bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016 to 2018 (N = 64 684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR = 0.98 [0.98–0.99]) as did PWH with MH multimorbidity (aPR = 0.99 [0.99–1.00]) compared with PWH without MHD.Conclusion: The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Introduction: Studies examining hospitalization among infants with HIV in resource-limited settings, in the context of early infant diagnosis and early antiretroviral therapy (ART) initiation, are limited.Methods: We used routinely collected data on infants who initiated ART aged 1 hospitalization. Median age at ART initiation decreased from 57 days (interquartile range [IQR] 22–74; 2013–2015) to 19 days (IQR 5–54; 2016–2017). Early neonatal hospitalization (age…

Objective: To characterize the prevalence of anemia and risk factors between 2007 and 2017 for moderate/severe anemia among people with HIV (PWH) in North America who have initiated antiretroviral therapy (ART).Design: Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).Methods: We estimated the annual prevalence between 1 January 2007 and 31 December 2017 of mild (11.0–12.9 g/dl men, 11.0–11.9 g/dl women), moderate (8.0–10.9 g/dl regardless of sex) and severe (1 year of ART) (aPR = 1.66 [1.61–1.72]).Conclusion: The prevalence of anemia among PWH is reduced after ART initiation but remains high. Risk factors differ by sex and include comorbidities and HIV disease severity. The persistent, substantial prevalence of anemia among PWH merits further investigation, targeted screening, and clinical interventions.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Objectives: Despite suppressive antiretroviral therapy (ART), HIV can persist in a diverse range of CD4+ T-cell subsets. Through longitudinal env sampling from people with HIV (PWH) on ART, we characterized the persistence and phenotypic properties of HIV envs over two time-points (T1 and T2).Methods: Longitudinal blood and lymphoid tissue samples were obtained from eight PWH on suppressive ART. Single genome amplification (SGA) was performed on env to understand the genetic diversity and degree of clonal expansions over time. A subset of envs were used to generate pseudovirus particles to assess sensitivity to autologous plasma IgG and broadly neutralizing antibodies (bNAbs).Results: Identical env sequences indicating clonal expansion persisted between T1 and T2 and within multiple T-cell subsets. At both time-points, CXCR4-tropic (X4) Envs were more prevalent in naive and central memory cells; the proportion of X4 Envs did not significantly change in each subset between T1 and T2. Autologous purified plasma IgG showed variable neutralization of Envs, with no significant difference in neutralization between R5 and X4 Envs. X4 Envs were more sensitive to neutralization with clinical bNAbs, with CD4+-binding site bNAbs demonstrating high breadth and potency against Envs.Conclusion: Our data suggest the viral reservoir in PWH on ART was predominantly maintained over time through proliferation and potentially differentiation of infected cells. We found the humoral immune response to Envs within the latent reservoir was variable between PWH. Finally, we identified coreceptor usage can influence bNAb sensitivity and may need to be considered for future bNAb immunotherapy approaches.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Objective: Prior genomewide association studies have identified variation in MHC Class I alleles and CCR5Δ32 as genetic predictors of viral control, especially in “elite” controllers, individuals who remain virally suppressed in the absence of therapy.Design: Cross-sectional genomewide association study.Methods: We analyzed custom whole exome sequencing and direct HLA typing from 202 ART-suppressed HIV+ non-controllers in relation to four measures of the peripheral CD4+ T cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression.Results: Previously reported “protective” host genetic mutations related to viral setpoint (e.g., among elite controllers) were found to predict smaller HIV reservoir size. The HLA “protective” B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3x10−3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (p = 4.3x10−3) and usRNA (p = 8.7x10−3). In addition, genomewide analysis identified several SNPs in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression.Conclusions: We observed a significant association between previously reported “protective” MHC class I alleles and CCR5Δ32 with the HIV reservoir size in non-controllers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Objective(s): To describe the dynamics of neutralizing antibody (NAbs) response after yellow fever (YF) vaccine in young adults and adolescents with perinatally acquired HIV (pHIV).Design: A retrospective cross-sectional study at three time points around YF vaccination and a matched case-control comparison of NAbs titers several years after YF vaccination.Methods: We selected patients who had both documented YF vaccination and perinatally acquired HIV (n = 46). The NAbs titers were measured in plasma samples from the following three time points: during the two years before (TP0), within the year after (TP1) and more than one year after (TP2) administration of the YF vaccine. The impact of perinatal infection was assessed by comparing pHIV YF vaccinees with 44 controls infected with HIV during adulthood.Results: The median time between the YF vaccine and TP1 and TP2 was 123 days and 7,3 years respectively. After YF vaccination, 85% of vaccinees experienced seroconversion. The proportion of pHIV patients with NAbs above the protective threshold was stable between TP1 and TP2 (91% and 86% respectively) but levels of NAbs decreased significantly between TP1 and TP2 (p = 0.0122). The case-control analysis found slightly higher geometrical mean titers (GMT) in pHIV than patients infected during adulthood.Conclusions: Patients with pHIV showed high seroconversion rate and NAbs persistence at levels above the protective threshold after first YF vaccination. However, a decline in antibody levels over time suggests that at least one revaccination may be necessary to maintain circulating antibodies, contrary to recommendations for the general population.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Background: The impact of pre-antiretroviral treatment (ART) HIV-RNA on time to successful virological suppression and subsequent failure in HIV patients remains poorly investigated.Methods: We used the Swedish InfCareHIV database and the Danish HIV Cohort Study to evaluate impact of pre-ART HIV-RNA on primary virological suppression (HIV-RNA < 50 copies/ml) and risk of secondary virological failure (two consecutive HIV-RNA > 200 copies/ml or one >1000 copies/ml). The study included 3366 Swedish and 2050 Danish ART naïve individuals who initiated ART in the period 2000–2018. We used Kaplan–Meier estimates and Cox regression analyses to estimate absolute risks and hazard ratios.Results: In both cohorts, >95% of patients with a pre-ART HIV-RNA 1 000 000 copies/ml. Almost all patients obtained virological suppression after four years irrespective of pre-ART HIV-RNA. In contrast, we observed no substantial impact of pre-ART HIV-RNA on risk of virological failure once virological suppression was obtained.Conclusion: High pre-ART HIV-RNA is strongly associated with increased time to successful virological suppression, but pre-ART HIV-RNA has no impact on risk of subsequent virological failure.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Objectives: Molecular epidemiology is a powerful tool to characterize HIV epidemics and prioritize public health interventions. Typically, HIV clusters are assumed to have uniform patterns over time. We hypothesized that assessment of cluster evolution would reveal distinct cluster behavior, possibly improving molecular epidemic characterization, towards disrupting HIV transmission.Design: Retrospective cohort.Methods: Annual phylogenies were inferred by cumulative aggregation of all available HIV-1 pol sequences of individuals with HIV-1 in Rhode Island (RI) between 1990 and 2020, representing a statewide epidemic. Molecular clusters were detected in annual phylogenies by strict and relaxed cluster definition criteria, and the impact of annual newly-diagnosed HIV-1 cases to the structure of individual clusters was examined over time.Results: Of 2,153 individuals, 31% (strict criteria) - 47% (relaxed criteria) clustered. Longitudinal tracking of individual clusters identified three cluster types: normal, semi-normal and abnormal. Normal clusters (83%-87% of all identified clusters) showed predicted growing/plateauing dynamics, with ∼3-fold higher growth rates in large (15%-18%) vs. small (∼5%) clusters. Semi-normal clusters (1%-2% of all clusters) temporarily fluctuated in size and composition. Abnormal clusters (11%-16% of all clusters) demonstrated collapses and re-arrangements over time. Borderline values of cluster-defining parameters explained dynamics of non-normal clusters.Conclusions: Comprehensive tracing of molecular HIV clusters over time in a statewide epidemic identified distinct cluster types, likely missed in cross-sectional analyses, demonstrating that not all clusters are equal. This knowledge challenges current perceptions of consistent cluster behavior over time and could improve molecular surveillance of local HIV epidemics to better inform public health strategies.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Introduction: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis.Methods: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide level association in 8512 HIV-positive persons across five clinical trial cohorts.Results: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants.Conclusion: Genetic variation in TET2 was associated with HIV-VL in two large ART-naïve clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Objectives: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people living with HIV (PLWH). Our objective was to compare COVID-19 vaccine immunogenicity in PLWH to HIV-negative individuals.Design: In a Canadian multi-centre prospective, observational cohort of PLWH receiving ≥2 COVID-19 vaccinations, we measured vaccine-induced immunity at three and six months post 2nd and one month post 3rd doses.Methods: The primary outcome was the percentage of PLWH mounting vaccine-induced immunity (co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor binding domain (RBD) proteins) six months post 2nd dose. Univariable and multivariable logistic regression were used to compare COVID-19-specific immune responses between groups and within sub-groups.Results: Data from 294 PLWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-RBD levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and one month post 3rd dose. A lower proportion of PLWH vs controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose (92% vs 99%; OR 0.14[95% CI 0.03, 0.80; p = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type or timing between doses were associated with reduced IgG response.Conclusion: Vaccine-induced IgG was elicited in the vast majority of PLWH and overall similar between groups. A slightly lower proportion of PLWH vs controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Objectives: Increasing numbers of women living with HIV (WLHIV) worldwide receive combination antiretroviral therapy (cART) during pregnancy. We aimed to assess the risk of adverse perinatal outcomes in pregnant WLHIV receiving cART compared with pregnant WLHIV receiving zidovudine monotherapy.Design: Systematic review and meta-analysis.Methods: We searched four electronic literature databases (PubMed, CINAHL, Global Health, EMBASE) for studies published between 01 January 1980 to 20 April 2020 using a comprehensive search strategy. Studies reporting data on WLHIV receiving cART compared with WLHIV receiving monotherapy for 11 adverse perinatal outcomes were sought: preterm birth (PTB), very PTB, spontaneous PTB, low birthweight (LBW), very LBW, preterm and term LBW, small-for-gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted to calculate relative risk (RR) and 95% confidence intervals (95% CI).Results: We included 30 studies reporting on 317 101 women in 27 countries. WLHIV receiving cART were at increased risk of PTB (RR 1.32, 95% CI 1.18–1.46), LBW (1.35, 1.19–1.53), SGA (1.32, 1.13–1.53), VSGA (1.64, 1.34–2.02), and stillbirth (2.41, 1.83–3.17) compared to WLHIV receiving monotherapy. The significance of these results was maintained in subgroup analyses for studies conducted in low-and-middle-income countries and average quality studies. Additionally, WLHIV receiving nonnucleoside reverse transcriptase inhibitor-based cART were associated with increased risk of PTB, LBW, and stillbirth, while WLHIV receiving protease inhibitor-based cART were associated with increased risk of PTB, compared with WLHIV receiving monotherapy.Conclusion: Pregnant WLHIV receiving cART are associated with increased risk of adverse perinatal outcomes, compared with WLHIV receiving monotherapy.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Objective: To compare the estimated glomerular filtration rate (eGFR) using the creatinine equation (eGFRcreat) or the cystatin C equation (eGFRcys) in people with HIV (PWH) under antiretroviral drugs. We specifically included patients with an eGFRcreat around 60 ml/min/1.73 m2 to evaluate agreement on stage 2 and 3 chronic kidney disease (CKD) classification.Design: eGFRcreat, eGFRcys and resulting CKD staging were determined in 262 consecutive patients with HIV-1 (PWH) with a suppressed viral load (…

Objective: To evaluate HIV care continuum trends over time among women with HIV (WWH).Design: The Medical Monitoring Project (MMP) is a complex sample survey of adults with diagnosed HIV in the United States.Methods: We used 2015–2019 MMP data collected from 5139 adults with diagnosed HIV infection who identified as cisgender women. We calculated weighted percentages with 95% confidence intervals (CIs) for all characteristics and estimated annual percent change (EAPC) and the associated 95% CI to assess trends. EAPCs were considered meaningful from a public health perspective if ≥1% with p-values…

Objective: Liver disease is accelerated in people living with HIV (PLWH) with hepatitis B (HBV) coinfection. We hypothesised that liver fibrosis in HIV-HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products.Design: Sera from PLWH with HBV coinfection versus from those with HBV only or putative mediators were used to examine the pathogenesis of liver disease in HIV-HBV.Methods: We applied sera from PLWH and HBV coinfection versus HBV alone, or putative mediators (including HMGB1), to primary human hepatic stellate cells (hHSC) and examined pro-fibrogenic changes at the single cell level using flow cytometry. HMGB1 levels in the applied sera were assessed according to donor fibrosis stage.Results: Quantitative flow cytometric assessment of pro-fibrogenic and inflammatory changes at the single cell level revealed an enhanced capacity for sera from PLWH with HBV coinfection to activate hHSC. This effect was recapitulated by LPS, HIV-gp120, hepatocyte conditioned-media and the alarmin HMGB1. Induction of hepatocyte cell death increased their pro-fibrogenic potential, an effect blocked by HMGB1 antagonist glycyrrhizic acid. Consistent with a role for this alarmin, HMGB1 levels were elevated in sera from PLWH and hepatitis B coinfection compared to HBV alone and higher in those with HIV-HBV with liver fibrosis compared to those without.Conclusions: Sera from PLWH and HBV coinfection have an enhanced capacity to activate primary hHSC. We identified an increase in circulating HMGB1 which, in addition to HIV-gp120 and translocated microbial products, drove pro-fibrogenic changes in hHSC, as mechanisms contributing to accelerated liver disease in HIV-HBV.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Objective: Cervical cancer is a common preventable cancer among African women living with HIV (WLWH). Molecular diagnostics for high-risk human papillomavirus (HR-HPV) genotypes are standard components of cervical cancer screening in resource-rich countries but not in resource-limited settings. We evaluated HR-HPV genotypes among women with and without HIV in four African countries to inform cervical cancer preventive strategies.Methods: The African Cohort Study (AFRICOS) enrolled participants with and without HIV at 12 clinics in Tanzania, Kenya, Uganda and Nigeria. Cervical cytobrush specimens from women were genotyped for 14 HR-HPV types using the multiplex Seegene Anyplex real-time PCR assay. Robust Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with HR-HPV in WLWH.Results: From January 2015 to March 2020, 868 WLWH and 134 WLWoH were tested for HR-HPV with prevalence of 50.9% and 38.1%, respectively (p = 0.007). Among WLWH, 844 (97.4%) were ART-experienced and 772 (89.7%) virally suppressed ≦1000 copies/mL. The most frequent HR-HPV types among WLWH were HPV-16 (13.5%), HPV-52 (9.5%) and HPV-35 (9.3%). HR-HPV infection was more common among Tanzanian WLWH (adjusted RR: 1.23, 95% CI: 1.05–1.44, p = 0.012). Also, WLWH with CD4 T cells of…

Objective: To systematically assess the efficacy, safety, and tolerability of isoniazid preventive therapy (IPT) for tuberculosis (TB) in people living with human immunodeficiency virus (PLHIV).Design: Systematic review and meta-analysis.Methods: A thorough literature search was performed using PubMed, Cochrane CENTRAL, and Google Scholar from their inception to June 30, 2021. All randomized controlled trials (RCTs) investigating the efficacy, safety, or tolerability of IPT on PLHIV compared to placebo or active comparators were included in the study. The heterogeneity among the studies was identified by using the I2 statistic and Cochran's Q test.Results: Out of the 924 non-duplicate RCTs identified through database searching and other sources, 26 studies comprising 38005 patients were included. The overall effect estimate identified the reduction of active TB incidence (OR 0.69; 95% CI 0.57, 0.84; P …

Ian Frazer, Douglas Lowy, and John Schiller have been recognised for their work on HPV vaccines, and Ralph DeFronzo wins for work on diabetes. Talha Burki reports.

SummaryMitochondria are the controllers of cell metabolism and are recognized as decision makers in cell death pathways, organizers of cytoplasmic signaling networks, managers of cellular stress responses and regulators of nuclear gene expression. Cells of the immune system are particularly dependent on mitochondrial resources, as they must swiftly respond to danger signals with activation, trafficking, migration, and generation of daughter cells. Analogously, faulty immune responses that lead to autoimmunity and tissue inflammation rely on mitochondria to supply energy, cell building blocks and metabolic intermediates. Emerging data endorse the concept that mitochondrial fitness, and the lack of it, is of particular relevance in the autoimmune disease rheumatoid arthritis (RA) where deviations of bioenergetic and biosynthetic flux affect T cells during early and late stages of disease. During early stages of RA, mitochondrial deficiency allows naïve RA T cells to lose self-tolerance, biasing fundamental choices of the immune system towards immune-mediated tissue damage and away from host protection. During late stages of RA, mitochondrial abnormalities shape the response patterns of RA effector T cells engaged in the inflammatory lesions, enabling chronicity of tissue damage and tissue remodeling. In the inflamed joint, autoreactive T cells partner with metabolically reprogrammed tissue macrophages that specialize in antigen-presentation and survive by adapting to the glucose-deplete tissue microenvironment. Here, we summarize recent data on dysfunctional mitochondria and mitochondria-derived signals relevant in the RA disease process that offer novel opportunities to deter autoimmune tissue inflammation by metabolic interference.

SummarySignal transducer and activator of transcription 1 (STAT1) is a well-known and pivotal molecule in the regulation of the Janus activating kinases (JAK)-STAT pathway, an extensive signalling pathway downstream of several cytokine receptors that plays an indispensable role in immune defence in humans. In the JAK-STAT pathway, STAT1 homodimer-dependent IFN-γ immunity is crucial for defence against intra-macrophagic bacteria, and STAT1/STAT2/IRF9 complex-dependent IFN-α/β immunity is essential for protection against viruses. STAT1 dysfunction causes a wide range of immune dysregulation phenotypes, which have been classified into four disease types, namely, (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD STAT1 gain-of-function (GOF), based on their mode of inheritance and function. Disease types (i, ii, and iii) are caused by STAT1 loss-of-function (LOF) mutations, whereas disease type (iv) is caused by STAT1 GOF mutations. Notably, rapid and accurate diagnosis of these four diseases can be difficult. In particular, the differential diagnosis of AD STAT1 deficiency and AD STAT1 GOF, which are caused by LOF- and GOF-STAT1 mutations, respectively, can be complicated due to their overlapping clinical symptoms. In addition, more than 150 pathological mutations have been identified in STAT1 across all domains, making functional prediction of novel mutations difficult. Thus, the functional analysis of mutations is necessary for diagnosis. The recently proposed reference database of mutant STAT1 functions based on comprehensive alanine scanning is a useful tool for evaluating unknown STAT1 mutations with high accuracy.

AbstractBackgroundPersons with opioid use disorder (OUD) may present with infectious complications from injection drug use, thus ID physicians are uniquely positioned to treat OUD. Buprenorphine is safe and effective for OUD but remains underutilized. The prevalence and geographic distribution of ID physicians who are waivered to prescribe buprenorphine are unknown.MethodsThis cross-sectional study merged data from several publicly available datasets from November 1, 2021 to January 15, 2022. Our primary outcome was proportion of ID physicians possessing buprenorphine waivers in the United States. We identified individual and county-level characteristics associated with buprenorphine waiver possession. We then used geospatial analysis to determine geographic distribution of waivered ID physicians.ResultsWe identified 6372 ID physicians in the US, among whom 170 (2.7%) possessed waivers. Most ID physicians (97.3%) practiced in metropolitan counties. In our multivariable analysis, ID physicians had lower odds of having a waiver for every 10-year increase since graduating medical school (OR 0.79, 95% CI 0.68-0.91). ID physicians practicing in counties with higher proportion of uninsured residents had lower odds of having a waiver (OR 0.75, 95% CI 0.62-0.90). Among counties with at least one ID physician (n = 729), only 11.2% had at least one waivered ID physician.ConclusionsWe found an extremely low prevalence and skewed geographic distribution of ID physicians with buprenorphine waivers. Our findings suggest an urgent need to increase the workforce of ID physicians waivered to prescribe buprenorphine and a call for increased integration of OUD education into ID training and continuing medical education.

NIH10.13039/100000002NIDCR10.13039/100000072…

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

Proceedings of the National Academy of Sciences, Volume 119, Issue 48, November 2022.

AbstractBiological dinitrogen (N2) fixation supplies nitrogen to the oceans, supporting primary productivity, and is carried out by some bacteria and archaea referred to as diazotrophs. Cyanobacteria are conventionally considered to be the major contributors to marine N2 fixation, but non-cyanobacterial diazotrophs (NCDs) have been shown to be distributed throughout ocean ecosystems. However, the biogeochemical significance of marine NCDs has not been demonstrated. This review synthesizes multiple datasets, drawing from cultivation-independent molecular techniques and data from extensive oceanic expeditions, to provide a comprehensive view into the diversity, biogeography, ecophysiology, and activity of marine NCDs. A NCD nifH gene catalog was compiled containing sequences from both PCR-based and PCR-free methods, identifying taxa for future studies. NCD abundances from a novel database of NCD nifH-based abundances were colocalized with environmental data, unveiling distinct distributions and environmental drivers of individual taxa. Mechanisms that NCDs may use to fuel and regulate N2 fixation in response to oxygen and fixed nitrogen availability are discussed, based on a metabolic analysis of recently available Tara Oceans expedition data. The integration of multiple datasets provides a new perspective that enhances understanding of the biology, ecology, and biogeography of marine NCDs and provides tools and directions for future research.

Abstract Background Cytomegalovirus (CMV) infection is a leading cause of morbidity and mortality after transplantation. This study aimed to investigate CMV seroprevalence, infection, and disease in Chinese thoracic organ transplant recipients. Methods The clinical data of the patients who underwent lung and/or heart transplantation between January 2015 and October 2020 were retrospectively collected from four transplantation centers in China. Results A total of 308 patients were analyzed. The CMV serostatus was donor positive (D+) recipient negative (R−) in 19 (6.17%) patients, D+/R+ in 233 (75.65%), D−/R+ in 36 (11.69%), and D−/R− in 20 (6.50%). CMV DNAemia was detected in 52.3% of the patients and tissue-invasive CMV disease was diagnosed in 16.2% of the patients. Only 31.8% of the patients adhered to the postdischarge valganciclovir therapy. The D+/R− serostatus (odds ratio [OR]: 18.32; 95% confidence interval [CI]:1.80-188.68), no valganciclovir prophylaxis (OR: 2.64; 95% CI: 1.05–6.64), and higher doses of rabbit anti-human thymocyte globulin (> 2 mg/kg) (OR: 4.25; 95% CI: 1.92–9.42) were risk factors of CMV disease. Conclusion CMV seroprevalence was high in Chinese thoracic organ transplant donors and recipients. The low adherence rate to the postdischarge CMV prophylaxis therapy in Chinese patients is still an unresolved issue. …

Abstract Background Obstetrical infection is one of the causes of maternal death and a difficult problem for many clinicians. Changes in the demographic and obstetric background of pregnant women following the Universal Two-Child Policy may have an impact on some fertility phenomena. And with the increase in the number of deliveries, the limited medical resources become more scarce. How will China's health system quickly adapt to the growing needs and expectations for maternal health and ensure the provision of qualified and accessible medical services? In addition, what social support measures should be provided to reduce preventable obstetric complications? Given the relatively low per capita share of medical resources in China, how should China deal with the impact of the Universal Two-Child Policy? Therefore, more studies based on the change of fertility policy are needed. We try to analyze the epidemiological characteristics and risk factors of obstetric infection before and after the Universal Two-Child Policy, with a view to providing reference for the prevention and control of obstetric infection in regions after the change of fertility policy, and also hope to make corresponding contributions to the solution of the above problems through relevant studies. Methods The subjects of the survey were 268,311 pregnant women from Hebei Province Maternal Near Miss Surveillance System (HBMNMSS) of Hebei Women and Children's Health Center from January 1, 2013 to December 31, 2017. We analyzed the region, time and population distribution characteristics of obstetric infection, compared the epidemiological factors of obstetric infection before and after the Universal Two-Child Policy, and analyzed the relevant risk factors of obstetric infection. Results The incidence of obstetric infection increased nearly twice after the Universal Two-Child Policy. The incidence of obstetric infection was highest in Chengde (1.9%), a city with a northward geographical distribution, Baoding (1.6%), Cangzhou (1.5%) followed; The higher the hospital grade, the higher the incidence; The incidence of obstetric infections in hospitals at all levels has increased; The age of onset before the Universal Two-Child Policy was (27.82 ± 5.047) years old, and the age after the Universal Two-Child Policy was (28.97 ± 4.880) years old; The incidence of obstetric infections is higher in winter. The rate of abortion-related infection (increased from 0.61 to 1.65%) and the rate of pregnant women with high school education (increased from 0.35 to 0.74%) increased significantly. The results of multivariate Logistic regression analysis after the Universal Two-Child Policy showed that anemia (OR = 1.249, 95%CI: 1.071–1.458), chronic hypertension (OR = 1.934, 95%CI: 1.375–2.722), mild preeclampsia (OR = 2.103, 95%CI: 1.323–3.344) and severe preeclampsia (OR = 2.228, 95%CI: 1.703–2.916) were independent risk factors for obstetric infection. Gestational age ≥ 37 weeks was a protective factor. Conclusion After the Universal Two-Child Policy, the prevention and control of obstetric infections should be strengthened, especially for abortion-related infections and elderly maternal with obstetric complications and complication in high-grade hospitals in winter. Educational background is also one of the factors that should be considered in the prevention of obstetric sensation. Prolonging gestational age is helpful to reduce the incidence of obstetric infection. …

Abstract Background Bedaquiline (BDQ) is a core drug for rifampicin-resistant tuberculosis (RR-TB) treatment. Accurate prediction of a BDQ-resistant phenotype from genomic data is not yet possible. A Bayesian method to predict BDQ resistance probability from next-generation sequencing data has been proposed as an alternative. Methods We performed a qualitative study to investigate the decision-making of physicians when facing different levels of BDQ resistance probability. Fourteen semi-structured interviews were conducted with physicians experienced in treating RR-TB, sampled purposefully from eight countries with varying income levels and burden of RR-TB. Five simulated patient scenarios were used as a trigger for discussion. Factors influencing the decision of physicians to prescribe BDQ at macro-, meso- and micro levels were explored using thematic analysis. Results The perception and interpretation of BDQ resistance probability values varied widely between physicians. The limited availability of other RR-TB drugs and the high cost of BDQ hindered physicians from altering the BDQ-containing regimen and incorporating BDQ resistance probability in their decision-making. The little experience with BDQ susceptibility testing and whole-genome sequencing results, and the discordance between phenotypic susceptibility and resistance probability were other barriers for physicians to interpret the resistance probability estimates. Especially for BDQ resistance probabilities between 25% and 70%, physicians interpreted the resistance probability value dynamically, and other factors such as clinical and bacteriological treatment response, history of exposure to BDQ, and resistance profile were often considered more important than the BDQ probability value for the decision to continue or stop BDQ. In this grey zone, some physicians opted to continue BDQ but added other drugs to strengthen the regimen. Conclusions This study highlights the complexity of physicians' decision-making regarding the use of BDQ in RR-TB regimens for different levels of BDQ resistance probability.. Ensuring sufficient access to BDQ and companion drugs, improving knowledge of the genotype–phenotype association for BDQ resistance, availability of a rapid molecular test, building next-generation sequencing capacity, and developing a clinical decision support system incorporating BDQ resistance probability will all be essential to facilitate the implementation of BDQ resistance probability in personalizing treatment for patients with RR-TB. …

Abstract Background Bacterial infections are a common complication in patients with seasonal viral respiratory tract infections and are associated with poor prognosis, increased risk of intensive care unit admission and 29–55% mortality. Yet, there is limited data on the burden of bacterial infections among COVID-19 patients in Africa, where underdeveloped healthcare systems are likely to play a pertinent role in the epidemiology of the COVID-19 pandemic. Here, we evaluated the etiologies, antimicrobial resistance profiles, risk factors, and outcomes of bacterial infections in severely ill COVID-19 patients. Methods A descriptive cross-sectional study design was adopted in severely ill COVID-19 patients at Kenyatta National Hospital, Kenya, from October to December 2021. We used a structured questionnaire and case report forms to collect sociodemographics, clinical presentation, and hospitalization outcome data. Blood, nasal/oropharyngeal swabs and tracheal aspirate samples were collected based on the patient's clinical presentation and transported to the Kenyatta National Hospital microbiology laboratory for immediate processing following the standard bacteriological procedures. Results We found at least one bacterial infection in 44.2% (53/120) of the patients sampled, with a 31.7% mortality rate. Pathogens were mainly from the upper respiratory tract (62.7%, 42/67), with gram-negative bacteria dominating (73.1%, 49/67). Males were about three times more likely to acquire bacterial infection (p = 0.015). Those aged 25 to 44 years (p = 0.009), immunized against SARS-CoV-2 (p = 0.027), and admitted to the infectious disease unit ward (p = 0.031) for a short length of stay (0–5 days, p < 0.001) were more likely to have a positive outcome. Multidrug-resistant isolates were the majority (64.3%, 46/67), mainly gram-negative bacteria (69.6%, 32/46). The predominant multidrug-resistant phenotypes were in Enterococcus cloacae (42.9%, 3/7), Klebsiella pneumonia (25%, 4/16), and Escherichia coli (40%, 2/5). Conclusion Our findings highlight a high prevalence of multidrug-resistant bacterial infections in severely ill COVID-19 patients, with male gender as a risk factor for bacterial infection. Elderly Patients, non-SARS-CoV-2 vaccination, intensive care unit admission, and long length of hospital stay were associated with poor outcomes. There is a need to emphasize strict adherence to infection and prevention at KNH-IDU and antimicrobial stewardship in line with local and global AMR control action plans. …

Abstract Background Eosinophilia is defined as a blood eosinophil count > 500/mcL with etiology usually an allergic reaction or parasitic infection which can lead to serious organ damage. Case presentation A patient being treated for hardware infection develops eosinophilia while on daptomycin in the setting of a positive strongyloides antibody. The patient was on chronic steroids prior to admission for epitheliopathy which complicated care. The daptomycin was discontinued, ivermectin initiated to treat strongyloidiasis, and high dose steroids initiated simultaneously. Eosinophilia resolved and patient discharged home after two months in the hospital. Conclusion Multifactorial eosinophilia poses question of steroid harm in the setting of parasitic infection. Patient was treated for both strongyloides and daptomycin induced eosinophilia with improvement and discharge from the hospital. …

Abstract The Mycobacterium abscessus complex (MABC) is a group of acid-fast, rapidly dividing non-tuberculous mycobacteria (NTM) that include a number of clinically important subspecies, including M. abscessus, M. bolletii, and M. massiliense. These organisms are prevalent in the environment and are primarily associated with human pulmonary or skin and skin structure infections (SSSI) but may cause more deep-seeded disseminated infections and bacteremia in the immunocompromised. Importantly, these NTM are resistant to most first-line anti-tuberculous agents and, due to intrinsic or acquired resistance, exhibit exceedingly low, variable, and geographically distinct susceptibilities to commonly used antibacterial agents including older tetracyclines, macrolides, aminoglycosides, cephalosporins, carbapenems, and sulfamethoxazole-trimethoprim. Omadacycline is a novel third-generation member of the tetracycline family of antibacterials that has recently been demonstrated to have potent anti-NTM effects and clinical efficacy against MABC, including M. abscessus. The purpose of this review is to present a comprehensive and up-to-date assessment on the body of literature on the role of omadacycline for M. abscessus infections. Specifically, the in vitro and in vivo microbiology, mechanisms of action, mechanisms of resistance, clinical pharmacokinetics, clinical efficacy, adverse effects, dosage and administration, and place in therapy of omadacycline in management of M. abscessus infections will be detailed.…

Abstract Background The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. Methods To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. Results 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57–73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61–2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63–2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. Conclusions Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020 …

Abstract Background In Bangladesh, safely managed sanitation (SMS) coverage is low, and diarrheal disease is a significant health problem. This study estimated the inequality in access to SMS facilities at the national and sub-national levels and assessed the prevalence of diarrheal diseases in connection with these improved facilities. Methods Data were extracted from the Bangladesh Demographic and Health Survey, conducted during 2017–2018. SMS was defined as using an improved sanitation facility, which designed to hygienically separate excreta from human contact and include the use of a flush toilet connected to piped sewer system, septic tank, ventilated improved pit latrine, pit latrine with a slab, and composting toilet. The slope index of inequality (SII) and multi-level regression models were used for inequality and risk factors of SMS respectively. Results The national coverage of SMS was 44.0% (45.3% and 43.5% in urban and rural areas, respectively). At the sub-national level, the lowest and highest coverage of SMS was observed in Mymensingh (32.9%) and Chittagong (54.1%) divisions, respectively. The national level SII indicated that wealthy households had access to higher SMS by 60.8 percentage points than poor households. Additionally, greater inequality was observed in rural areas, which was 71.9 percentage points higher in the richest households than in the poorest households. The coverage gap between the rich and poor was highest in the Sylhet division (85.3 percentage points higher in rich than in poor) and lowest in Dhaka (34.9 percentage points). Old and highly educated household heads and richest households had better access to higher levels of adequate sanitation. After adjusting for confounding variables, the prevalence of diarrheal disease was 14.0% lower in the SMS user group than in their counterparts. Conclusion Substantial inequalities in access to SMS exist at both national and sub-national levels of Bangladesh, with the prevalence of diarrhea being lower among SMS users. These findings may help to prioritize resources for reducing inequality and expanding the coverage of improved sanitation in Bangladesh. …

Abstract Background This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. Methods Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months’ bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. Results Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. Conclusion Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk–benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment. …

Abstract Background Malaria is a priority global health disease with high morbidity and mortality especially among children under-five and pregnant women. Malaria elimination requires an effective surveillance system. The malaria surveillance system in Benue State was evaluated to assess its attributes and performance in line with set objectives. Methods The updated United States Centers for Disease Control and Prevention guideline for evaluating surveillance systems was used. The surveillance system’s key attributes was quantitatively and qualitatively assessed. Semi-structured questionnaires were administered to all Local Government Area (LGA) Roll Back Malaria (RBM) focal persons and five key informants were interviewed at the State level. The Benue State District Health Information System-2 (DHIS-2) malaria data and monthly summary forms were reviewed from January 2015 to December 2019. Results A total of 46 RBM focal persons and 5 key-informants participated. About 56.9% were males, the mean-age 43.8 (SD ± 9.3) years and 32 (62.8%) had ≥ 20-year experience on malaria surveillance with mean-year-experience 20.8 (SD ± 7.8) years. All 46 (100%) RBMs understood the case definition; 43 (93.5%) found it easy-to-fill the standardized data tools and understood the data flow channels. The malaria surveillance system in Benue is simple, acceptable and useful to all stakeholders, 36 (70.6%) found switching from the paper-based to the electronic-data tools with ease and 45 (88.2%) stated that analysed data were used for decision-making. Data flow from LGA to State is clearly defined, however majority of the data is collected from public health facilities through the DHIS-2 Platform. The overall timeliness and completeness of reporting was 76.5% and 95.7%, respectively, which were below the ≥ 80% and 100% targets, respectively. Conclusions The malaria surveillance system in Benue State is simple, useful, acceptable, and flexible, but it is not representative and timely. Public–private and public-public-partnerships should be strengthened to encourage reporting from both private and tertiary health facilities and improve representativeness, and frequent feedback to improve reporting timeliness. …

Abstract Background Malaria is an infectious disease which has been globally targeted for elimination in at least 35 of 90 endemic countries by 2030. Most successful malaria elimination country programmes have engaged the private health sector in an effort to identify, document, investigate, provide effective treatment, and follow-up cases. However, there has been limited rigorous research showing evidence of adherence among healthcare providers of the formal private health sector to national malaria diagnosis and treatment guidelines in Ethiopia, starting from malaria control to elimination phases. The aims of this study were to investigate and explain the level of adherence to malaria diagnosis and treatment guidelines among healthcare providers working in formal private health facilities in north-western Ethiopia. Methods An explanatory sequential mixed method design was conducted in the West Gojjam Zone of Ethiopia. Quantitative data were extracted from 1650 medical records of adult uncomplicated malaria outpatients served in 11 private-for-profit health facilities. In addition, using a qualitative approach, 33 in-depth interviews (IDIs) with healthcare providers were conducted. All interviews were audio-recorded, transcribed verbatim, and analysed using eight steps. Results Of 1650 suspected malaria cases in adult outpatients, 80.6% (1330/1650) were screen tested using microscopy and the remainder 19.4% (320/1650) were tested using multispecies rapid diagnosis tests (RDTs). Hence, the results revealed that private healthcare providers universally adhered to diagnosis guidelines. In addition, after following-up and excluding other causes of fever, 4.1% (56/1376) patients were clinically diagnosed with uncomplicated malaria. Despite this, the proportion of private healthcare provider adherence with confirmed malaria case treatment guidelines was 20.9% (69/330). In addition, 1320 (95.9%) of adult outpatients with negative laboratory results were not treated. Some of the identified determinant factors for sub-optimal adherence of healthcare providers to malaria guidelines were interruptions in supply and lack of availability of recommended anti-malarial drugs, lack of availability of quality assured laboratory supplies, and poor knowledge of the recommendations of the national standards. Conclusions Private healthcare providers adhered to universal parasitological diagnosis, providing comprehensive counseling, and linking patients with community health workers. In addition, almost all laboratory negative patients were not treated with anti-malarial drugs. However, only one-fifth of confirmed patients were treated in line with national guideline recommendations. Malaria control and elimination efforts across Ethiopia could be improved through establishing a collaborative function of a win-win public private mix partnership model. In addition, including the data of the private health sector in the health information system could show real malaria burden and use the information to improve the adherence to malaria diagnosis, treatment, and reporting standards within the targeted era of elimination. Therefore, building the capacity of private healthcare providers and ensuring the availability of all nationally recommended drugs and supplies in private health sector facilities is recommended to improve the quality of services. …

New England Journal of Medicine, Ahead of Print.

Background silence, ambient noise.Wave in// Emerging unrest—distinctive—bass. Gradual loudness, high pitch, increasing frequency—and incidence rate// Wave out.Sudden blast: lockdown.

James Belich is interested in death. Not so much for its own sake; he does not dwell on how exactly Yersinia pestis kills. It is the consequences of all those deaths that take centre stage in the intensively researched and heavily detailed book The world the plague made: the Black Death and the rise of Europe. The Black Death first hit Europe in 1346. If half the continent's population was eradicated, which seems a reasonable estimate, then each survivor was presented with substantially increased resources.

IDWeek 2022 was held as hybrid virtual and in-person event in Washington, DC from Oct 19 to 23, 2022, Farooq Kazi and Ammara Mushtaq report.

To evaluate the activity of cefiderocol against sequential P. aeruginosa isolates from chronically-infected cystic fibrosis (CF) patients as well as to investigate the potential mechanisms involved in resistance through whole genome sequencing.

Journal of Medical Virology, Accepted Article.

Journal of Medical Virology, Accepted Article.

Journal of Medical Virology, Accepted Article.