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Abstract Introduction The COVID-19 pandemic has globally impacted health service access, delivery and resources. There are limited data regarding the impact on the prevention of mother to child transmission (PMTCT) service delivery in low-resource settings. Neotree ( www.neotree.org ) combines data collection, clinical decision support and education to improve care for neonates. Here we evaluate impacts of COVID-19 on care for HIV-exposed neonates. Methods Data on HIV-exposed neonates admitted to the neonatal unit (NNU) at Sally Mugabe Central Hospital, Zimbabwe, between 01/06/2019 and 31/12/2021 were analysed, with pandemic start defined as 21/03/2020 and periods of industrial action (doctors (September 2019-January 2020) and nurses (June 2020-September 2020)) included, resulting in modelling during six time periods: pre-doctors’ strike (baseline); doctors’ strike; post-doctors’ strike and pre-COVID; COVID and pre-nurses’ strike; nurses’ strike; post nurses’ strike. Interrupted time series models were used to explore changes in indicators over time. Results Of 8,333 neonates admitted to the NNU, 904 (11%) were HIV-exposed. Mothers of 706/765 (92%) HIV-exposed neonates reported receipt of antiretroviral therapy (ART) during pregnancy. Compared to the baseline period when average admissions were 78 per week (95% confidence interval (CI) 70–87), significantly fewer neonates were admitted during all subsequent periods until after the nurses’ strike, with the lowest average number during the nurses’ strike (28, 95% CI 23–34, p 0.22) in numbers of admissions or mortality by HIV exposure status. Fewer HIV-exposed neonates received a PCR test during the pandemic (23%) compared to the pre-pandemic periods (40%) (RR 0.59, 95% CI 0.41–0.84, p

The COVID-19 pandemic and associated measures may have disrupted delivery of maternal and neonatal health services and reversed the progress made towards dual elimination of mother-to-child transmission of HIV and syphilis in Zimbabwe. This qualitative study explores the impact of the pandemic on the provision and uptake of prevention of mother-to-child transmission (PMTCT) services from the perspectives of women and maternal healthcare providers. Longitudinal in-depth interviews were conducted with 20 pregnant and breastfeeding women aged 20-39 years living with HIV and 20 healthcare workers in two maternity polyclinics in low-income suburbs of Harare, Zimbabwe. Semi-structured interviews were held after the second and third waves of COVID-19 in March and November 2021, respectively. Data were analysed using a modified grounded theory approach. While eight antenatal care contacts are recommended by Zimbabwe's Ministry of Health and Child Care, women reported only being able to access two contacts. Although HIV testing, antiretroviral therapy (ART) refills and syphilis screening services were accessible at first contact, other services such as HIV-viral load monitoring and enhanced adherence counselling were not available for those on ART. Closure of clinics and shortened operating hours during the second COVID-19 wave resulted in more antenatal bookings occurring later during pregnancy and more home deliveries. Six of the 20 (33%) interviewed women reported giving birth at home, assisted by untrained traditional midwives as clinics were closed. Babies delivered at home missed ART prophylaxis and HIV testing at birth despite being HIV-exposed. Although women faced multiple challenges, they continued to attempt to access services after delivery. These findings underline the importance of investing in robust health systems that can respond to emergency situations to ensure continuity of essential HIV prevention, treatment, and care services.

Abstract Introduction Dolutegravir‐based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre‐conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub‐study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. Methods We conducted the sub‐study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir‐based ART (DTG) and non‐dolutegravir‐based standard‐of‐care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24‐weekly in all ODYSSEY participants. Samples analysed in the sub‐study were collected between September 2016 and October 2020. Results A total of 229 children aged ≥6 years were included in the sub‐study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG‐SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p

Zimbabwe is targeting elimination of mother-to-child transmission of HIV by December 2025, however the COVID-19 pandemic challenged health service delivery globally. Monthly aggregated data were extracted from DHIS-2 for all facilities delivering antenatal care (ANC). ZIMSTAT and Spectrum demographic estimates were used for population-level denominators. Programme indicators are among those in HIV care and population indicators reflect the total population. The mean estimated proportion of pregnant women booking for ANC per month did not change (91% pre-pandemic vs 91% during pandemic, p = 0.95), despite dropping to 47% in April 2020. At a programme-level, the estimated proportion of women who received at least one HIV test fell in April 2020 (3.6% relative reduction vs March (95% CI 2.2-5.1), p

Summary: The Btla inhibitory receptor limits innate and adaptive immune responses, both preventing the development of autoimmune disease and restraining anti-viral and anti-tumor responses. It remains unclear how the functions of Btla in diverse lymphocytes contribute to immunoregulation. Here, we show that Btla inhibits activation of genes regulating metabolism and cytokine signaling, including Il6 and Hif1a, indicating a regulatory role in humoral immunity. Within mucosal Peyer's patches, we find T-cell-expressed Btla-regulated Tfh cells, while Btla in T or B cells regulates GC B cell numbers. Treg-expressed Btla is required for cell-intrinsic Treg homeostasis that subsequently controls GC B cells. Loss of Btla in lymphocytes results in increased IgA bound to intestinal bacteria, correlating with altered microbial homeostasis and elevations in commensal and pathogenic bacteria. Together our studies provide important insights into how Btla functions as a checkpoint in diverse conventional and regulatory lymphocyte subsets to influence systemic immune responses.

BackgroundEarly infant HIV diagnosis (EID) is critical to ensuring timely diagnosis of HIV-exposed infants, and treatment in those found to be infected. However estimates of coverage vary considerably, depending on data sources used. We used 4 methods to estimate coverage among a historical cohort of HIV-exposed infants in rural South Africa, between 2010-2016.MethodsWe estimated the proportion of infants ever tested (methods 1-3) and tested by 7 weeks of age (1-4) as follows: (1) infants born to women identified as HIV-positive in demographic surveillance were linked to those with ≥1 EID result in routine laboratory surveillance; (2) the number of infants with ≥1 EID result in laboratory surveillance divided by the estimated number of HIV-exposed infants, calculated as total live births multiplied by antenatal HIV seroprevalence; (3) the number of infants with ≥1 EID result in routine laboratory surveillance, divided by the number of HIV-exposed infants as estimated by the district health service; (4) from documentation in infants' Road-to-Health-booklets.ResultsThe proportion ever tested was 43%, 88% and 138% for methods 1-3, and by 7 weeks of age was 25%, 49%, 86% and 46% for methods 1-4 respectively.ConclusionsThe four methods, applied to a range of routine data sources, resulted in estimates varying considerably, and the true coverage of EID remains unclear. Our findings highlight the importance of developing unique patient identifiers, improving training of healthcare providers using reporting systems, and ensuring the accuracy of healthcare records, to ensure the best possible health outcomes for HIV-exposed infants.

Genome-wide co-expression analysis is often used for annotating novel gene functions from high-dimensional data. Here, we developed an R package with a Shiny visualization app that creates immuno-networks from RNAseq data using a combination of Weighted Gene Co-expression Network Analysis (WGCNA), xCell immune cell signatures, and Bayesian Network Learning. Using a large publicly available RNAseq dataset we generated a Gene Module-Immune Cell (GMIC) network that predicted causal relationships between DEAH-box RNA helicase (DHX)15 and genes associated with humoral immunity, suggesting that DHX15 may regulate B cell fate. Deletion of DHX15 in mouse B cells led to impaired lymphocyte development, reduced peripheral B cell numbers, and dysregulated expression of genes linked to antibody-mediated immune responses similar to the genes predicted by the GMIC network. Moreover, antigen immunization of mice demonstrated that optimal primary IgG1 responses required DHX15. Intrinsic expression of DHX15 was necessary for proliferation and survival of activated of B cells. Altogether, these results support the use of co-expression networks to elucidate fundamental biological processes.

BackgroundPublished estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.Methods and findingsChildren with perinatal HIV aged 6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged 400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.ConclusionsIn our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

Objectives To assess the effectiveness of radiofrequency denervation (RD) of lumbosacral anatomical targets for the management of chronic back pain.Design Systematic review and meta-analysis of randomised controlled trials (RCTs).Methods A database search (Medline, Medline in Process, Embase, CINHAL and the Cochrane library) was conducted from January 2014 to April 2019 for placebo or no-treatment controlled trials of RD for the management of chronic back pain. Included trials were quality assessed using the Cochrane Risk-of-Bias Tool and the quality of outcomes assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Meta-analysis was conducted to calculate mean difference (MD) in post-treatment Pain Score.Results Nineteen RCTs were included in the review. There appears to be short-term pain relief (1–3 months) provided by RD of the sacroiliac joint (five trials, MD −1.53, CI −2.62 to 0.45) and intervertebral discs (four trials, MD −0.98, CI −1.84 to 0.12), but the placebo effect is large and additional intervention effect size is small (6 months) is uncertain.Conclusions RD of selected lumbosacral targets appears to have a small, short-term, positive effect for the management of patients with chronic back pain. However, the quality of evidence for the majority of outcomes is low or very low quality and there is still a degree of uncertainty, particularly around the duration of effect.