Substantial but spatially heterogeneous progress in male circumcision for HIV prevention in South Africa.

BACKGROUND: Voluntary medical male circumcision (VMMC) reduces the risk of male HIV acquisition by 60%. Programmes to provide VMMCs for HIV prevention have been introduced in sub-Saharan African countries with high HIV burden. Traditional circumcision is also a long-standing male coming-of-age ritual, but practices vary considerably across populations. Accurate estimates of circumcision coverage by age, type, and time at subnational levels are required for planning and delivering VMMCs to meet targets and evaluating their impacts on HIV incidence. METHODS: We developed a Bayesian competing risks time-to-event model to produce region-age-time-type specific probabilities and coverage of male circumcision with probabilistic uncertainty. The model jointly synthesises data from household surveys and health system data on the number of VMMCs conducted. We demonstrated the model using data from five household surveys and VMMC programme data to produce estimates of circumcision coverage for 52 districts in South Africa between 2008 and 2019. RESULTS: Nationally, in 2008, 24.1% (95% CI: 23.4-24.8%) of men aged 15-49 were traditionally circumcised and 19.4% (18.9-20.0%) were medically circumcised. Between 2010 and 2019, 4.25 million VMMCs were conducted. Circumcision coverage among men aged 15-49 increased to 64.0% (63.2-64.9%) and medical circumcision coverage to 42% (41.3-43.0%). Circumcision coverage varied widely across districts, ranging from 13.4 to 86.3%. The average age of traditional circumcision ranged between 13 and 19 years, depending on local cultural practices. CONCLUSION: South Africa has made substantial, but heterogeneous, progress towards increasing medical circumcision coverage. Detailed subnational information on coverage and practices can guide programmes to identify unmet need to achieve national and international targets.

Voluntary medical male circumcision reduces the risk of male HIV acquisition. Programmes to provide circumcisions for HIV prevention have been introduced in sub-Saharan African countries with high HIV burden. Estimates of circumcision coverage are needed for planning and delivering circumcisions to meet targets and evaluate their impacts on HIV incidence. We developed a model to integrate date from both household surveys and health systems on the number of circumcisions conducted, and applied it to understand how the practices and coverage of circumcision are changing in South Africa. National circumcision coverage increased considerably between 2008 and 2019, however, there remains a substantial subnational variation across districts and age groups. Further progress is needed to reach national and international targets.

Risk scores for predicting HIV incidence among adult heterosexual populations in sub-Saharan Africa: a systematic review and meta-analysis.

INTRODUCTION: Several HIV risk scores have been developed to identify individuals for prioritized HIV prevention in sub-Saharan Africa. We systematically reviewed HIV risk scores to: (1) identify factors that consistently predicted incident HIV infection, (2) review inclusion of community-level HIV risk in predictive models and (3) examine predictive performance. METHODS: We searched nine databases from inception until 15 February 2021 for studies developing and/or validating HIV risk scores among the heterosexual adult population in sub-Saharan Africa. Studies not prospectively observing seroconversion or recruiting only key populations were excluded. Record screening, data extraction and critical appraisal were conducted in duplicate. We used random-effects meta-analysis to summarize hazard ratios and the area under the receiver-operating characteristic curve (AUC-ROC). RESULTS: From 1563 initial search records, we identified 14 risk scores in 13 studies. Seven studies were among sexually active women using contraceptives enrolled in randomized-controlled trials, three among adolescent girls and young women (AGYW) and three among cohorts enrolling both men and women. Consistently identified HIV prognostic factors among women were younger age (pooled adjusted hazard ratio: 1.62 [95% confidence interval: 1.17, 2.23], compared to above 25), single/not cohabiting with primary partners (2.33 [1.73, 3.13]) and having sexually transmitted infections (STIs) at baseline (HSV-2: 1.67 [1.34, 2.09]; curable STIs: 1.45 [1.17; 1.79]). Among AGYW, only STIs were consistently associated with higher incidence, but studies were limited (n = 3). Community-level HIV prevalence or unsuppressed viral load strongly predicted incidence but was only considered in 3 of 11 multi-site studies. The AUC-ROC ranged from 0.56 to 0.79 on the model development sets. Only the VOICE score was externally validated by multiple studies, with pooled AUC-ROC 0.626 [0.588, 0.663] (I2 : 64.02%). CONCLUSIONS: Younger age, non-cohabiting and recent STIs were consistently identified as predicting future HIV infection. Both community HIV burden and individual factors should be considered to quantify HIV risk. However, HIV risk scores had only low-to-moderate discriminatory ability and uncertain generalizability, limiting their programmatic utility. Further evidence on the relative value of specific risk factors, studies populations not restricted to "at-risk" individuals and data outside South Africa will improve the evidence base for risk differentiation in HIV prevention programmes. PROSPERO NUMBER: CRD42021236367.

Naomi: a new modelling tool for estimating HIV epidemic indicators at the district level in sub-Saharan Africa.

INTRODUCTION: HIV planning requires granular estimates for the number of people living with HIV (PLHIV), antiretroviral treatment (ART) coverage and unmet need, and new HIV infections by district, or equivalent subnational administrative level. We developed a Bayesian small-area estimation model, called Naomi, to estimate these quantities stratified by subnational administrative units, sex, and five-year age groups. METHODS: Small-area regressions for HIV prevalence, ART coverage and HIV incidence were jointly calibrated using subnational household survey data on all three indicators, routine antenatal service delivery data on HIV prevalence and ART coverage among pregnant women, and service delivery data on the number of PLHIV receiving ART. Incidence was modelled by district-level HIV prevalence and ART coverage. Model outputs of counts and rates for each indicator were aggregated to multiple geographic and demographic stratifications of interest. The model was estimated in an empirical Bayes framework, furnishing probabilistic uncertainty ranges for all output indicators. Example results were presented using data from Malawi during 2016-2018. RESULTS: Adult HIV prevalence in September 2018 ranged from 3.2% to 17.1% across Malawi's districts and was higher in southern districts and in metropolitan areas. ART coverage was more homogenous, ranging from 75% to 82%. The largest number of PLHIV was among ages 35 to 39 for both women and men, while the most untreated PLHIV were among ages 25 to 29 for women and 30 to 34 for men. Relative uncertainty was larger for the untreated PLHIV than the number on ART or total PLHIV. Among clients receiving ART at facilities in Lilongwe city, an estimated 71% (95% CI, 61% to 79%) resided in Lilongwe city, 20% (14% to 27%) in Lilongwe district outside the metropolis, and 9% (6% to 12%) in neighbouring Dowa district. Thirty-eight percent (26% to 50%) of Lilongwe rural residents and 39% (27% to 50%) of Dowa residents received treatment at facilities in Lilongwe city. CONCLUSIONS: The Naomi model synthesizes multiple subnational data sources to furnish estimates of key indicators for HIV programme planning, resource allocation, and target setting. Further model development to meet evolving HIV policy priorities and programme need should be accompanied by continued strengthening and understanding of routine health system data.

Tumor Necrosis Factor Inhibitor Monotherapy Versus Combination Therapy for the Treatment of Psoriatic Arthritis: Combined Analysis of European Biologics Databases.

OBJECTIVE: To investigate whether tumor necrosis factor inhibitor (TNFi) combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARD) is more effective for psoriatic arthritis (PsA) and/or improves TNFi drug survival compared to TNFi monotherapy. METHODS: Five PsA biologics cohorts were investigated between 2000 and 2015: the ATTRA registry (Czech Republic); the Swiss Clinical Quality Management PsA registry; the Hellenic Registry of Biologics Therapies (Greece); the University of Bari PsA biologics database (Italy); and the Bath PsA cohort (UK). Drug persistence was analyzed using Kaplan-Meier and equality of survival using log-rank tests. Comparative effectiveness was investigated using logistic regression with propensity scores. Separate analyses were performed on (1) the combined Italian/Swiss cohorts for change in rate of Disease Activity Score in 28 joints (DAS28); and (2) the combined Italian, Swiss, and Bath cohorts for change in rate of Health Assessment Questionnaire (HAQ). RESULTS: In total, 2294 patients were eligible for the drug survival analysis. In the Swiss (P = 0.002), Greek (P = 0.021), and Bath (P = 0.014) databases, patients starting TNFi in combination with methotrexate had longer drug survival compared to monotherapy, while in Italy the monotherapy group persisted longer (P = 0.030). In eligible patients from the combined Italian/Swiss dataset (n = 1056), there was no significant difference between treatment arms in rate of change of DAS28. Similarly, when also including the Bath cohort (n = 1205), there was no significant difference in rate of change of HAQ. CONCLUSION: Combination therapy of a TNFi with a csDMARD does not appear to affect improvement of disease activity or HAQ versus TNFi monotherapy, but it may improve TNFi drug survival.

Towards an assessment of the health impact of industrially contaminated sites: waste landfills in Europe.

OBJECTIVES: this paper is based upon work from COST Action ICSHNet. To develop and apply recently proposed methods for assessing the health impact of pollution from contaminated sites and apply them to the case of landfills using available large European datasets. METHODS: standard methods for health impact assessment and burden of disease were applied using the available evidence on the health effects of living near a landfill. Geo-referenced data on landfills from the European Pollutant and Transfer Register (E-PRTR) were combined with population density data (European Environment Agency dataset) and disease frequency data from European health for all database (HfA); uncertainty was assessed via simulation methods. Countries covered by the European Environment Agency's E-PRTR registry on contaminated sites were considered (European Union Member States plus four additional European Countries) for the period 2007-2014. Four outcomes, for which suggestive evidence is available, were included: - low birth weight; - congenital anomalies; - respiratory disease; - annoyance from odour. Firstly, they were analysed separately, in terms of excess number of cases, and then combined into disability-adjusted life years (DALYs). RESULTS: 1,544 landfill sites were considered. 29.3 million people (6% of the total population) live within 4 km from one or more of these sites. The number of yearly attributable cases associated with low birth weight, congenital anomalies, respiratory diseases, and annoyance from odour were estimated, respectively, at 1,239, 70, 33,039, and 1,582,624. Associated DALYs were 10,192, 958, 2,688, and 47,505, respectively; 61,325 in total. CONCLUSIONS: estimates indicate a sizable health impact, largest for annoyance from odour, given the high frequency of the outcome and in spite of its lesser severity compared to the other ones. Application of the methodology is relatively straightforward, once the main assumption of causality is made. The present work offers a first approximation of the impact on health of waste landfills in Europe and can be further applied to other contaminated sites.

Data Integration for the Assessment of Population Exposure to Ambient Air Pollution for Global Burden of Disease Assessment.

Air pollution is a leading global disease risk factor. Tracking progress (e.g., for Sustainable Development Goals) requires accurate, spatially resolved, routinely updated exposure estimates. A Bayesian hierarchical model was developed to estimate annual average fine particle (PM2.5) concentrations at 0.1° × 0.1° spatial resolution globally for 2010-2016. The model incorporated spatially varying relationships between 6003 ground measurements from 117 countries, satellite-based estimates, and other predictors. Model coefficients indicated larger contributions from satellite-based estimates in countries with low monitor density. Within and out-of-sample cross-validation indicated improved predictions of ground measurements compared to previous (Global Burden of Disease 2013) estimates (increased within-sample R2 from 0.64 to 0.91, reduced out-of-sample, global population-weighted root mean squared error from 23 µg/m3 to 12 µg/m3). In 2016, 95% of the world's population lived in areas where ambient PM2.5 levels exceeded the World Health Organization 10 µg/m3 (annual average) guideline; 58% resided in areas above the 35 µg/m3 Interim Target-1. Global population-weighted PM2.5 concentrations were 18% higher in 2016 (51.1 µg/m3) than in 2010 (43.2 µg/m3), reflecting in particular increases in populous South Asian countries and from Saharan dust transported to West Africa. Concentrations in China were high (2016 population-weighted mean: 56.4 µg/m3) but stable during this period.

Effect of anti-TNF and conventional synthetic disease-modifying anti-rheumatic drug treatment on work disability and clinical outcome in a multicentre observational cohort study of psoriatic arthritis.

Objectives: To determine the effect of medical treatment on work disability in patients with active PsA in a real-world setting. Methods: Four hundred patients with active PsA commencing or switching to anti-TNF or conventional synthetic DMARD (csDMARD) were recruited to a multicentre UK prospective observational cohort study. Work disability was measured using the work productivity and activity-specific health problem instrument and peripheral joint activity was measured with the disease activity in PsA composite measure. Results: Four hundred patients were recruited, of whom 229 (57.25%) were working (of any age). Sixty-two patients of working age (24%) were unemployed. At 6 months there was a 10% improvement in presenteeism ( P = 0.007) and a 15% improvement in work productivity ( P = 0.001) among working patients commenced on csDMARDs ( n = 164) vs a larger and more rapid 30% improvement in presenteeism ( P < 0.001) and 40% improvement in work productivity ( P < 0.001) among those commenced on anti-TNF therapy ( n = 65). Clinical response was poor among patients commenced on a csDMARD ( n = 272), with an 8.4 point improvement in disease activity in PsA ( P < 0.001) vs those commenced on anti-TNF therapy ( n = 121), who had a 36.8 point improvement ( P < 0.001). Conclusion: We report significant and clinically meaningful improvements in both work disability and clinical outcomes after commencement of anti-TNF therapy in a real-world setting. Improvements in all outcomes among those commencing csDMARDs were slower and of a smaller magnitude.

B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity.

Spontaneous loss-of-function mutations in the protein-tyrosine phosphatase Shp1 cause the motheaten phenotype, characterized by widespread inflammation and autoimmunity. Because Shp1 is expressed in all hematopoietic cells, it has been unclear which aspects of the motheaten phenotypes are primary effects of Shp1 deficiency. We generated mice (Ptpn6(f/f);CD19-cre) that delete Shp1 specifically in B cells. Analysis of these mice indicates that the increase in B-1a cells in motheaten mice is a cell-autonomous consequence of Shp1 deficiency. Shp1-deficient B-1a cells could be derived from adult bone marrow and had N-nucleotide additions, consistent with an adult origin. Shp1 deficiency altered calcium response evoked by B cell antigen receptors and impaired CD40-evoked proliferation. Young Ptpn6(f/f);CD19-cre mice exhibited elevated serum immunoglobulins and impaired antibody responses to immunization, whereas older Ptpn6(f/f);CD19-cre mice developed systemic autoimmunity, characterized by DNA antibodies and immune complex glomerulonephritis. Thus, Shp1 deficiency in B cells alone perturbs B cell development and causes autoimmune disease.

Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor.

PAG/Cbp (hereafter named PAG) is a transmembrane adaptor molecule found in lipid rafts. In resting human T cells, PAG is tyrosine phosphorylated and associated with Csk, an inhibitor of Src-related protein tyrosine kinases. These modifications are rapidly lost in response to T-cell receptor (TCR) stimulation. Overexpression of PAG was reported to inhibit TCR-mediated responses in Jurkat T cells. Herein, we have examined the physiological relevance and the mechanism of PAG-mediated inhibition in T cells. Our studies showed that PAG tyrosine phosphorylation and association with Csk are suppressed in response to activation of normal mouse T cells. By expressing wild-type and phosphorylation-defective (dominant-negative) PAG polypeptides in these cells, we found that the inhibitory effect of PAG is dependent on its capacity to be tyrosine phosphorylated and to associate with Csk. PAG-mediated inhibition was accompanied by a repression of proximal TCR signaling and was rescued by expression of a constitutively activated Src-related kinase, implying that it is due to an inactivation of Src kinases by PAG-associated Csk. We also attempted to identify the protein tyrosine phosphatases (PTPs) responsible for dephosphorylating PAG in T cells. Through cell fractionation studies and analyses of genetically modified mice, we established that PTPs such as PEP and SHP-1 are unlikely to be involved in the dephosphorylation of PAG in T cells. However, the transmembrane PTP CD45 seems to play an important role in this process. Taken together, these data provide firm evidence that PAG is a bona fide negative regulator of T-cell activation as a result of its capacity to recruit Csk. They also suggest that the inhibitory function of PAG in T cells is suppressed by CD45. Lastly, they support the idea that dephosphorylation of proteins on tyrosine residues is critical for the initiation of T-cell activation.

Targeting of CD45 protein tyrosine phosphatase activity to lipid microdomains on the T cell surface inhibits TCR signaling.

CD45, a transmembrane protein tyrosine phosphatase (PTP), can either positively or negatively regulate Src-family protein tyrosine kinase (PTK) activity in vivo. It is proposed that TCR-initiated signaling requires the segregation of PTP activities from the engaged TCR, based upon the differential membrane compartmentalization on the T cell surface. To test the importance of CD45 exclusion from lipid microdomains for proper TCR signaling, a chimeric molecule was generated by fusing the CD45 cytoplasmic region, which contains the PTP domains, to the amino-terminal 12 amino acids of Lck, which target Lck to lipid microdomains. Using 3A9 T lymphocyte hybridoma (3A9H) cells whose TCR recognizes hen egg-white lysozyme (HEL), Lck-CD45 expression resulted in its targeting to lipid microdomains. The 3A9H cells expressing Lck-CD45 were reduced in their responses to HEL or co-cross-linking of CD3 and CD4, as assessed by IL-2 production and Ca(2+) mobilization. Src-family PTK activity associated with lipid microdomains was also decreased. These results suggest that the segregation of CD45 from proximal TCR signaling components is necessary for TCR signaling and that the targeting of CD45 PTP activity to lipid microdomains on the T cell surface results in decreased sensitivity of TCR-mediated signaling.