Quality and turnaround times of viral load monitoring under prevention of mother-to-child transmission of HIV Option B+ in six South African districts with a high antenatal HIV burden

Background. Barriers to monitoring maternal HIV viral load (VL) and achieving 90% viral suppression during pregnancy and breastfeeding still need to be understood in South Africa (SA).Objectives. To measure quality of VL care and turnaround times (TATs) for returning VL results to women enrolled in the prevention of mother-to-child transmission of HIV (PMTCT) programme in primary healthcare facilities.Methods. Data were obtained from a 2018 cross-sectional evaluation of the PMTCT Option B+ programme in six SA districts with high antenatal and infant HIV prevalence. Quality of VL care was measured as the proportion of clients reporting that results were explained to them. TATs for VL results were calculated using dates abstracted from four to five randomly selected facility-based client records to report overall facility ‘short TAT’ (≥80% of records with TAT ≤7 days). Logistical regression and logit-based risk difference statistics were used.Results. Achieving overall short TAT was uncommon. Only 50% of facilities in one rural district, zero in one urban metro district and 9 - 38% in other districts had short TAT. The significant difference between districts was influenced by the duration of keeping results in facilities after receipt from the laboratory. Expected quality of VL care received ranged between 66% and 85%. Client-related factors significantly associated with low quality of care, observed in two urban districts and one rural district, included lower education, recent initiation of antiretroviral treatment and experiencing barriers to clinic visits. Experiencing clinic visit barriers was also negatively associated with short TATs.Conclusions. We demonstrate above-average quality of care and delayed return of results to PMTCT clients. Context-specific interventions are needed to shorten TATs

Improving Data Sharing in Research with Contect-free Encoded Missing Data

Lack of attention to missing data in research may result in biased results, loss of power and reduced generalizability. Registering reasons for missing values at the time of data collection, or — in the case of sharing existing data — before making data available to other teams, can save time and efforts, improve scientific value and help to prevent erroneous assumptions and biased results. To ensure that encoding of missing data is sufficient to understand the reason why data are missing, it should ideally be context-free. Therefore, 11 context-free codes of missing data were carefully designed based on three completed randomized controlled clinical trials and tested in a new randomized controlled clinical trial by an international team consisting of clinical researchers and epidemiologists with extended experience in designing and conducting trials and an Information System expert. These codes can be divided into missing due to participant and/or participation characteristics (n=6), missing by design (n=4), and due a procedural error (n=1). Broad implementation of context-free missing data encoding may enhance the possibilities of data sharing and pooling, thus allowing more powerful analyses using existing data. Keywords: missing data; data pooling; data sharing; context free encodingHATICE (www.hatice.eu) is a collaborative project co-funded by the European Union’s Seventh Framework Program (FP7, 2007-2013), under grant agreement No 305374. The research leading to these results has also been funded by the “Multimodal preventive trials for Alzheimer´s Disease: towards multinational strategies-programme: MIND-AD”, Academy of Finland (291803) and VTR, Kuopio University Hospital (5772815)

Quality and turnaround times of viral load monitoring under prevention of mother-to-child transmission of HIV Option B+ in six South African districts with a high antenatal HIV burden

BACKGROUND : Barriers to monitoring maternal HIV viral load (VL) and achieving 90% viral suppression during pregnancy and breastfeeding still need to be understood in South Africa (SA). OBJECTIVES : To measure quality of VL care and turnaround times (TATs) for returning VL results to women enrolled in the prevention of mother-to-child transmission of HIV (PMTCT) programme in primary healthcare facilities. METHODS : Data were obtained from a 2018 cross-sectional evaluation of the PMTCT Option B+ programme in six SA districts with high antenatal and infant HIV prevalence. Quality of VL care was measured as the proportion of clients reporting that results were explained to them. TATs for VL results were calculated using dates abstracted from four to five randomly selected facility-based client records to report overall facility ‘short TAT’ (≥80% of records with TAT ≤7 days). Logistical regression and logit-based risk difference statistics were used. RESULTS : Achieving overall short TAT was uncommon. Only 50% of facilities in one rural district, zero in one urban metro district and 9 - 38% in other districts had short TAT. The significant difference between districts was influenced by the duration of keeping results in facilities after receipt from the laboratory. Expected quality of VL care received ranged between 66% and 85%. Client-related factors significantly associated with low quality of care, observed in two urban districts and one rural district, included lower education, recent initiation of antiretroviral treatment and experiencing barriers to clinic visits. Experiencing clinic visit barriers was also negatively associated with short TATs. CONCLUSIONS : We demonstrate above-average quality of care and delayed return of results to PMTCT clients. Context-specific interventions are needed to shorten TATs.The President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC). The publication of this manuscript was funded by the South African Medical Research Council.http://www.samj.org.zadm2022Paediatrics and Child Healt

Scaling Up Mental Health Services in Zambia: Challenges and Opportunities Reported in an Education Project.

yesThe need to increase the capacity of developing countries to meet the mental health needs of their populations is widely acknowledged. This article examines some of the challenges associated with a British Council DelPHE project aimed at strengthening the capacity of mental health educators to prepare the mental health workforce in Zambia for a shift from an institutional to a community-based model of care. The analysis draws on data from two focus groups in which the participants were drawn from college educators who had taken part in workshops intended to enhance curriculum alignment to ensure that the education and training provided for clinical officers (psychiatry) and mental health nurses was "fit for purpose." In particular, the article highlights their perspectives on some of the tensions in focusing on mental health as opposed to broader health care and in ensuring appropriate opportunities for practice or field placements. The continuing impact of stigma and limited resources available for mental ill-health is acknowledged within the wider context of inequities in mental health care. Findings of this evaluation may be applicable to other sub-Saharan contexts, but should be understood only within the Zambian context

Uptake of antenatal care in high HIV-prevalence settings: Results from three population-based surveys in South Africa.

BACKGROUND: Despite substantial progress in reducing pregnancy-related preventable morbidity and mortality, these remain unacceptably high in developing countries. In 2016, the World Health Organization (WHO) revised recommendations for antenatal care (ANC) from a 4-visit model to a minimum of 8 ANC contacts to reduce perinatal mortality further and improve women's experience of care. The guidelines also recommend that the first ANC visit (ANC-1) should occur during the first trimester. OBJECTIVES: To describe the uptake of routine ANC and its associated factors in South Africa (SA) prior to the 2016 WHO recommendations, when the country recommended 4 ANC visits, to bring to light potential challenges in achieving the current recommendations. METHODS: Secondary data analyses were performed from 3 facility-based, cross-sectional national surveys, conducted to measure 6-week mother-to-child transmission of HIV and coverage of related interventions in SA. These surveys recruited mother-infant pairs attending selected public primary healthcare facilities for their infants' 6-week immunisation in 2010, 2011 -2012 and 2012 -2013. Quantitative questionnaires were used to gather sociodemographic and antenatal-to-peripartum information from Road to Health cards and maternal recall. The inclusion criteria for this secondary assessment were at least 1 ANC visit, the primary outcome being uptake of ≥4 ANC visits. A multivariable logistic regression model was used to: (i) identify maternal factors associated with ANC visits; and (ii) establish whether receiving selected ANC activities was associated with frequency or timing of ANC-1. RESULTS: Of the 9 470, 9 646 and 8 763 women who attended at least 1 ANC visit, only 47.5% (95% confidence interval (CI) 45.4 -49.6), 55.6% (95% CI 53.2 -58.0) and 56.7% (95% CI 54.3 -59.1) adhered to ≥4 ANC visits, while 36.0% (95% CI 34.5 -37.5), 43.5% (95% CI 42.0 -45.1) and 50.8% (95% CI 49.3 -52.2) attended ANC-1 early (before 20 weeks' gestation) in 2010, 2011 -2012 and 2012 -2013, respectively. Multiparity and lower socioeconomic status were significantly associated with non-adherence to the 4-visit ANC recommendation, while a later survey year, higher education, being married, >19 years old, HIV-positive, planned pregnancy and knowing how HIV is transmitted vertically were strongly related to ≥4 ANC visits. The number of women who received selected ANC activities increased significantly with survey year and ≥4 ANC visits, but was not associated with timing of ANC-1. CONCLUSIONS: Despite increases in the uptake of ≥4 ANC visits and early ANC-1 rates between 2010 and 2013, these practices remain suboptimal. Adhering to ≥4 ANC visits improved coverage of selected ANC activities, implying that strengthening efforts to increase the uptake of ANC from at least 4 to 8, could improve overall outcomes

Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Background: Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods: We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope. Results: We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis. Conclusions: Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease.

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer’s disease

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer’s disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10−5 to 1.3 × 10−44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049–1.4 × 10−5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD

Evidence of HIV-1 adaptation to host HLA alleles following chimp-to-human transmission

<p>Abstract</p> <p>Background</p> <p>The cytotoxic T-lymphocyte immune response is important in controlling HIV-1 replication in infected humans. In this immune pathway, viral peptides within infected cells are presented to T-lymphocytes by the polymorphic human leukocyte antigens (HLA). HLA alleles exert selective pressure on the peptide regions and immune escape mutations that occur at some of the targeted sites can enable the virus to adapt to the infected host. The pattern of ongoing immune escape and reversion associated with several human HLA alleles has been studied extensively. Such mutations revert upon transmission to a host without the HLA allele because the escape mutation incurs a fitness cost. However, to-date there has been little attempt to study permanent loss of CTL epitopes due to escape mutations without an effect on fitness.</p> <p>Results</p> <p>Here, we set out to determine the extent of adaptation of HIV-1 to three well-characterized HLA alleles during the initial exposure of the virus to the human cytotoxic immune responses following transmission from chimpanzee. We generated a chimpanzee consensus sequence to approximate the virus sequence that was initially transmitted to the human host and used a method based on peptide binding affinity to HLA crystal structures to predict peptides that were potentially targeted by the HLA alleles on this sequence. Next, we used codon-based phylogenetic models to quantify the average selective pressure that acted on these regions during the period immediately following the zoonosis event, corresponding to the branch of the phylogenetic tree leading to the common ancestor of all of the HIV-1 sequences. Evidence for adaptive evolution during this period was observed at regions recognised by HLA A*6801 and A*0201, both of which are common in African populations. No evidence of adaptive evolution was observed at sites targeted by HLA-B*2705, which is a rare allele in African populations.</p> <p>Conclusion</p> <p>Our results suggest that the ancestral HIV-1 virus experienced a period of positive selective pressure due to immune responses associated with HLA alleles that were common in the infected human population. We propose that this resulted in permanent escape from immune responses targeting unconstrained regions of the virus.</p