Multiple GF-1 binding sites flank the erythroid specific transcription unit of the human carbonic anhydrase I gene

AbstractSix potential GF-1 sites which bind an erythroid factor are present in the 5' and 3' regions flanking the erythroid-speciflc transcription unit of the human carbonic anhydrase 1 (HCAI) gene. When two of these sites are placed upstream of a minimal eukaryotic promoter they confer upregulated expression in erythroid over non-erythroid cells. The presence of the erythroid factor in TPA-treated HEL cells in which the level of HCAI transcript has greatly decreased and in non-HCAI-expressing K562 cells suggests that in these cases the presence of the factor is not sufficient for HCAI expression

Community-facility linkage models and maternal and infant health outcomes in Malawi’s PMTCT/ART program: a cohort study

Background: In sub-Saharan Africa, 3 community-facility linkage (CFL) models—Expert Clients, Community Health Workers (CHWs), and Mentor Mothers—have been widely implemented to support pregnant and breastfeeding women (PBFW) living with HIV and their infants to access and sustain care for prevention of mother-to-child transmission of HIV (PMTCT), yet their comparative impact under real-world conditions is poorly understood. Methods and findings: We sought to estimate the effects of CFL models on a primary outcome of maternal loss to follow-up (LTFU), and secondary outcomes of maternal longitudinal viral suppression and infant “poor outcome” (encompassing documented HIV-positive test result, LTFU, or death), in Malawi’s PMTCT/ART program. We sampled 30 of 42 high-volume health facilities (“sites”) in 5 Malawi districts for study inclusion. At each site, we reviewed medical records for all newly HIV-diagnosed PBFW entering the PMTCT program between July 1, 2016 and June 30, 2017, and, for pregnancies resulting in live births, their HIV-exposed infants, yielding 2,589 potentially eligible mother–infant pairs. Of these, 2,049 (79.1%) had an available HIV treatment record and formed the study cohort. A randomly selected subset of 817 (40.0%) cohort members underwent a field survey, consisting of a questionnaire and HIV biomarker assessment. Survey responses and biomarker results were used to impute CFL model exposure, maternal viral load, and early infant diagnosis (EID) outcomes for those missing these measures to enrich data in the larger cohort. We applied sampling weights in all statistical analyses to account for the differing proportions of facilities sampled by district. Of the 2,049 mother–infant pairs analyzed, 62.2% enrolled in PMTCT at a primary health center, at which time 43.7% of PBFW were ≤24 years old, and 778 (38.0%) received the Expert Client model, 640 (31.2%) the CHW model, 345 (16.8%) the Mentor Mother model, 192 (9.4%) ≥2 models, and 94 (4.6%) no model. Maternal LTFU varied by model, with LTFU being more likely among Mentor Mother model recipients (adjusted hazard ratio [aHR]: 1.45; 95% confidence interval [CI]: 1.14, 1.84; p = 0.003) than Expert Client recipients. Over 2 years from HIV diagnosis, PBFW supported by CHWs spent 14.3% (95% CI: 2.6%, 26.1%; p = 0.02) more days in an optimal state of antiretroviral therapy (ART) retention with viral suppression than women supported by Expert Clients. Infants receiving the Mentor Mother model (aHR: 1.24, 95% CI: 1.01, 1.52; p = 0.04) and ≥2 models (aHR: 1.44, 95% CI: 1.20, 1.74; p < 0.001) were more likely to undergo EID testing by age 6 months than infants supported by Expert Clients. Infants receiving the CHW and Mentor Mother models were 1.15 (95% CI: 0.80, 1.67; p = 0.44) and 0.84 (95% CI: 0.50, 1.42; p = 0.51) times as likely, respectively, to experience a poor outcome by 1 year than those supported by Expert Clients, but not significantly so. Study limitations include possible residual confounding, which may lead to inaccurate conclusions about the impacts of CFL models, uncertain generalizability of findings to other settings, and missing infant medical record data that limited the precision of infant outcome measurement. Conclusions: In this descriptive study, we observed widespread reach of CFL models in Malawi, with favorable maternal outcomes in the CHW model and greater infant EID testing uptake in the Mentor Mother model. Our findings point to important differences in maternal and infant HIV outcomes by CFL model along the PMTCT continuum and suggest future opportunities to identify key features of CFL models driving these outcome differences

Improving PMTCT outcomes for mother-infant pairs through community-facility linkage: Results from a mixed methods study in Malawi

To improve MIP care retention in Malawi, several prevention of mother-to-child transmission of HIV (PMTCT) care delivery models have emerged to strengthen community-facility linkage (CFL), a concept defined as any “formalized connection between a health facility and the communities it serves to support improved health outcomes.” Similar to other settings in sub-Saharan Africa, three models have been widely implemented to complement Malawi’s National PMTCT Programme: 1) mentor mothers; 2) expert clients; and 3) community health workers. While the rationale underpinning these models has been substantiated by evidence generated from general antiretroviral therapy and PMTCT programs across SSA, a clear and rigorous description of each model, including characterization of supervisory structures, training, and relationships with clinical services, is currently unavailable. Equally important, the comparative impact of these models and their components on MIP care retention and other health outcomes have not been well characterized, particularly in the era of test and start. In the USAID-funded Project SOAR “Maternal-Infant Retention Study” reported here, we have attempted to address these existing evidence gaps by rigorously characterizing these community-facility linkage models and comparing their impact against each other and the “traditional” standard of care according to routinely collected health outcomes for mother-infant pairs (MIPs), including maternal retention in care and viral suppression, and infant HIV-free survival. To this end, specific objectives of this study were to: (1) establish a clear typology for CFL models by describing the main components of, and patient and key stakeholder perspectives on, three such models in Malawi; (2) describe MIP health outcomes in each model, and compare outcomes across models; and (2a) examine associations between individual components of CFL models and MIP health outcomes, controlling for confounding

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. </p

Are venue-based strategies the ticket to the last mile in HIV prevention in Malawi

Background: In 2016, Blantyre District had the highest adult HIV prevalence in Malawi (17% overall; 22% in women) and the lowest viral suppression rate (60%). In response, the MOH expanded prevention and treatment strategies. We hypothesized that social venues patronized by people with high sexual partnerships rates could identify sub-groups currently missed. Methods: We conducted cross-sectional bio-behavioral surveys of representative samples of individuals seeking care in government clinics (n=2313) and social venue patrons (n=1802) Jan-Mar 2022. Clinics were randomly selected from government clinics providing HIV testing. Venues were randomly sampled from urban and rural strata with oversampling of rural venues. Sampling weights were based on 2-stage sampling probabilities. We followed national testing protocols for rapid tests, recency testing and viral load measurements. Acute infections were identified by pooling dried blood spots from persons with an HIV- rapid test. Results: Compared to the clinic population, the venue population was more likely to: be male (68% vs 28%); aged >25 years (61% vs 51%); unmarried (62% vs 40%); drink alcohol daily (43% vs 8%); have more sexual partners in the last year (mean 16 vs 2); report a new sex partner in the past 4 weeks (42% vs 14%); and report transactional sex (52% vs 12%). HIV prevalence (Table 1) was higher among the venue population (19% vs 9%); the proportion HIV+ suppressed was similar (78%). Among women recruited at venues, prevalence increased by age: 0% among age 15-17 to 41% among age 18-21. At venues, factors associated with HIV infection include female sex (39% vs 10%); having a new partner in the past 4 weeks (28% vs 13%) and transactional sex (25% vs 13%). Acute and recent infections were uncommon. Clinic participants who reported visiting venues were less likely to have a suppressed viral load than other PLHIV clinic participants (53% vs 81%). Among both populations, reporting a genital sore in the past 4 weeks was associated with non-suppression (40% vs 20% in clinic; 48% vs 20% in venues). Conclusions: Lower HIV prevalence and greater viral suppression suggests that Blantyre’s HIV epidemic is slowing. Strategies to further reduce transmission should include outreach to venues with higher prevalence of unsuppressed infection and to young women at venues. Testing for acute or recent infection yielded few cases and thus did not provide sufficient value to warrant the cost

The value of indirect ties in citation networks:SNA analysis with OWA operator weights

This paper seeks to advance the theory and practice of the dynamics of complex networks in relation to direct and indirect citations. It applies social network analysis (SNA) and the ordered weighted averaging operator (OWA) to study a patent citations network. So far the SNA studies investigating long chains of patents citations have rarely been undertaken and the importance of a node in a network has been associated mostly with its number of direct ties. In this research OWA is used to analyse complex networks, assess the role of indirect ties, and provide guidance to reduce complexity for decision makers and analysts. An empirical example of a set of European patents published in 2000 in the renewable energy industry is provided to show the usefulness of the proposed approach for the preference ranking of patent citations

Fetal programming of neuropsychiatric disorders by maternal pregnancy depression: a systematic mini review

BACKGROUND: Maternal depression complicates a large proportion of pregnancies. Current evidence shows numerous harmful effects on the offspring. Reviews, which include depression, concluded that stress has harmful effects on the offspring's outcomes neuro-cognitive development, temperament traits, and mental disorders. OBJECTIVE: This mini review of recent studies, sought to narrow the scope of exposure and identify studies specifically assessing prenatal depression and offspring neuropsychiatric outcomes. STUDY ELIGIBILITY CRITERIA: The review included longitudinal, cohort, cross-sectional, clinical, quasi-experimental, epidemiological, or intervention study designs published in English from 2014 to 2018. PARTICIPANTS: Study populations included mother-child dyads, mother-father-child triads, mother-alternative caregiver-child triads, and family studies utilizing sibling comparisons. METHODS: We searched PubMED and Web of Science. Study inclusion and data extraction were based on standardized templates. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Thirteen studies examining neuropsychiatric outcomes were included. We judged the evidence to be moderate to high quality. CONCLUSIONS: Our review supports that maternal prenatal depression is associated with neuropsychiatric adversities in children.Peer reviewe