Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure–associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42’s role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9–mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Sero-Prevalence of HIV Infection Among Commercial Sex Workers in Ibadan, Nigeria

Context: Commercial sex workers (CSWs) are an important group for the transmission of human immunodeficiency virus (HIV) infection all over the world. In view of the upsurge in the prevalence of HIV in Nigeria, it is desirable to determine the magnitude of their contribution to the problem and how to incorporate them into control efforts. Objective: The main objective of this study was to determine the sero-prevalence of HIV infection among commercial sex workers (CSWs) in Ibadan, Nigeria. Study Design: This was a cross-sectional survey involving 169 CSWs that were randomly selected from 18 brothels in Ibadan and 136 other women without HIV-related symptoms who visited the Special Treatment Clinic, University College Hospital Ibadan who served as the control group. Results: Of the 169 CSWs investigated, 58 (34.3%) had HIV infection whilst only 3 (2.2%) of the control subjects were seropositive for HIV, a highly statistically significant difference (p < 0.000001). Vaginal candidiasis was the most common STD diagnosed in both CSWs and the control subjects. All the 13 CSWs that had scabies, 4 (36.4%) of those with genital warts and 19 (67.9%) of those with genital ulcers had HIV infection. Apart from HIV infection, the only condition that was markedly more prevalent among the CSWs was genital ulcer (16.6% vs 1.5%; p < 0.0001). Conclusion: These findings indicate a high seroprevalence of HIV among CSWs in Ibadan and the need to direct efforts to prevent them from spreading it further in the population. Key Words: HIV, Seroprevalence, Commercial Sex Workers. [Trop J Obstet Gynaecol, 2003, 20: 12-15

Preliminary Phytochemical Screening and Antibacterial Properties of Crude Stem Bark Extracts and Fractions of Parkia biglobosa (Jacq.)

A methanolic crude extract of Parkia biglobosa was prepared and later partitioned in succession with different solvents of increasing polarity ranging from n-hexane, chloroform and ethyl acetate to butanol. Phytochemical screening of the extract revealed the presence of alkaloids, tannins, saponins, flavonoids, steroids, glycoside and sugars. The inhibition zones exhibited by the extract against the tested bacteria ranged between 14 ± 0.00 mm (against Escherichia coli) and 28 ± 0.71 mm (against Pseudomonas aeruginosa). The MIC of the methanolic extract of P. biglobosa against isolates ranged between 0.63 mg/mL and 5 mg/mL, while the MIC values exhibited by the n-hexane and aqueous fractions ranged between 0.63 mg/mL and 10 mg/mL. Overall the extract and fractions of P. biglobosa used in this work were found to possess antimicrobial properties which compared favourably with those of streptomycin. These observations make this plant a potential source of bioactive compounds that can be used in management of bacterial infections. The use of this plant as herbal medicaments in African countries and the reports on the toxicity of the plant further show that the plant is non-toxic to humans

Tracking Lower Urinary Tract Symptoms and Tamsulosin Side Effects Among Older Men Using a Mobile App (PERSONAL): Feasibility and Usability Study.

BackgroundContinuous α1a-blockade is the first-line treatment for lower urinary tract symptoms (LUTS) among older men with suspected benign prostatic hyperplasia. Variable efficacy and safety for individual men necessitate a more personalized, data-driven approach to prescribing and deprescribing tamsulosin for LUTS in older men.ObjectiveWe aim to evaluate the feasibility and usability of the PERSONAL (Placebo-Controlled, Randomized, Patient-Selected Outcomes, N-of-1 Trials) mobile app for tracking daily LUTS severity and medication side effects among older men receiving chronic tamsulosin therapy.MethodsWe recruited patients from the University of California, San Francisco health care system to participate in a 2-week pilot study. The primary objectives were to assess recruitment feasibility, study completion rates, frequency of symptom tracking, duration of tracking sessions, and app usability rankings measured using a follow-up survey. As secondary outcomes, we evaluated whether daily symptom tracking led to changes in LUTS severity, perceptions of tamsulosin, overall quality of life, medication adherence between baseline and follow-up surveys, and perceived app utility.ResultsWe enrolled 19 men within 23 days, and 100% (19/19) of the participants completed the study. Each participant selected a unique combination of symptoms to track and recorded data in the PERSONAL app, with a median daily completion rate of 79% (11/14 days). The median duration of the app session was 44 (IQR 33) seconds. On a scale of 1 (strongly disagree) to 5 (strongly agree), the participants reported that the PERSONAL app was easy to use (mean 4.3, SD 1.0), that others could learn to use it quickly (mean 4.2, SD 0.9), and that they felt confident using the app (mean 4.4, SD 0.8). LUTS severity, quality of life, and medication adherence remained unchanged after the 2-week study period. Fewer men were satisfied with tamsulosin after using the app (14/19, 74% vs 17/19, 89% at baseline), although the perceived benefit from tamsulosin remained unchanged (18/19, 95% at baseline and at follow-up). In total, 58% (11/19) of the participants agreed that the PERSONAL app could help people like them manage their urinary symptoms.ConclusionsThis pilot study demonstrated the high feasibility and usability of the PERSONAL mobile app to track patient-selected urinary symptoms and medication side effects among older men taking tamsulosin to manage LUTS. We observed that daily symptom monitoring had no adverse effects on the secondary outcomes. This proof-of-concept study establishes a framework for future mobile app studies, such as digital n-of-1 trials, to collect comprehensive individual-level data for personalized LUTS management in older men

Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies

Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure–associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42’s role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9–mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies