Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).

Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment, and Findings from Low- and Middle-Income Countries: A Scoping Review.

INTRODUCTION: Pharmacovigilance (PV), or the ongoing safety monitoring after a medication has been licensed, plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. It is important to understand how pregnancy PV projects operate in low- and middle-income countries (LMICs), where there is a disproportionate lack of PV data yet a high burden of adverse pregnancy outcomes. We conducted a scoping review to assess how exposures and outcomes were measured in recently published pregnancy PV projects in LMICs. METHODS: We utilized a search string, secondary review, and team knowledge to review publications focusing on therapeutic or vaccine exposures among pregnant people in LMICs. We screened abstracts for relevance before conducting a full text review, and documented measurements of exposures and outcomes (categorized as maternal, birth, or neonatal/infant) among other factors, including study topic, setting, and design, comparator groups, and funding sources. RESULTS: We identified 31 PV publications spanning at least 24 LMICs, all focusing on therapeutics or vaccines for infectious diseases, including HIV (n = 17), tuberculosis (TB; n = 9), malaria (n = 7), pertussis, tetanus, and diphtheria (n = 1), and influenza (n = 3). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Among HIV-specific publications, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy and adverse outcomes. For TB-specific publications, the main exposures of interest were second-line drug-resistant TB and isoniazid-based prevention therapeutics for pregnant people living with HIV. For malaria-specific publications, the primary exposure-outcome relationship of interest was antimalarial medication exposure during pregnancy and adverse outcomes. Among vaccine-focused publications, the exposure was assessed during a specific time during pregnancy, with an overall interest in vaccine safety and/or efficacy. The study settings were frequently from Africa, designs varied from cohort or cross-sectional studies to clinical trials, and funding sources were largely from high-income countries. CONCLUSION: The published pregnancy PV projects were largely centered in Africa and concerned with infectious diseases. This may reflect the disease burden in LMICs but also funding priorities from high-income countries. As the prevalence of non-communicable diseases increases in LMICs, PV projects will have to broaden their scope. Birth and neonatal/infant outcomes were most reported, with fewer reporting on maternal outcomes and none on longer-term child outcomes; additionally, heterogeneity existed in definitions and ascertainment of specific measures. Notably, almost all projects covered a single therapeutic exposure, missing an opportunity to leverage their projects to cover additional exposures, add scientific rigor, create uniformity across health services, and bolster existing health systems. For many publications, the timing of exposure, specifically by trimester, was crucial to maternal and neonatal safety. While currently published pregnancy PV literature offer insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements, integrate PV projects across health services, and establish longer-term monitoring.

Understanding Women's Preferences for Prevention of Mother-to-Child HIV Transmission Services in Kenya.

Background and Objective: Understanding the preferences of women living with HIV (WLH) for the prevention of mother-to-child HIV transmission (PMTCT) services is important to ensure such services are person-centered. Methods: From April to December 2022, we surveyed pregnant and postpartum WLH enrolled at five health facilities in western Kenya to understand their preferences for PMTCT services. WLH were stratified based on the timing of HIV diagnosis: known HIV-positive (KHP; before antenatal clinic [ANC] enrollment), newly HIV-positive (NHP; on/after ANC enrollment). Multivariable logistic regression was used to determine associations between various service preferences and NHP (vs. KHP) status, controlling for age, facility, gravidity, retention status, and pregnancy status. Results: Among 250 participants (median age 31 years, 31% NHP, 69% KHP), 93% preferred integrated versus non-integrated HIV and maternal-child health (MCH) services; 37% preferred male partners attend at least one ANC appointment (vs. no attendance/no preference); 54% preferred support groups (vs. no groups; 96% preferred facility - over community-based groups); and, preferences for groups was lower among NHP (42%) versus KHP (60%). NHP had lower odds of preferring support groups versus KHP (aOR 0.45, 95% CI 0.25-0.82), but not the other services. Conclusion and Global Health Implications: Integrated services were highly preferred by WLH, supporting the current PMTCT service model in Kenya. Further research is needed to explore the implementation of facility-based support groups for WLH as well as the reasons underlying women's preferences.

Hydrochemical Characterization, Geothermometry, and Origin of Ain Al-Harrah Hot Spring and Its Relationship to Al-Lith Geothermal System, Saudi Arabia.

The Al-Lith geothermal field in western Saudi Arabia is a characteristic medium-high enthalpy geothermal system, exhibiting features associated with tectonic activities linked to the Red Sea rifting. Ain Al-Harrah hot spring is located in the Al-Lith field, with discharge temperatures varying from 56 to 81 °C. The determination of water temperature and composition in a geothermal reservoir is critical to the design of utilization strategies, surface production facilities, and choice of materials. This research presents a comprehensive hydrochemical characterization of the Ain Al-Harrah hot spring and its relationship with the underlying geothermal system. This study was conducted in two main phases; first, the fieldwork involved the collection of water samples from the hot spring, measuring the temperature, pH, and electrical conductivity (EC) of the water. The second phase involved laboratory analyses of the collected samples, including major and trace element analyses, isotopic analysis, and geothermometry. The dominant hydrogeochemical processes in the region were determined by analyzing the hydrochemistry of the water samples. Thermal waters analyzed exhibited high concentrations of Na+ (410-463 mg/L), HCO3 - (64.48-90 mg/L), and Cl- (472.76-581.95 mg/L), intermediate levels of K+ (50.2-93.0 mg/L), and low levels of Mg2+ (1.27-2.04 mg/L). The total dissolved solids (TDS) concentration ranges between 1830 and 2055 mg/L. The hot spring is categorized as Na-HCO3 type facies that are moderately alkaline, with pH values ranging between 7.9 and 8.2. Analysis of trace element concentrations revealed that the hydrochemical processes were primarily governed by the abundance and solubility of trace elements in the rocks surrounding the hot spring, the pH, and the temperature of the hot spring water. The stable isotope data for δD (-12.36 to 15.21%) and δ18O (-2.84 to -3.38%) provided evidence that the thermal spring is of meteoric origin. Based on Na-K-Ca, K2/Mg, and quartz geothermometers, the temperature range of the reservoir was determined to be between 150 and 205 °C. The temperature range suggests a medium-to-high enthalpy geothermal system.

Impact of Maternal Viral Suppression on Growth Patterns for HIV-Exposed Uninfected Infants in Kenya.

Background and Objective: Children born to mothers living with human immunodeficiency virus (HIV) are at risk for poor health outcomes but data characterizing these associations are limited. Our objective was to determine the impact of maternal viral suppression on growth patterns and malnutrition for infants who are HIV-exposed but uninfected (HEU). Methods: We conducted a retrospective cohort analysis of clinical data for infants who were HEU and their mothers (September 2015 - March 2019) in Kenya. Infants were stratified based on maternal viral suppression status (≥ or <1000 copies/mL); t-tests were used to compare groups. Growth indicators were evaluated with Chi-square, Fisher's exact, and area under the curve. Moderate-to-severe underweight status, stunting, and wasting were defined by weight-for-age (WFA), height-for-age (HFA), and weight-for-height (WFH), z-scores ≤2, and were used to define malnutrition. Multivariate logistic regression analyses were performed to evaluate potential associations with malnutrition indicators between WFH and HFA. Results: Among 674 infants who were HEU, 48.7% were male and 85.0% had mothers who were virally suppressed. The median age at first and last clinic visits was 1.5 and 16.4 months, respectively. WFA and HFA z-scores over time differed by sex, and WFA and HFA differed based on maternal viral suppression (P < 0.05). Male infants had higher adjusted odds for stunted status, and as children aged, they had slightly increased odds of becoming underweight or stunted. Maternal viral suppression and timing of maternal antiretroviral therapy initiation in relation to the prevention of vertical transmission (PVT) enrollment did not significantly affect malnutrition indicators. Conclusion and Global Health Implications: Maternal viral suppression status was not associated with increased odds of more severe malnutrition indicators in children who were HEU. However, overall growth patterns over time, measured by z-scores of growth indicators, did differ based on maternal viral suppression status, and to a lesser degree, by gender.

Evaluating Diatomaceous Earth for Long-Term Use in Hydrogen Storage.

Efficient hydrogen storage is essential for its use as a sustainable energy carrier. Diatomaceous earth, a high-surface-area siliceous geomaterial, shows potential as a physisorption material for hydrogen storage. This study analyzes diatomaceous earth's long-term characteristics when subjected to high-pressure hydrogen injection. The diatomaceous earth was subjected to a hydrogen pressure of 1200 psi for a period of 80 days at room temperature. Neither notable morphological or mineralogical changes were observed. Nevertheless, there was a slight reduction in fine particles and a slight increase in larger particles. The Brunauer-Emmett-Teller (BET) surface area decreased slightly with a significant decrease in pore width. However, the hydrogen adsorption at 77 K temperature was increased significantly (45.5%) after the hydrogen storage test. Moreover, there was a delayed release of molecular water as the temperature increased. These changes suggest that a condensation reaction has occurred involving some of the opal-A silanol groups (Si-O-H), producing molecular water. Bonding through siloxane bridges (Si-O-Si) results in a significant decrease in pore width and increased hydrophobicity (i.e., the interaction between diatomaceous surface and H2 was increased), thereby enhancing hydrogen adsorption capacity. These findings indicate that diatomaceous earth holds promise as a material for hydrogen storage, with the potential for its hydrogen adsorption capacity to improve over time.

Suitability of treated wastewater for irrigation and its impact on groundwater resources in arid coastal regions: Insights for water resources sustainability.

Water scarcity threatens agriculture and food security in arid regions like Saudi Arabia. The nation produces significant quantities of municipal wastewater, which, with adequate treatment, could serve as an alternative water source for irrigation, thereby reducing reliance on fossil and non-renewable groundwater. This study assessed the appropriateness of using treated wastewater (TWW) for irrigation in a dry coastal agricultural region in Eastern Saudi Arabia and its impact on groundwater resources. Field investigations were conducted in Qatif to collect water samples and field measurements. A multi-criteria approach was applied to evaluate the TWW's suitability for irrigation, including complying with Saudi Standards, the Irrigation Water Quality Index (IWQI), the National Sanitation Foundation water quality index (NSFWQI), and the individual irrigation indices. In addition, the impact of TWW on groundwater was assessed through hydrogeological and isotope approaches. The results indicate that the use of TWW in the study area complied with the Saudi reuse guidelines except for nitrate, aluminum, and molybdenum. However, irrigation water quality indices classify TWW as having limitations that necessitate the use for salt-tolerant crops on permeable and well-drained soils. Stable isotopic analysis (δ2H, δ18O) revealed that long-term irrigation with TWW affected the shallow aquifer, while deep aquifers were minimally impacted due to the presence of aquitard layer. The application of TWW irrigation has successfully maintained groundwater sustainability in the study area, as evidenced by increased groundwater levels up to 2.3 m. Although TWW contributes to crop productivity, long term agricultural sustainability could be enhanced by improving effluent quality, regulating irrigation practices, implementing buffer zones, and monitoring shallow groundwater. An integrated approach that combines advanced wastewater treatment methods, community involvement, regulatory oversight, and targeted monitoring is recommended to be implemented.

Preswitch Regimens Influence the Rate of Weight Gain After Switch to Tenofovir Disoproxil Fumarate, Lamivudine, and Dolutegravir (TLD): Study From an East African Cohort.

Background: Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to dolutegravir (DTG) has been associated with greater weight gain. Methods: We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate. Results: A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens. Conclusions: Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch.

Preferences of Pregnant and Postpartum Women for Differentiated Service Delivery in Kenya.

BACKGROUND: Differentiated service delivery models are implemented by HIV care programs globally, but models for pregnant and postpartum women living with HIV (PPWH) are lacking. We conducted a discrete choice experiment to determine women's preferences for differentiated service delivery. SETTING: Five public health facilities in western Kenya. METHODS: PPWH were enrolled from April to December 2022 and asked to choose between pairs of hypothetical clinics that differed across 5 attributes: clinic visit frequency during pregnancy (monthly vs. every 2 months), postpartum visit frequency (monthly vs. only with routine infant immunizations), seeing a mentor mother (each visit vs. as needed), seeing a clinician (each visit vs. as needed), and basic consultation cost (0, 50, or 100 Kenya Shillings [KSh]). We used multinomial logit modeling to determine the relative effects (ß) of each attribute on clinic choice. RESULTS: Among 250 PPWH (median age 31 years, 42% pregnant, 58% postpartum, 20% with a gap in care), preferences were for pregnancy visits every 2 months (ß = 0.15), postpartum visits with infant immunizations (ß = 0.36), seeing a mentor mother and clinician each visit (ß = 0.05 and 0.08, respectively), and 0 KSh cost (ß = 0.39). Preferences were similar when stratified by age, pregnancy, and retention status. At the same cost, predicted market choice for a clinic model with fewer pregnant/postpartum visits was 75% versus 25% for the standard of care (ie, monthly visits during pregnancy/postpartum). CONCLUSION: PPWH prefer fewer clinic visits than currently provided within the standard of care in Kenya, supporting the need for implementation of differentiated service delivery for this population.

The Relationship between Pain Catastrophizing and Cognitive Function in Chronic Musculoskeletal Pain: A Scoping Review.

Objective: Chronic musculoskeletal pain (CMP) poses a considerable threat to physical, mental, and financial health worldwide. Beyond physical difficulties, CMP has a pronounced impact on pain behaviors and cognitive function. The purpose of this scoping review was to examine the relationship between pain catastrophizing (PC) and cognitive function in CMP, identify gaps in the literature, and provide future directions for research on the topic. Methods: Search strings were entered in the following databases: PubMed, CINAHL, Nursing and Allied Health, Ovid Emcare, PsycInfo, and Scopus. Data from the included articles were extracted thematically based on diagnostic classification and included author(s), year of publication, country, aim, sample, methods, intervention (if applicable), and key findings. Results: 30 articles were included after screening. The studied populations included patients with fibromyalgia, chronic low back pain, and CMP. Two studies were designed to assess the relationship between PC and cognition as the primary aim. The included studies demonstrated variable evidence regarding the relationship between PC and cognition. Only four studies included clinically relevant PC populations (i.e., Pain Catastrophizing Scale score >30), and all found significant correlations. Conclusion: Although evidence exists for the relationship between cognitive function and PC, there is a lack of rigorous research to indicate the strength of this relationship and the specific cognitive functions affected. The literature lacks appropriate populations needed to investigate clinically relevant PC and is limited by heterogeneous neuropsychological test batteries. Future research should include populations demonstrating the behaviors being studied, intentional analysis of outcomes, and appropriate cognitive tests.

Integration of HIV care into maternal and child health services in the global IeDEA consortium.

The WHO recommends the integration of routine HIV services within maternal and child health (MCH) services to reduce the fragmentation of and to promote retention in care for pregnant and postpartum women living with HIV (WWH) and their infants and children exposed to HIV (ICEH). During 2020-2021, we surveyed 202 HIV treatment sites across 40 low- and middle-income countries within the global International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. We determined the proportion of sites providing HIV services integrated within MCH clinics, defined as full [HIV care and antiretroviral treatment (ART) initiation in MCH clinic], partial (HIV care or ART initiation in MCH clinic), or no integration. Among sites serving pregnant WWH, 54% were fully and 21% partially integrated, with the highest proportions of fully integrated sites in Southern Africa (80%) and East Africa (76%) compared to 14%-40% in other regions (i.e., Asia-Pacific; the Caribbean, Central and South America Network for HIV Epidemiology; Central Africa; West Africa). Among sites serving postpartum WWH, 51% were fully and 10% partially integrated, with a similar regional integration pattern to sites serving pregnant WWH. Among sites serving ICEH, 56% were fully and 9% were partially integrated, with the highest proportions of fully integrated sites in East Africa (76%), West Africa (58%) and Southern Africa (54%) compared to ≤33% in the other regions. Integration was heterogenous across IeDEA regions and most prevalent in East and Southern Africa. More research is needed to understand this heterogeneity and the impacts of integration on MCH outcomes globally.

Effects of the COVID-19 pandemic on late postpartum women living with HIV in Kenya.

Although an estimated 1.4 million women living with HIV (WHIV) are pregnant each year globally, data describing the effects of the COVID-19 pandemic on postpartum women in low- and middle-income countries (LMICs) are limited. To address this gap, we conducted phone surveys among 170 WHIV ≥18 years and 18-24 months postpartum enrolled in HIV care at the Academic Model Providing Access to Healthcare in western Kenya, and assessed the effects of the pandemic across health, social and economic domains. We found that 47% of WHIV experienced income loss and 71% experienced food insecurity during the pandemic. The majority (96%) of women reported having adequate access to antiretroviral treatment and only 3% reported difficulties refilling medications, suggesting that the program's strategies to maintain HIV service delivery during the early phase of the pandemic were effective. However, 21% of WHIV screened positive for depression and 8% for anxiety disorder, indicating the need for interventions to address the mental health needs of this population. Given the scale and duration of the pandemic, HIV programs in LMICs should work with governments and non-governmental organizations to provide targeted support to WHIV at highest risk of food and income insecurity and their associated adverse health outcomes.

Design and implementation of a global site assessment survey among HIV clinics participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) research consortium.

INTRODUCTION: Timely descriptions of HIV service characteristics and their evolution over time across diverse settings are important for monitoring the scale-up of evidence-based program strategies, understanding the implementation landscape, and examining service delivery factors that influence HIV care outcomes. METHODS: The International epidemiology Databases to Evaluate AIDS (IeDEA) consortium undertakes periodic cross-sectional surveys on service availability and care at participating HIV treatment sites to characterize trends and inform the scientific agenda for HIV care and implementation science communities. IeDEA's 2020 general site assessment survey was developed through a consultative, 18-month process that engaged diverse researchers in identifying content from previous surveys that should be retained for longitudinal analyses and in developing expanded and new content to address gaps in the literature. An iterative review process was undertaken to standardize the format of new survey questions and align them with best practices in survey design and measurement and lessons learned through prior IeDEA site assessment surveys. RESULTS: The survey questionnaire developed through this process included eight content domains covered in prior surveys (patient population, staffing and community linkages, HIV testing and diagnosis, new patient care, treatment monitoring and retention, routine HIV care and screening, pharmacy, record-keeping and patient tracing), along with expanded content related to antiretroviral therapy (differentiated service delivery and roll-out of dolutegravir-based regimens); mental health and substance use disorders; care for pregnant/postpartum women and HIV-exposed infants; tuberculosis preventive therapy; and pediatric/adolescent tuberculosis care; and new content related to Kaposi's sarcoma diagnostics, the impact of COVID-19 on service delivery, and structural barriers to HIV care. The survey was distributed to 238 HIV treatment sites in late 2020, with a 95% response rate. CONCLUSION: IeDEA's approach for site survey development has broad relevance for HIV research networks and other priority health conditions.

Screen technology exposure and infant cognitive development: A scoping review.

PROBLEM: There has been some concern that screen exposure is harmful to an infant's cognitive development, but the effects of screen technologies on cognition are not fully understood. A scoping review was conducted to determine what evidence exists about screen exposure and cognitive development in children ages birth to 24 months. ELIGIBILITY CRITERIA: Inclusion = 1) English language; 2) studies focusing on children under 24 months of age; 3) cognitive development; 4) screen exposure. Exclusion = 1) articles over 25 years old; 2) structure, function and physiology of the brain; 3) social development; 4) psychosocial development; 5) motor development; 6) abnormal development/mental health; 7) behavior; 8) content only, not screen exposure e.g., social media; 9) secondary sources. SAMPLE: Ten studies met the inclusion criteria. Articles included one retrospective chart review, six longitudinal studies, two cross-sectional studies, and one prospective study. RESULTS: Of the ten studies in this review, six reported correlations between screen exposure and cognitive delay, one study reported positive cognitive outcomes and three reported no significant positive or negative outcomes. CONCLUSIONS: From the evidence in this scoping review, no causal relationship has been found between screen exposure and infant cognitive harm. Some correlations between screen exposure and cognitive delay were reported. Some positive cognitive outcomes were also reported. IMPLICATIONS: Future research should focus on the context of screen viewing as opposed to dosage or exposure. More robust methodologies should be used to assess infant cognition and screen usage.

Pediatric Occupational Therapists and Occupational Stress: A Scoping Review.

The purpose of this scoping review was to provide further insight into the stress and the stressors experienced by pediatric occupational therapists in the work environment. Using the Arksey and O'Malley framework, the search was conducted in eight databases, nine electronic journals, and eight gray literature sources to identify articles related to stress and stressors of pediatric occupational therapists. Review selection and characterization were performed by two independent reviewers. Twelve articles published from 2011 to 2020 were identified and varied in terms of purpose, population, and results although the articles all shared similar methodologies and outcome measures. Only 25% of the articles (3/12) addressed pediatric occupational therapy stress and stressors directly while the remaining addressed occupational stress, but with varying levels of attention to pediatric occupational therapists. Stress and stressors experienced by pediatric occupational therapists have been studied to a limited extent. Occupational stress is associated with increased burnout, decreased health, and decreased job satisfaction and performance. Several knowledge gaps have been identified, as well as priorities for future research into pediatric occupational therapists and occupational stress.

Impacts of the COVID-19 pandemic on access to HIV and reproductive health care among women living with HIV (WLHIV) in Western Kenya: A mixed methods analysis.

Introduction: The COVID-19 pandemic has impacted access to health services. Our objective was to understand the pandemic's impact on access to HIV, pregnancy, and family planning (FP) care among women living with HIV (WLHIV). Methods: Data were collected after June 2020, when questions about the pandemic were added to two ongoing mixed methods studies using telephone surveys and in-depth interviews among WLHIV in western Kenya. The Chaguo Langu (CL) study includes primarily non-pregnant WLHIV receiving HIV care at 55 facilities supported by AMPATH and the Opt4Mamas study includes pregnant WLHIV receiving antenatal care at five facilities supported by FACES. Our outcomes were self-reported increased difficulty refilling medication, accessing care, and managing FP during the pandemic. We summarized descriptive data and utilized multivariable logistic regression to evaluate predictors of difficulty refilling medication and accessing care. We qualitatively analyzed the interviews using inductive coding with thematic analysis. Results: We analyzed 1,402 surveys and 15 in-depth interviews. Many (32%) CL participants reported greater difficulty refilling medications and a minority (14%) reported greater difficulty accessing HIV care during the pandemic. Most (99%) Opt4Mamas participants reported no difficulty refilling medications or accessing HIV/pregnancy care. Among the CL participants, older women were less likely (aOR = 0.95, 95% CI: 0.92-0.98) and women with more children were more likely (aOR = 1.13, 95% CI: 1.00-1.28) to report difficulty refilling medications. Only 2% of CL participants reported greater difficulty managing FP and most (95%) reported no change in likelihood of using FP or desire to get pregnant. Qualitative analysis revealed three major themes: (1) adverse organizational/economic implications of the pandemic, (2) increased importance of pregnancy prevention during the pandemic, and (3) fear of contracting COVID-19. Discussion: The two unique participant groups included in our study encountered overlapping problems during the COVID-19 epidemic. Access to HIV services and antiretrovirals was interrupted for a large proportion of non-pregnant WLHIV in western Kenya, but access to pregnancy/family planning care was less affected in our cohort. Innovative solutions are needed to ensure HIV and reproductive health outcomes do not worsen during the ongoing pandemic.

Divergent Serpentoviruses in Free-Ranging Invasive Pythons and Native Colubrids in Southern Florida, United States.

Burmese python (Python bivittatus) is an invasive snake that has significantly affected ecosystems in southern Florida, United States. Aside from direct predation and competition, invasive species can also introduce nonnative pathogens that can adversely affect native species. The subfamily Serpentovirinae (order Nidovirales) is composed of positive-sense RNA viruses primarily found in reptiles. Some serpentoviruses, such as shingleback nidovirus, are associated with mortalities in wild populations, while others, including ball python nidovirus and green tree python nidovirus can be a major cause of disease and mortality in captive animals. To determine if serpentoviruses were present in invasive Burmese pythons in southern Florida, oral swabs were collected from both free-ranging and long-term captive snakes. Swabs were screened for the presence of serpentovirus by reverse transcription PCR and sequenced. A total serpentovirus prevalence of 27.8% was detected in 318 python samples. Of the initial swabs from 172 free-ranging pythons, 42 (24.4%) were positive for multiple divergent viral sequences comprising four clades across the sampling range. Both sex and snout-vent length were statistically significant factors in virus prevalence, with larger male snakes having the highest prevalence. Sampling location was statistically significant in circulating virus sequence. Mild clinical signs and lesions consistent with serpentovirus infection were observed in a subset of sampled pythons. Testing of native snakes (n = 219, 18 species) in part of the python range found no evidence of python virus spillover; however, five individual native snakes (2.3%) representing three species were PCR positive for unique, divergent serpentoviruses. Calculated pairwise uncorrected distance analysis indicated the newly discovered virus sequences likely represent three novel genera in the subfamily Serpentovirinae. This study is the first to characterize serpentovirus in wild free-ranging pythons or in any free-ranging North America reptile. Though the risk these viruses pose to the invasive and native species is unknown, the potential for spillover to native herpetofauna warrants further investigation.

Contraception use and HIV outcomes among women initiating dolutegravir-containing antiretroviral therapy in Kenya: a retrospective cohort study.

INTRODUCTION: The rollout of dolutegravir (DTG) in low- and middle-income countries was disrupted by a potential association reported with periconceptional DTG exposure among women living with HIV (WLHIV) and infant neural tube defects. This prompted countries to issue interim guidance limiting DTG use among women of reproductive potential to those on effective contraception. Data to understand the potential impact of such guidance on WLHIV are limited. METHODS: We conducted a retrospective cohort analysis of WLHIV 15-49 years initiating DTG-containing antiretroviral treatment (ART) in Kenya from 2017 to 2020. We determined baseline effective (oral, injectable or lactational amenorrhea) and very effective (implant, intrauterine device or female sterilization) contraception use among women who initiated DTG before (Group 1) or during (Group 2) the interim guideline period. We defined incident contraception use in each group as the number of contraceptive methods initiated ≤180 days post-guideline (Group 1) or post-DTG initiation (Group 2). We determined the proportions of all women who switched from DTG- to non-nucleoside reverse transcriptase inhibitor (NNRTI)- (efavirenz or nevirapine) containing ART ≤12 months post-DTG initiation, compared their viral suppression (<1000 copies/ml) and conducted multivariable logistic regression to determine factors associated with switching from DTG to NNRTI-containing ART. RESULTS: Among 5155 WLHIV in the analysis (median age 43 years), 89% initiated DTG after transitioning from an NNRTI. Baseline effective and very effective contraception use, respectively, by the group were: Group 1 (12% and 13%) and Group 2 (41% and 35%). Incident contraception use in each group was <5%. Overall, 498 (10%) women switched from DTG to an NNRTI. Viral suppression among those remaining on DTG versus switched to NNRTI was 95% and 96%, respectively (p = 0.63). In multivariable analysis, incident effective and very effective contraception use was not associated with switching. CONCLUSIONS: Baseline, but not incident, effective contraception use was higher during the interim guideline period compared to before it, suggesting women already using effective contraception were preferentially selected to initiate DTG after the guideline was released. These findings reveal challenges in the implementation of policy which ties antiretroviral access to contraceptive use. Future guidance should capture nuances of contraception decision-making and support women's agency to make informed decisions.

Integrated Hydrogeological, Hydrochemical, and Isotopic Assessment of Seawater Intrusion into Coastal Aquifers in Al-Qatif Area, Eastern Saudi Arabia.

Seawater intrusion (SWI) is the main threat to fresh groundwater (GW) resources in coastal regions worldwide. Early identification and delineation of such threats can help decision-makers plan for suitable management measures to protect water resources for coastal communities. This study assesses seawater intrusion (SWI) and GW salinization of the shallow and deep coastal aquifers in the Al-Qatif area, in the eastern region of Saudi Arabia. Field hydrogeological and hydrochemical investigations coupled with laboratory-based hydrochemical and isotopic analyses (18O and 2H) were used in this integrated study. Hydrochemical facies diagrams, ionic ratio diagrams, and spatial distribution maps of GW physical and chemical parameters (EC, TDS, Cl-, Br-), and seawater fraction (fsw) were generated to depict the lateral extent of SWI. Hydrochemical facies diagrams were mainly used for GW salinization source identification. The results show that the shallow GW is of brackish and saline types with EC, TDS, Cl-, Br- concentration, and an increasing fsw trend seaward, indicating more influence of SWI on shallow GW wells located close to the shoreline. On the contrary, deep GW shows low fsw and EC, TDS, Cl-, and Br-, indicating less influence of SWI on GW chemistry. Moreover, the shallow GW is enriched in 18O and 2H isotopes compared with the deep GW, which reveals mixing with recent water. In conclusion, the reduction in GW abstraction in the central part of the study area raised the average GW level by three meters. Therefore, to protect the deep GW from SWI and salinity pollution, it is recommended to implement such management practices in the entire region. In addition, continuous monitoring of deep GW is recommended to provide decision-makers with sufficient data to plan for the protection of coastal freshwater resources.

Early Pleistocene stratigraphy, sedimentary environments, and formation contexts at Dmanisi in the Georgian Caucasus.

The Early Pleistocene site of Dmanisi is now well known for its large number of fossils of early Homo erectus as well as associated artifacts and faunal remains, recovered mainly in pipe-related geologic features. Testing in the M5 unit 100 m to the west of the main excavations revealed a thick stratigraphy with no evidence of pipes or gullies, indicating that the geologic record at Dmanisi included spatially distinct sedimentary environments that needed further investigation. Here we report the results of a geoarchaeological program to collect data bearing on contexts and formation processes over a large area of the promontory. That work has defined over 40,000 m2 of in situ deposits with artifacts and faunas. Stratum A ashes bury the uppermost Mashavera Basalt, which we have dated to 1.8 Ma in the M5 block. The Stratum A deposits contain stratified occupations that accumulated quickly and offer good potential for recovery of in situ materials. Stratum B1 deposits above the A/B unconformity include all of the pipe and gully facies at Dmanisi, reflecting a brief but very intense phase of geomorphic change. Those deposits contain the majority of faunas and all of the hominin fossils. B1 slope facies offer excellent formation contexts away from the piped area, and all B1 deposits are sealed by Stratum B2 over the whole promontory. Strata B2 to B5 register a return to slope facies, with no further evidence of pipes or gullies. Those deposits also present excellent contexts for recovery of in situ occupations. Overall, Dmanisi's geologic history preserves an exceptional record of the activities and environmental context of occupations during the first colonization of Eurasia.