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BackgroundYoung adults have a disproportionately high rate of HIV infection, high rates of attrition at all stages of the HIV care continuum, and an elevated probability of disease progression and transmission. Tracking and monitoring objective measures of antiretroviral therapy (ART) adherence in real time is critical to bolster the accuracy of research data, support adherence, and improve clinical outcomes. However, adherence monitoring often relies on self-reported and retrospective data or requires additional effort from providers to understand individual adherence patterns. In this study, we will monitor medication-taking using a real-time objective measure of adherence that does not rely on self-report or healthcare providers for measurement.MethodsThe Youth Ending the HIV Epidemic (YEHE) study will pilot a novel automated directly observed therapy-conditional economic incentive (aDOT-CEI) intervention to improve ART adherence among youth with HIV (YWH) in California and Florida who have an unsuppressed HIV viral load. The aDOT app uses facial recognition to record adherence each day, and then economic incentives are given based on a participant's confirmed adherence. We will enroll participants in a 3-month pilot study to assess the feasibility and acceptability of the aDOT-CEI intervention using predefined metrics. During and after the trial, a subsample of the pilot participants and staff/providers from participating AIDS Healthcare Foundation (AHF) clinics will participate in individual in-depth interviews to explore intervention and implementation facilitators and barriers.DiscussionYEHE will provide data on the use of an aDOT-CEI intervention to improve adherence among YWH who are not virologically suppressed. The YEHE study will document the feasibility and acceptability and will explore preliminary data to inform a trial to test the efficacy of aDOT-CEI. This intervention has the potential to effectively improve ART adherence and virologic suppression among a key population experiencing health disparities.Trial registrationThe trial registration number is NCT05789875.

[This corrects the article DOI: 10.1371/journal.pone.0249149.].

BackgroundIn the last three decades, much effort has been invested in measuring and improving the quality of diabetes care. We assessed the association between adherence to diabetes quality indicators and all-cause mortality in the primary care setting.MethodsA nationwide, population-based, historical cohort study of all people aged 45-80 with pharmacologically-treated diabetes in 2005 (n = 222,235). Data on annual performance of quality indicators (including indicators for metabolic risk factor management and glycemic control) and vital status were retrieved from electronic medical records of the four Israeli health maintenance organizations. Cox proportional hazards and time-dependent models were used to estimate hazard ratios (HRs) for mortality by degree of adherence to quality indicators.ResultsDuring 2,000,052 person-years of follow-up, 35.8% of participants died. An inverse dose-response association between the degree of adherence and mortality was shown for most of the quality indicators. Participants who were not tested for proteinuria or did not visit an ophthalmologist during the first-5-years of follow-up had HRs of 2.60 (95%CI:2.49-2.69) and 2.09 (95%CI:2.01-2.16), respectively, compared with those who were fully adherent. In time-dependent analyses, not measuring LDL-cholesterol, blood pressure, HbA1c, or HbA1c>9% were similarly associated with mortality (HRs ≈1.5). The association of uncontrolled blood pressure with mortality was modified by age, with increased mortality shown for those with controlled blood pressure at older ages (≥65 years).ConclusionsLongitudinal adherence to diabetes quality indicators is associated with reduced all-cause mortality. Primary care professionals need to be supported by health care systems to perform quality indicators.

IntroductionAgriculture is the primary source of income and household food for >75% of rural Kenyans, including people living with HIV (PLHIV), making agricultural yields an important factor in food security and nutrition. Previous studies have shown the interconnectedness of food insecurity, malnutrition, and poor HIV health by elucidating that having one of these conditions increases the likelihood and severity of having another. However, few studies have explored the linkages between agricultural practices, food security and nutrition for PLHIV, or how agricultural livelihood interventions may affect these domains. This study aimed to examine the mechanisms through which an agricultural livelihood intervention can positively or negatively affect agricultural practices, food security, and nutrition for PLHIV.MethodsFrom July 2012-August 2013, we interviewed participants with HIV on antiretroviral therapy (ART) enrolled in a pilot randomized controlled trial (RCT) of an agricultural livelihood and finance intervention to understand the mechanisms through which the intervention may have affected HIV health outcomes. The intervention included agricultural and finance training and a microfinance loan to purchase the MoneyMaker hip pump, a human-powered water pump, seeds, and other farming implements. A purposive sample of 45 intervention and a random subset of 9 control participants were interviewed at 12-month endline visit with a subset of 31 intervention participants interviewed longitudinally at both the 3- and 12-month visits. Transcripts were double coded using an inductive-deductive approach and analyzed for impacts of the intervention on agricultural practices, food security, and nutrition using analytic reports for each key theme.ResultsAll intervention participants described improvements in agricultural practices and yields attributed to the intervention while many also described improvements in income; these changes in turn contributed to improved HIV health, including suppressed viral loads, and a few people noted improved immunologic parameters. Key mechanisms included the knowledge gained from agricultural training which led to improved yields and access to new markets. The use of the irrigation pump was also identified as an additional, lesser important mechanism. All intervention participants reported sustained improvements in food security and nutrition through increased yields and income from the sale of excess crops used to purchase food, and diversification of fresh fruits and vegetables consumed through agricultural production. This led to self-reported weight gain which was a nutritional mechanism towards improved health.ConclusionsAgricultural and finance interventions that improve farming practices could lead to improved health outcomes through the pathways of improved food security, income, and diversified diet. The results from this study helped the team to enhance the intervention prior to implementation of the larger cluster RCT (cRCT). By understanding how agricultural livelihood interventions act upon pathways towards improved health, policy options can be developed and implemented to include components that are needed to achieve sustainable outcomes.Trial registrationClinicalTrials.gov NCT01548599.

Long-acting injectable (LAI) antiretroviral therapy (ART) is a novel HIV treatment option for people with HIV. The first LAI ART regimen for HIV treatment received regulatory approval in the United States in January 2021. In February 2020, we collected qualitative data from 18 consumers and 23 clinical and non-clinical stakeholders to catalog anticipated individual-consumer, healthcare system, and structural levels barriers and facilitators to LAI ART implementation in Los Angeles County, California. Thematic analysis was guided by the CFIR implementation science model. CFIR constructs of intervention characteristics, individual characteristics, outer and inner setting, intervention characteristics, and implementation process emerged in analysis. Under intervention characteristics, anticipated facilitators included the relative advantage of LAI ART over pills for adherence and reduced treatment management burden and related anxiety; anticipated barriers included non-adherence to injection appointments, concerns of developing HIV resistance, discomfort with injection and cost. Anticipated facilitators based on individual characteristics included overall acceptability based on knowledge and positive beliefs about LAI ART. Participant noted several characteristics of the outer setting that could negatively impact implementation, such as medical mistrust, external policies, and LAI ART eligibility (i.e., to be virally suppressed prior to initiation). Participants were optimistic about the potential to decrease stigma but expressed that provider willingness for adoption could be hindered by challenges in organizational inner setting related to payment authorizations, increased staffing needs, medication procurement and storage, and provider and healthcare system readiness. Results from this pre-implementation study may inform rollout and scale-up of LAI ART in Los Angeles County.

A combination of machine learning and expert analyst review was used to detect odontocete echolocation clicks, identify dominant click types, and classify clicks in 32 years of acoustic data collected at 11 autonomous monitoring sites in the western North Atlantic between 2016 and 2019. Previously-described click types for eight known odontocete species or genera were identified in this data set: Blainville's beaked whales (Mesoplodon densirostris), Cuvier's beaked whales (Ziphius cavirostris), Gervais' beaked whales (Mesoplodon europaeus), Sowerby's beaked whales (Mesoplodon bidens), and True's beaked whales (Mesoplodon mirus), Kogia spp., Risso's dolphin (Grampus griseus), and sperm whales (Physeter macrocephalus). Six novel delphinid echolocation click types were identified and named according to their median peak frequencies. Consideration of the spatiotemporal distribution of these unidentified click types, and comparison to historical sighting data, enabled assignment of the probable species identity to three of the six types, and group identity to a fourth type. UD36, UD26, and UD28 were attributed to Risso's dolphin (G. griseus), short-finned pilot whale (G. macrorhynchus), and short-beaked common dolphin (D. delphis), respectively, based on similar regional distributions and seasonal presence patterns. UD19 was attributed to one or more species in the subfamily Globicephalinae based on spectral content and signal timing. UD47 and UD38 represent distinct types for which no clear spatiotemporal match was apparent. This approach leveraged the power of big acoustic and big visual data to add to the catalog of known species-specific acoustic signals and yield new inferences about odontocete spatiotemporal distribution patterns. The tools and call types described here can be used for efficient analysis of other existing and future passive acoustic data sets from this region.

The most common pediatric primary malignant bone tumor, osteosarcoma, is often described as genetically non-recurrent and heterogeneous. Neoadjuvant chemotherapy is typically followed by resection and assessment of treatment response, which helps inform prognosis. Identifying biomarkers that may impact chemotherapy response and survival could aid in upfront risk stratification and identify patients in highest need of innovative therapies for future clinical trials. Relative to conventional genetics, little is known about osteosarcoma epigenetics. We aimed to characterize the methylation and phosphorylation status in osteosarcoma using histone markers found in primary diagnostic biopsies and their paired metastases. We constructed two tissue microarray sets from 58 primary diagnostic samples and 54 temporally-separated but related metastatic or recurrent samples, with tissue blocks available from 2002-2022. Clinical charts were reviewed for post-therapy necrosis response, presence of metastatic disease or recurrence, and overall survival. We evaluated 6 histone H3 residues using immunohistochemistry, including H3K4me3, H3K9me3, H3K27me2, H3K27me3, H3S10T11phos, and H3S28phos. Tumors were scored with low (

BackgroundThe prevalence of eczema has increased with industrialization. Industrial practices generate ambient air pollution, including fine particulate matter of diameter ≤ 2.5μm (PM2.5). Studies investigating the relationship between PM2.5 and eczema in the US are scarce. The objective of this study was to determine the risk of eczema with PM2.5 exposure in a diverse national cohort of American adults.MethodsIn this cross-sectional study, eczema cases in the All of Us Research Program were linked via three-digit zip code to average annual PM2.5 concentrations from the Center for Air, Climate, and Energy Solutions. Eczema cases and controls were compared using Pearson's χ2 test for categorical variables and one-way analysis of variance for continuous variables. The relationship between PM2.5 and eczema was assessed via logistic regression adjusting for demographic factors, smoking, and atopic comorbidities.ResultsIndividuals with eczema (n = 12,695) lived in areas with significantly higher PM2.5 concentrations than did individuals without eczema (n = 274,127) (0.83 x 10 μg/m3 v. 0.81 x 10 μg/m3, P < .001). PM2.5 concentration was significantly associated with eczema in univariable analysis (odds ratio 1.97, 95% confidence interval 1.77-2.19, P < .001), and in multivariable analyses, both controlling for demographics and smoking status (odds ratio 2.21, 95% confidence interval 1.98-2.47, P < .001) and with the addition of atopic comorbidities (odds ratio 2.38, 95% confidence interval 2.12-2.67, P < .001).ConclusionsThe odds of eczema increased with greater PM2.5 concentration in this large, diverse, adult American cohort. Ambient air pollution is an environmental hazard that influences inflammatory skin disease, suggesting possible targeted interventions.

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597.

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4'-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5'-bipyrimidine]-2,2'-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-β1)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (e.g., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-β1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.

In this article we study the social dynamic of temporal partitioning congestion games (TPGs), in which participants must coordinate an optimal time-partitioning for using a limited resource. The challenge in TPGs lies in determining whether users can optimally self-organize their usage patterns. Reaching an optimal solution may be undermined, however, by a collectively destructive meta-reasoning pattern, trapping users in a socially vicious oscillatory behavior. TPGs constitute a dilemma for both human and animal communities. We developed a model capturing the dynamics of these games and ran simulations to assess its behavior, based on a 2×2 framework that distinguishes between the players' knowledge of other players' choices and whether they use a learning mechanism. We found that the only way in which an oscillatory dynamic can be thwarted is by adding learning, which leads to weak convergence in the no-information condition and to strong convergence in the with-information condition. We corroborated the validity of our model using real data from a study of bats' behaviour in an environment of water scarcity. We conclude by examining the merits of a complexity-based, agent-based modelling approach over a game-theoretic one, contending that it offers superior insights into the temporal dynamics of TPGs. We also briefly discuss the policy implications of our findings.

ObjectivePosttraumatic Stress Disorder (PTSD) affects millions of people worldwide. While the relationship between direct exposure to traumatic events and PTSD is well-established, the influence of indirect trauma exposure on PTSD remains unclear. It is similarly unclear what role cumulative exposure to direct and indirect traumas play in the risk of PTSD.MethodsThe study uses data from the Houston Trauma and Recovery Study, conducted on 2020-2021, and involved a random sampling of 1,167 individuals residing in Houston during Hurricane Harvey in 2017. Participants were asked about their experiences related to both Hurricane Harvey and the subsequent COVID-19 pandemic. Exposures were categorized as direct or indirect traumas, in line with the criteria delineated in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Cumulative exposures were also calculated.ResultsAmong participants, 12.6% were experiencing current PTSD. There were significant associations between both direct [OR = 3.18, 95% CI 1.85, 5.46] and indirect [OR = 1.91, 95% CI 1.05, 3.46] traumas related to Harvey, as well as direct [OR = 2.13, 95% CI 1.20, 3.77] and indirect [OR = 1.69, 95% CI 0.93, 3.09] traumas due to COVID and the risk of PTSD in fully adjusted models. Further, significant associations were found between the cumulative exposure to traumas from both Hurricane Harvey and COVID-19 and the risk of PTSD, considering both direct [OR = 2.53, 95% CI 1.36, 4.70] and indirect exposures [OR = 2.79, 95% CI 1.47, 5.28].ConclusionsOur study offers support for connections between exposure to both direct and indirect traumas stemming from large-scale disasters and PTSD. Moreover, we show that cumulative exposures to multiple large-scale events increase the risk of PTSD. This highlights the importance of the consideration of a range of exposures as risks for PTSD, particularly in a time of compounding disasters and broad population exposures to these events.

A longstanding debate concerns the function of carinated elements in both, the Levantine, and European Aurignacian. The present study aims to contribute to this topic with the evaluation of the carinated assemblage from layer D in Hayonim Cave, Western Galilee, Israel, one of the type sites of the Levantine Aurignacian. An operational chain reconstruction with an attribute analysis is paired with a typological approach to the preparation and maintenance products based on artefacts defined as West European Aurignacian. The results of this study are investigated with multivariate statistics offering a methodological contribution. The data is subjected to a transformation into a distance matrix using the Gower distance and tested with the adonis-algorithm for significance. The results clearly indicate that the carinated items in Hayonim Cave did fully or partially function as cores. They are accompanied by diagnostic preparation- and- maintenance products known from the literature e.g. Thèmes bladelets. The statistical analysis indicates only a minor correlation with stratigraphy yet supports the techno-typological criteria applied for defining artefact categories (cores, debitage, tools), as well as the proposed differentiation of carinated 'core' types. The non-carinated cores in Hayonim Cave are characterised by a high variability in typology and reduction concepts. A curious similarity to the Levallois-concept is observed on some of the flake cores. It is therefore suggested that the frequent recycling of Middle Palaeolithic artefacts in the Levantine Aurignacian might have given the Aurignacian flint-knappers the opportunity to study the Levallois concept and apply an approximation of it in their own core reduction strategies. The notion that Palaeolithic flint-knappers actively observed former technological systems through the discarded artefacts directly opens up a new trajectory for the understanding of lithic reduction concept permanence. The conceptual diversification and variability in Hayonim Cave D indicate a highly dynamic period in the Levantine Upper Palaeolithic which increased the adaptive potential and promoted a rapid cultural change.

The prevalence of depression in U.S. adults during the COVID-19 pandemic has been high overall and particularly high among persons with fewer assets. Building on previous work on assets and mental health, we document the burden of depression in groups based on income and savings during the first two years of the COVID-19 pandemic. Using a nationally representative, longitudinal panel study of U.S. adults (N = 1,271) collected in April-May 2020 (T1), April-May 2021 (T2), and April-May 2022 (T3), we estimated the adjusted odds of reporting probable depression at any time during the COVID-19 pandemic with generalized estimating equations (GEE). We explored probable depression-defined as a score of ≥10 on the Patient Health Questionnaire-9 (PHQ-9)-by four asset groups, defined by median income (≥$65,000) and savings (≥$20,000) categories. The prevalence of probable depression was consistently high in Spring 2020, Spring 2021, and Spring 2022 with 27.9% of U.S. adults reporting probable depression in Spring 2022. We found that there were four distinct asset groups that experienced different depression trajectories over the COVID-19 pandemic. Low income-low savings asset groups had the highest level of probable depression across time, reporting 3.7 times the odds (95% CI: 2.6, 5.3) of probable depression at any time relative to high income-high savings asset groups. While probable depression stayed relatively stable across time for most groups, the low income-low savings group reported significantly higher levels of probable depression at T2, compared to T1, and the high income-low savings group reported significantly higher levels of probable depression at T3 than T1. The weighted average of probable depression across time was 42.9% for low income-low savings groups, 24.3% for high income-low savings groups, 19.4% for low income-high savings groups, and 14.0% for high income-high savings groups. Efforts to ameliorate both savings and income may be necessary to mitigate the mental health consequences of pandemics.

BackgroundOvarian cancer is a challenging disease to diagnose and treat effectively with five-year survival rates below 50%. Previous patient experience research in high-income countries highlighted common challenges and opportunities to improve survival and quality of life for women affected by ovarian cancer. However, no comparable data exist for low-and middle-income countries, where 70% of women with the disease live. This study aims to address this evidence gap.MethodsThis is an observational multi-country study set in low- and middle-income countries. We aim to recruit over 2000 women diagnosed with ovarian cancer across multiple hospitals in 24 countries in Asia, Africa and South America. Country sample sizes have been calculated (n = 70-96 participants /country), taking account of varying national five-year disease prevalence rates. Women within five years of their diagnosis, who are in contact with participating hospitals, are invited to take part in the study. A questionnaire has been adapted from a tool previously used in high-income countries. It comprises 57 multiple choice and two open-ended questions designed to collect information on demographics, women's knowledge of ovarian cancer, route to diagnosis, access to treatments, surgery and genetic testing, support needs, the impact of the disease on women and their families, and their priorities for action. The questionnaire has been designed in English, translated into local languages and tested according to local ethics requirements. Questionnaires will be administered by a trained member of the clinical team.ConclusionThis study will inform further research, advocacy, and action in low- and middle-income countries based on tailored approaches to the national, regional and global challenges and opportunities. In addition, participating countries can choose to repeat the study to track progress and the protocol can be adapted for other countries and other diseases.

Background/purposeLeptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report an assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE).MethodsThis was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR).ResultsLME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008).Conclusion7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

The phytohormone auxin plays a critical role in plant growth and development. Despite significant progress in elucidating metabolic pathways of the primary bioactive auxin, indole-3-acetic acid (IAA), over the past few decades, key components such as intermediates and enzymes have not been fully characterized, and the dynamic regulation of IAA metabolism in response to environmental signals has not been completely revealed. In this study, we established a protocol employing a highly sensitive liquid chromatography-mass spectrometry (LC-MS) instrumentation and a rapid stable isotope labeling approach. We treated Arabidopsis seedlings with two stable isotope labeled precursors ([13C6]anthranilate and [13C8, 15N1]indole) and monitored the label incorporation into proposed indolic compounds involved in IAA biosynthetic pathways. This Stable Isotope Labeled Kinetics (SILK) method allowed us to trace the turnover rates of IAA pathway precursors and product concurrently with a time scale of seconds to minutes. By measuring the entire pathways over time and using different isotopic tracer techniques, we demonstrated that these methods offer more detailed information about this complex interacting network of IAA biosynthesis, and should prove to be useful for studying auxin metabolic network in vivo in a variety of plant tissues and under different environmental conditions.

BackgroundThe CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease.MethodsLinear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ≥96 weeks.ResultsCorrelations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values ConclusionsEach domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease.Trial registrationNCT01907087, NCT02485899.

In various biological systems, analyzing how cell behaviors are coordinated over time would enable a deeper understanding of tissue-scale response to physiologic or superphysiologic stimuli. Such data is necessary for establishing both normal tissue function and the sequence of events after injury that lead to chronic disease. However, collecting and analyzing these large datasets presents a challenge-such systems are time-consuming to process, and the overwhelming scale of data makes it difficult to parse overall behaviors. This problem calls for an analysis technique that can quickly provide an overview of the groups present in the entire system and also produce meaningful categorization of cell behaviors. Here, we demonstrate the application of an unsupervised method-the Variational Autoencoder (VAE)-to learn the features of cells in cartilage tissue after impact-induced injury and identify meaningful clusters of chondrocyte behavior. This technique quickly generated new insights into the spatial distribution of specific cell behavior phenotypes and connected specific peracute calcium signaling timeseries with long term cellular outcomes, demonstrating the value of the VAE technique.

BackgroundGlobal evidence on psychosis is dominated by studies conducted in Western, high-income countries. The objectives of the Study of Context Of Psychoses to improve outcomes in Ethiopia (SCOPE) are (1) to generate rigorous evidence of psychosis experience, epidemiology and impacts in Ethiopia that will illuminate aetiological understanding and (2) inform development and testing of interventions for earlier identification and improved first contact care that are scalable, inclusive of difficult-to-reach populations and optimise recovery.MethodsThe setting is sub-cities of Addis Ababa and rural districts in south-central Ethiopia covering 1.1 million people and including rural, urban and homeless populations. SCOPE comprises (1) formative work to understand care pathways and community resources (resource mapping); examine family context and communication (ethnography); develop valid measures of family communication and personal recovery; and establish platforms for community engagement and involvement of people with lived experience; (2a) a population-based incidence study, (2b) a case-control study and (2c) a cohort study with 12 months follow-up involving 440 people with psychosis (390 rural/Addis Ababa; 50 who are homeless), 390 relatives and 390 controls. We will test hypotheses about incidence rates in rural vs. urban populations and men vs. women; potential aetiological role of khat (a commonly chewed plant with amphetamine-like properties) and traumatic exposures in psychosis; determine profiles of needs at first contact and predictors of outcome; (3) participatory workshops to develop programme theory and inform co-development of interventions, and (4) evaluation of the impact of early identification strategies on engagement with care (interrupted time series study). Findings will inform development of (5) a protocol for (5a) a feasibility cluster randomised controlled trial of interventions for people with recent-onset psychosis in rural settings and (5b) two uncontrolled pilot studies to test acceptability, feasibility of co-developed interventions in urban and homeless populations.

IntroductionMothers faced an increased risk of adverse mental health outcomes during the COVID-19 pandemic compared to other populations. However, there is little data on the factors that placed mothers at increased risk of distress.AimsThe present study explored a range of individual, familial, and environmental factors associated with psychological distress in mothers during the COVID-19 pandemic.MethodThis repeated cross-sectional study was composed of a convenience sample of mothers who completed an online survey that included a demographic questionnaire, an emotion regulation questionnaire, and the Depression, Anxiety, and Stress scale. The survey was administered during the second and third lockdowns in Israel in 2020-2021.ResultsThe study included 575 mothers (M age = 39). The findings of a hierarchical regression indicated that individual-level factors, composed of age and emotion regulation tendencies predicted psychological distress. The family-level factors of household income and number of children in the family also predicted distress. In terms of environmental-level factors, COVID-19-related media consumption and school status (open or closed) were also significant predictors of psychological distress. Importantly, the results showed that the most important predictors of psychological distress in mothers during the COVID-19 outbreak were school closures, household income, and the use of adaptive and maladaptive emotion regulation strategies.ConclusionsThe findings highlight the intersection of individual, familial, and environmental factors in mothers' mental health during crises.

BackgroundThe Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control).Methods and analysisThis parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy.Trial registrationThe study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.

ObjectiveThere is currently inconclusive evidence regarding the relationship between recidivism and mental illness. This retrospective study aimed to use rigorous machine learning methods to understand the unique predictive utility of mental illness for recidivism in a general population (i.e.; not only those with mental illness) prison sample in the United States.MethodParticipants were adult men (n = 322) and women (n = 72) who were recruited from three prisons in the Midwest region of the United States. Three model comparisons using Bayesian correlated t-tests were conducted to understand the incremental predictive utility of mental illness, substance use, and crime and demographic variables for recidivism prediction. Three classification statistical algorithms were considered while evaluating model configurations for the t-tests: elastic net logistic regression (GLMnet), k-nearest neighbors (KNN), and random forests (RF).ResultsRates of substance use disorders were particularly high in our sample (86.29%). Mental illness variables and substance use variables did not add predictive utility for recidivism prediction over and above crime and demographic variables. Exploratory analyses comparing the crime and demographic, substance use, and mental illness feature sets to null models found that only the crime and demographics model had an increased likelihood of improving recidivism prediction accuracy.ConclusionsDespite not finding a direct relationship between mental illness and recidivism, treatment of mental illness in incarcerated populations is still essential due to the high rates of mental illnesses, the legal imperative, the possibility of decreasing institutional disciplinary burden, the opportunity to increase the effectiveness of rehabilitation programs in prison, and the potential to improve meaningful outcomes beyond recidivism following release.

ObjectiveThis population-based, matched cohort study aimed to evaluate utilization of health care services by mothers of children with major congenital anomalies (MCAs), compared to mothers of children without MCAs over a 20-year post-birth time horizon in Denmark.MethodsOur analytic sample included mothers who gave birth to an infant with a MCA (n = 23,927) and a cohort of mothers matched to them by maternal age, parity and infant's year of birth (n = 239,076). Primary outcomes were period prevalence and mothers' quantity of health care utilization (primary, inpatient, outpatient, surgical, and psychiatric services) stratified by their child's age (i.e., ages 0-6 = before school, ages 7-13 = pre-school + primary education, and ages 14-18 = secondary education or higher). The secondary outcome measure was length of hospital stays. Outcome measures were adjusted for maternal age at delivery, parity, marital status, income quartile, level of education in the year prior to the index birth, previous spontaneous abortions, maternal pregnancy complications, maternal diabetes, hypertension, alcohol-related diseases, and maternal smoking.ResultsIn both cohorts the majority of mothers were between 26 and 35 years of age, married, and employed, and 47% were primiparous. Mothers of infants with anomalies had greater utilization of outpatient, inpatient, surgical, and psychiatric services, compared with mothers in the matched cohort. Inpatient service utilization was greater in the exposed cohort up to 13 years after a child's birth, with the highest risk in the first six years after birth [adjusted risk ratio, 1.13; 95% confidence interval (CI), 1.12-1.14], with a decrease over time. Regarding the quantity of health care utilization, the greatest difference between the two groups was in inpatient service utilization, with a 39% increased rate in the exposed cohort during the first six years after birth (adjusted rate ratio, 1.39; 95% CI, 1.37-1.42). During the first 6 years after birth, mothers of children with anomalies stayed a median of 6 days (interquartile range [IQR], 3-13) in hospital overall, while the comparison cohort stayed a median of 4 days (IQR, 2-7) in hospital overall. Rates of utilization of outpatient clinics (adjusted rate ratio, 1.36; 95% CI, 1.29-1.42), as well as inpatient (adjusted rate ratio, 1.77; 95% CI, 1.68-1.87), and surgical services (adjusted rate ratio, 1.33; 95% CI, 1.26-1.41) was higher in mothers of children with multiple-organ MCAs during 0 to 6 years after birth. Among mothers at the lowest income levels, utilization of psychiatric clinic services increased to 59% and when their child was 7 to 13 years of age (adjusted rate ratio, 1.59; 95% CI, 1.24-2.03).ConclusionMothers of infants with a major congenital anomaly had greater health care utilization across services. Health care utilization decreased over time or remained stable for outpatient, inpatient, and surgical care services, whereas psychiatric utilization increased for up to 13 years after an affected child's birth. Healthcare utilization was significantly elevated among mothers of children with multiple MCAs and among those at the lowest income levels.

IntroductionTo improve retention on HIV treatment in Africa, public health programs are promoting a family of innovations to service delivery-referred to as "differentiated service delivery" (DSD) models-which seek to better meet the needs of both systems and patients by reducing unnecessary encounters, expanding access, and incorporating peers and patients in patient care. Data on the relative desirability of different models to target populations, which is currently sparse, can help guide prioritization of specific models during scale-up.MethodsWe conducted a discrete choice experiment to assess patient preferences for various characteristics of treatment services. Clinically stable people living with HIV were recruited from an HIV clinic in Kisumu, Kenya. We selected seven attributes of DSD models drawn from literature review and previous qualitative work. We created a balanced and orthogonal design to identify main term effects. A total of ten choice tasks were solicited per respondent. We calculated relative utility (RU) for each attribute level, a numerical representation of the strength of patient preference. Data were analyzed using a Hierarchical Bayesian model via Sawtooth Software.ResultsOne hundred and four respondents (37.5% men, 41.1 years mean age) preferred receiving care at a health facility, compared with home-delivery or a community meeting point (RU = 69.3, -16.2, and -53.1, respectively; p << 0.05); receiving those services from clinicians and pharmacists-as opposed to lay health workers or peers (RU = 21.5, 5.9, -24.5; p < 0.05); and preferred an individual support system over a group support system (RU = 15.0 and 4.2; p < 0.05). Likewise, patients strongly preferred longer intervals between both clinical reviews (RU = 40.1 and -50.7 for 6- and 1-month spacing, respectively; p < 0.05) and between ART collections (RU = 33.6 and -49.5 for 6- and1-month spacing, respectively; p < 0.05).ConclusionAlthough health systems find community- and peer-based DSD models attractive, clinically stable patients expressed a preference for facility-based care as long as clinical visits were extended to biannual. These data suggest that multi-month scripting and fast-track models best align with patient preferences, an insight which can help prioritize use of different DSD models in the region.

BackgroundExisting social relationships are a potential source of "social capital" that can enhance support for sustained retention in HIV care. A previous pilot study of a social network-based 'microclinic' intervention, including group health education and facilitated HIV status disclosure, reduced disengagement from HIV care. We conducted a pragmatic randomized trial to evaluate microclinic effectiveness.MethodsIn nine rural health facilities in western Kenya, we randomized HIV-positive adults with a recent missed clinic visit to either participation in a microclinic or usual care (NCT02474992). We collected visit data at all clinics where participants accessed care and evaluated intervention effect on disengagement from care (≥90-day absence from care after a missed visit) and the proportion of time patients were adherent to clinic visits ('time-in-care'). We also evaluated changes in social support, HIV status disclosure, and HIV-associated stigma.ResultsOf 350 eligible patients, 304 (87%) enrolled, with 154 randomized to intervention and 150 to control. Over one year of follow-up, disengagement from care was similar in intervention and control (18% vs 17%, hazard ratio 1.03, 95% CI 0.61-1.75), as was time-in-care (risk difference -2.8%, 95% CI -10.0% to +4.5%). The intervention improved social support for attending clinic appointments (+0.4 units on 5-point scale, 95% CI 0.08-0.63), HIV status disclosure to close social supports (+0.3 persons, 95% CI 0.2-0.5), and reduced stigma (-0.3 units on 5-point scale, 95% CI -0.40 to -0.17).ConclusionsThe data from our pragmatic randomized trial in rural western Kenya are compatible with the null hypothesis of no difference in HIV care engagement between those who participated in a microclinic intervention and those who did not, despite improvements in proposed intervention mechanisms of action. However, some benefit or harm cannot be ruled out because the confidence intervals were wide. Results differ from a prior quasi-experimental pilot study, highlighting important implementation considerations when evaluating complex social interventions for HIV care.Trial registrationClinical trial number: NCT02474992.

HIV-related stigma is a frequently cited barrier to HIV testing and care engagement. A nuanced understanding of HIV-related stigma is critical for developing stigma-reduction interventions to optimize HIV-related outcomes. This qualitative study documented HIV-related stigma across eight communities in east Africa during the baseline year of a large HIV test-and-treat trial (SEARCH, NCT: 01864603), prior to implementation of widespread community HIV testing campaigns and efforts to link individuals with HIV to care and treatment. Findings revealed experiences of enacted, internalized and anticipated stigma that were highly gendered, and more pronounced in communities with lower HIV prevalence; women, overwhelmingly, both held and were targets of stigmatizing attitudes about HIV. Past experiences with enacted stigma included acts of segregation, verbal discrimination, physical violence, humiliation and rejection. Narratives among women, in particular, revealed acute internalized stigma including feelings of worthlessness, shame, embarrassment, and these resulted in anxiety and depression, including suicidality among a small number of women. Anticipated stigma included fears of marital dissolution, verbal and physical abuse, gossip and public ridicule. Anticipated stigma was especially salient for women who held internalized stigma and who had experienced enacted stigma from their partners. Anticipated stigma led to care avoidance, care-seeking at remote facilities, and hiding of HIV medications. Interventions aimed at reducing individual and community-level forms of stigma may be needed to improve the lives of PLHIV and fully realize the promise of test-and-treat strategies.

RationaleThere is little doubt that aerosols play a major role in the transmission of SARS-CoV-2. The significance of the presence and infectivity of this virus on environmental surfaces, especially in a hospital setting, remains less clear.ObjectivesWe aimed to analyze surface swabs for SARS-CoV-2 RNA and infectivity, and to determine their suitability for sequence analysis.MethodsSamples were collected during two waves of COVID-19 at the University of California, Davis Medical Center, in COVID-19 patient serving and staff congregation areas. qRT-PCR positive samples were investigated in Vero cell cultures for cytopathic effects and phylogenetically assessed by whole genome sequencing.Measurements and main resultsImproved cleaning and patient management practices between April and August 2020 were associated with a substantial reduction of SARS-CoV-2 qRT-PCR positivity (from 11% to 2%) in hospital surface samples. Even though we recovered near-complete genome sequences in some, none of the positive samples (11 of 224 total) caused cytopathic effects in cultured cells suggesting this nucleic acid was either not associated with intact virions, or they were present in insufficient numbers for infectivity. Phylogenetic analysis suggested that the SARS-CoV-2 genomes of the positive samples were derived from hospitalized patients. Genomic sequences isolated from qRT-PCR negative samples indicate a superior sensitivity of viral detection by sequencing.ConclusionsThis study confirms the low likelihood that SARS-CoV-2 contamination on hospital surfaces contains infectious virus, disputing the importance of fomites in COVID-19 transmission. Ours is the first report on recovering near-complete SARS-CoV-2 genome sequences directly from environmental surface swabs.

BackgroundHypertension (HTN) is the single leading risk factor for human mortality worldwide, and more prevalent in sub-Saharan Africa than any other region [1]-although resources for HTN screening, treatment, and control are few. Most regional pilot studies to leverage HIV programs for HTN control have achieved blood pressure control in half of participants or fewer [2,3,4]. But this control gap may be due to inconsistent delivery of services, rather than ineffective underlying interventions.MethodsWe sought to evaluate the consistency of HTN program delivery within the SEARCH study (NCT01864603) among 95,000 adults in 32 rural communities in Uganda and Kenya from 2013-2016. To achieve this objective, we designed and performed a fidelity evaluation of the step-by-step process (cascade) of HTN care within SEARCH, calculating rates of HTN screening, linkage to care, and follow-up care. We evaluated SEARCH's assessment of each participant's HTN status against measured blood pressure and HTN history.FindingsSEARCH completed blood pressure screens on 91% of participants. SEARCH HTN screening was 91% sensitive and over 99% specific for HTN relative to measured blood pressure and patient history. 92% of participants screened HTN+ received clinic appointments, and 42% of persons with HTN linked to subsequent care. At follow-up, 82% of SEARCH clinic participants received blood pressure checks; 75% received medication appropriate for their blood pressure; 66% remained in care; and 46% had normal blood pressure at their most recent visit.ConclusionThe SEARCH study's consistency in delivering screening and treatment services for HTN was generally high, but SEARCH could improve effectiveness in linking patients to care and achieving HTN control. Its model for implementing population-scale HTN testing and care through an existing HIV test-and-treat program-and protocol for evaluating the intervention's stepwise fidelity and care outcomes-may be adapted, strengthened, and scaled up for use across multiple resource-limited settings.

BackgroundIn recent years, sentinel lymph node excision and ultrastaging have been performed in endometrial carcinomas to obtain information about lymph node status, avoiding unnecessary complete pelvic and paraaortic lymphadenectomy. The purpose of this retrospective study was to provide a comprehensive evaluation of the pathological features of endometrial carcinomas and their significance in association with sentinel lymph node involvement.MethodsPatients with endometrial carcinomas, preceded by sentinel lymph node mapping, were classified into Group-I and Group-II with negative and positive involvement, respectively. The pathological features, associated with sentinel lymph node involvement, were statistically analyzed, including determination of test performance parameters.ResultsAmong 70 patients who had undergone hysterectomy and sentinel lymph node excision, 61 had carcinoma and 9 had atypical hyperplasia. There were 50 patients in Group-I and 10 in Group-II. In Group-II, the significant pathological features were: 1) lower uterine segment involvement (100%), 2) an average tumor size of ≥5 CM, 3) lymphovascular invasion (50%), 4) cervical stromal invasion (40%), and 5) depth of myometrial invasion of ≥50% (50%). The incidences of these pathological features were significantly less in Group-I. Statistical analyses singled out "lower uterine segment involvement" as the most important feature.ConclusionsWe have identified five pathological features which are associated with sentinel lymph node involvement. Since lower uterine segment involvement has occurred in all cases of the Group-II cohort, we recommend FIGO and other organizations that determine staging rules should consider whether tumors that involve the lower uterine segment should be staged as higher than "1a", if the findings in this small series are confirmed by other studies. The results of this study may guide pathologists and oncologists in the diagnostic and therapeutic approaches to management of endometrial carcinomas.

Understanding the coagulation process is critical to developing treatments for trauma and coagulopathies. Clinical studies on tranexamic acid (TXA) have resulted in mixed reports on its efficacy in improving outcomes in trauma patients. The largest study, CRASH-2, reported that TXA improved outcomes in patients who received treatment prior to 3 hours after the injury, but worsened outcomes in patients who received treatment after 3 hours. No consensus has been reached about the mechanism behind the duality of these results. In this paper we use a computational model for coagulation and fibrinolysis to propose that deficiencies or depletions of key anti-fibrinolytic proteins, specifically antiplasmin, a1-antitrypsin and a2-macroglobulin, can lead to worsened outcomes through urokinase-mediated hyperfibrinolysis.

BackgroundAn estimated 10% of male adults have split or dribbled stream leading to poor hygiene, embarrassment, and inconvenience. There is no current metric that measures male stream deviation.ObjectiveTo develop a novel method to measure spray in normal and abnormal anatomical conformations.Design, setting, and participantsWe developed a novel platform to reliably describe spray. We used cadaveric tissues and 3D Printed models to study the impact of meatal shape on the urinary stream. Cadaveric penile tissue and 3D printed models were affixed to a fluid pump and used to simulate micturition. Dye captured on fabric allowed for spray detection.Outcome measurements and statistical analysisSpray pattern area, deviation from normal location, and flowrates were recorded. Computational fluid dynamic models were created to study fluid vorticity.Results and limitationsObstructions at the penile tip worsened spray dynamics and reduced flow. Ventral meatotomy improved flowrate (p

Understanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.

Understanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.

BackgroundPrevious research indicates clinical outcomes among HIV-infected men in sub-Saharan Africa are sub-optimal. The SEARCH test and treat trial (NCT01864603) intervention included antiretroviral care delivery designed to address known barriers to HIV-care among men by decreasing clinic visit frequency and providing flexible, patient-centered care with retention support. We sought to understand facilitators and barriers to retention in care in this universal treatment setting through quantitative and qualitative data analysis.MethodsWe used a convergent mixed methods study design to evaluate retention in HIV care among adults (age > = 15) during the first year of the SEARCH (NCT01864603) test and treat trial. Cox proportional hazards regression was used to evaluate predictors of retention in care. Longitudinal qualitative data from n = 190 in-depth interviews with HIV-positive individuals and health care providers were analyzed to identify facilitators and barriers to HIV care engagement.ResultsThere were 1,863 men and 3,820 women who linked to care following baseline testing. Retention in care was 89.7% (95% CI 87.0-91.8%) among men and 89.0% (86.8-90.9%) among women at one year. In both men and women older age was associated with higher rates of retention in care at one year. Additionally, among men higher CD4+ at ART initiation and decreased time between testing and ART initiation was associated with higher rates of retention. Maintaining physical health, a patient-centered treatment environment, supportive partnerships, few negative consequences to disclosure, and the ability to seek care in facilities outside of their community of residence were found to promote retention in care.ConclusionsFeatures of the ART delivery system in the SEARCH intervention and social and structural advantages emerged as facilitators to retention in HIV care among men. Messaging around the health benefits of early ART start, decreasing logistical barriers to HIV care, support of flexible treatment environments, and accelerated linkage to care, are important to men's success in ART treatment programs. Men already benefit from increased social support following disclosure of their HIV-status. Future efforts to shift gender norms towards greater equity are a potential strategy to support high levels of engagement in care for both men and women.

[This corrects the article DOI: 10.1371/journal.pone.0200242.].

Endolithic microbial communities survive nutrient and energy deficient conditions while contributing to the weathering of their mineral substrate. This study examined the mineral composition and microbial communities of fully serpentinized weathered rock from 0.1 to 6.5 m depth at a site within the Khalilovsky massif, Orenburg Region, Southern Ural Mountains, Russia. The mineral composition includes a major content of serpentinite family (mostly consisting of lizardite and chrysotile), magnesium hydrocarbonates (hydromagnesite with lesser amounts of hydrotalcite and pyroaurite) concentrated in the upper layers, and clay minerals. We found that the deep-seated weathered serpentinites are chrysotile-type minerals, while the middle and surface serpentinites mostly consist of lizardite and chrysotile types. Microbial community analysis, based on 16S rRNA gene sequencing, showed a similar diversity of phyla throughout the depth profile. The dominant bacterial phyla were the Actinobacteria (of which unclassified genera in the orders Acidimicrobiales and Actinomycetales were most numerous), Chloroflexi (dominated by an uncultured P2-11E order) and the Proteobacteria (predominantly class Betaproteobacteria). Densities of several groups of bacteria were negatively correlated with depth. Occurrence of the orders Actinomycetales, Gaiellales, Solirubrobacterales, Rhizobiales and Burkholderiales were positively correlated with depth. Our findings show that endolithic microbial communities of the Khalilovsky massif have similar diversity to those of serpentine soils and rocks, but are substantially different from those of the aqueous environments of actively serpentinizing systems.

Opioid prescriptions for chronic pain and subsequent opioid-related complications have risen dramatically in the US. Recent data suggest that medical marijuana laws have been associated with lower state-level opioid overdose mortality. In a national survey, we examined the prevalence of substitution of marijuana for opioids among US adults taking opioids for pain.Using GfK's KnowledgePanel, we conducted an Internet-based survey of a nationally representative sample of 16,280 adults in 2017 about individual perceptions and use of marijuana. We developed questions designed to assess the extent and reasons for substitution of marijuana for opioids. We examined opioid substitution among respondents with a history of ever using marijuana who used opioids in the past 12 months. There were 9,003 respondents, corresponding to a 55.3% response rate. The mean age was 48 years. Among the 5% (n = 486) who reported ever using marijuana and using opioids in the past year, 43% used opioids daily, and 23% reported current (past 30 day) marijuana use. Forty-one percent reported a decrease or cessation of opioid use due to marijuana use; 46% reported no change in opioid use; and 8% reported an increase in opioid use. We found that a substantial number of US adults reported that they substituted marijuana for opioids.

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are potentially life-threatening conditions whose partially overlapping phenomenology-distorted perception of appearance, obsessions/compulsions, and limited insight-can make diagnostic distinction difficult in some cases. Accurate diagnosis is crucial, as the effective treatments for AN and BDD differ. To improve diagnostic accuracy and clarify the contributions of each of the multiple underlying factors, we developed a two-stage machine learning model that uses multimodal, neurobiology-based, and symptom-based quantitative data as features: task-based functional magnetic resonance imaging data using body visual stimuli, graph theory metrics of white matter connectivity from diffusor tensor imaging, and anxiety, depression, and insight psychometric scores. In a sample of unmedicated adults with BDD (n = 29), unmedicated adults with weight-restored AN (n = 24), and healthy controls (n = 31), the resulting model labeled individuals with an accuracy of 76%, significantly better than the chance accuracy of 35% ([Formula: see text]). In the multivariate model, reduced white matter global efficiency and better insight were associated more with AN than with BDD. These results improve our understanding of the relative contributions of the neurobiological characteristics and symptoms of these disorders. Moreover, this approach has the potential to aid clinicians in diagnosis, thereby leading to more tailored therapy.

BackgroundIn the state of Bihar, India a multi-faceted quality improvement nurse-mentoring program was implemented to improve provider skills in normal and complicated deliveries. The objective of this analysis was to examine changes in diagnosis and management of postpartum hemorrhage (PPH) of the mother and intrapartum asphyxia of the infant in primary care facilities in Bihar, during the program.MethodsDuring the program, mentor pairs visited each facility for one week, covering four facilities over a four-week period and returned for subsequent week-long visits once every month for seven to nine consecutive months. Between- and within-facility comparisons were made using a quasi-experimental and a longitudinal design over time, respectively, to measure change due to the intervention. The proportions of PPH and intrapartum asphyxia among all births as well as the proportions of PPH and intrapartum asphyxia cases that were effectively managed were examined. Zero-inflated negative binomial models and marginal structural methodology were used to assess change in diagnosis and management of complications after accounting for clustering of deliveries within facilities as well as time varying confounding.ResultsThis analysis included 55,938 deliveries from 320 facilities. About 2% of all deliveries, were complicated with PPH and 3% with intrapartum asphyxia. Between-facility comparisons across phases demonstrated diagnosis was always higher in the final week of intervention (PPH: 2.5-5.4%, intrapartum asphyxia: 4.2-5.6%) relative to the first week (PPH: 1.2-2.1%, intrapartum asphyxia: 0.7-3.3%). Within-facility comparisons showed PPH diagnosis increased from week 1 through 5 (from 1.6% to 4.4%), after which it decreased through week 7 (3.1%). A similar trend was observed for intrapartum asphyxia. For both outcomes, the proportion of diagnosed cases where selected evidence-based practices were used for management either remained stable or increased over time.ConclusionsThe nurse-mentoring program appears to have built providers' capacity to identify PPH and intrapartum asphyxia cases but diagnosis levels are still not on par with levels observed in Southeast Asia and globally.

BackgroundFemale positive/male negative HIV-serodiscordant couples express a desire for children and may engage in condomless sex to become pregnant. Current guidelines recommend antiretroviral treatment in HIV-serodiscordant couples, yet HIV RNA viral suppression may not be routinely assessed or guaranteed and pre-exposure prophylaxis may not be readily available. Therefore, options for becoming pregnant while limiting HIV transmission should be offered and accessible to HIV-affected couples desiring children.MethodsA prospective pilot study of female positive/male negative HIV-serodiscordant couples desiring children was conducted to evaluate the acceptability, feasibility, and effectiveness of timed vaginal insemination. Eligible women were 18-34 years with regular menses. Prior to timed vaginal insemination, couples were observed for two months, and tested and treated for sexually transmitted infections. Timed vaginal insemination was performed for up to six menstrual cycles. A fertility evaluation and HIV RNA viral load assessment was offered to couples who did not become pregnant.FindingsForty female positive/male negative HIV-serodiscordant couples were enrolled; 17 (42.5%) exited prior to timed vaginal insemination. Twenty-three couples (57.5%) were introduced to timed vaginal insemination; eight (34.8%) achieved pregnancy, and six live births resulted without a case of HIV transmission. Seven couples completed a fertility evaluation. Four women had no demonstrable tubal patency bilaterally; one male partner had decreased sperm motility. Five women had unilateral/bilateral tubal patency; and seven women had an HIV RNA viral load (≥ 400 copies/mL).ConclusionTimed vaginal insemination is an acceptable, feasible, and effective method for attempting pregnancy. Given the desire for children and inadequate viral suppression, interventions to support safely becoming pregnant should be integrated into HIV prevention programs.

BACKGROUND:Food insecurity and violence are two major public health issues facing U.S. women. The link between food insecurity and violence has received little attention, particularly regarding the temporal ordering of events. The present study used data from the Women's Interagency Human Immunodeficiency Virus Study to investigate the longitudinal association of food insecurity and violence in a cohort of women at risk for or living with HIV. METHODS:Study participants completed six assessments from 2013-16 on food insecurity (operationalized as marginal, low, and very low food security) and violence (sexual or physical, and psychological). We used multi-level logistic regression, controlling for visits (level 1) nested within individuals (level 2), to estimate the association of experiencing violence. RESULTS:Among 2,343 women (8,528 visits), we found that victims of sexual or physical violence (odds ratio = 3.10; 95% confidence interval: 1.88, 5.19) and psychological violence (odds ratio = 3.00; 95% confidence interval: 1.67, 5.50) were more likely to report very low food security. The odds of experiencing violence were higher for women with very low food security at both the current and previous visit as compared to only the current visit. HIV status did not modify these associations. CONCLUSIONS:Food insecurity was strongly associated with violence, and women exposed to persistent food insecurity were even more likely to experience violence. Food programs and policy must consider persistent exposure to food insecurity, and interpersonal harms faced by food insecure women, such as violence.

ObjectiveMachine learning techniques have demonstrated superior discrimination compared to conventional statistical approaches in predicting trauma death. The objective of this study is to evaluate whether machine learning algorithms can be used to assess risk and dynamically identify patient-specific modifiable factors critical to patient trajectory for multiple key outcomes after severe injury.MethodsSuperLearner, an ensemble machine-learning algorithm, was applied to prospective observational cohort data from 1494 critically-injured patients. Over 1000 agnostic predictors were used to generate prediction models from multiple candidate learners for outcomes of interest at serial time points post-injury. Model accuracy was estimated using cross-validation and area under the curve was compared to select among predictors. Clinical variables responsible for driving outcomes were estimated at each time point.ResultsSuperLearner fits demonstrated excellent cross-validated prediction of death (overall AUC 0.94-0.97), multi-organ failure (overall AUC 0.84-0.90), and transfusion (overall AUC 0.87-0.9) across multiple post-injury time points, and good prediction of Acute Respiratory Distress Syndrome (overall AUC 0.84-0.89) and venous thromboembolism (overall AUC 0.73-0.83). Outcomes with inferior data quality included coagulopathic trajectory (AUC 0.48-0.88). Key clinical predictors evolved over the post-injury timecourse and included both anticipated and unexpected variables. Non-random missingness of data was identified as a predictor of multiple outcomes over time.ConclusionsMachine learning algorithms can be used to generate dynamic prediction after injury while avoiding the risk of over- and under-fitting inherent in ad hoc statistical approaches. SuperLearner prediction after injury demonstrates promise as an adaptable means of helping clinicians integrate voluminous, evolving data on severely-injured patients into real-time, dynamic decision-making support.

Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p

The National i-THRIVE Programme seeks to evaluate the impact of the NHS England-funded whole system transformation on child and adolescent mental health services (CAMHS). This article reports on the design for a model of implementation that has been applied in CAMHS across over 70 areas in England using the 'THRIVE' needs-based principles of care. The implementation protocol in which this model, 'i-THRIVE' (implementing-THRIVE), will be used to evaluate the effectiveness of the THRIVE intervention is reported, together with the evaluation protocol for the process of implementation. To evaluate the effectiveness of i-THRIVE to improve care for children and young people's mental health, a cohort study design will be conducted. N = 10 CAMHS sites that adopt the i-THRIVE model from the start of the NHS England-funded CAMHS transformation will be compared to N = 10 'comparator sites' that choose to use different transformation approaches within the same timeframe. Sites will be matched on population size, urbanicity, funding, level of deprivation and expected prevalence of mental health care needs. To evaluate the process of implementation, a mixed-methods approach will be conducted to explore the moderating effects of context, fidelity, dose, pathway structure and reach on clinical and service level outcomes. This study addresses a unique opportunity to inform the ongoing national transformation of CAMHS with evidence about a popular new model for delivering children and young people's mental health care, as well as a new implementation approach to support whole system transformation. If the outcomes reflect benefit from i-THRIVE, this study has the potential to guide significant improvements in CAMHS by providing a more integrated, needs-led service model that increases access and involvement of patients with services and in the care they receive.

The objective of this study is to investigate the application of machine learning techniques to the large-scale human expert evaluation of the impact of academic research. Using publicly available impact case study data from the UK's Research Excellence Framework (2014), we trained five machine learning models on a range of qualitative and quantitative features, including institution, discipline, narrative style (explicit and implicit), and bibliometric and policy indicators. Our work makes two key contributions. Based on the accuracy metric in predicting high- and low-scoring impact case studies, it shows that machine learning models are able to process information to make decisions that resemble those of expert evaluators. It also provides insights into the characteristics of impact case studies that would be favoured if a machine learning approach was applied for their automated assessment. The results of the experiments showed strong influence of institutional context, selected metrics of narrative style, as well as the uptake of research by policy and academic audiences. Overall, the study demonstrates promise for a shift from descriptive to predictive analysis, but suggests caution around the use of machine learning for the assessment of impact case studies.

Mathematical models have suggested that spatially-targeted screening interventions for tuberculosis may efficiently accelerate disease control, but empirical data supporting these findings are limited. Previous models demonstrating substantial impacts of these interventions have typically simulated large-scale screening efforts and have not attempted to capture the spatial distribution of tuberculosis in households and communities at a high resolution. Here, we calibrate an individual-based model to the locations of case notifications in one district of Lima, Peru. We estimate the incremental efficiency and impact of a spatially-targeted interventions used in combination with household contact tracing (HHCT). Our analysis reveals that HHCT is relatively efficient with a median of 40 (Interquartile Range: 31.7 to 49.9) household contacts required to be screened to detect a single case of active tuberculosis. However, HHCT has limited population impact, producing a median incidence reduction of only 3.7% (Interquartile Range: 5.8% to 1.9%) over 5 years. In comparison, spatially targeted screening (which we modeled as active case finding within high tuberculosis prevalence areas 100 m2 grid cell) is far less efficient, requiring evaluation of ≈12 times the number of individuals as HHCT to find a single individual with active tuberculosis. Furthermore, the addition of the spatially targeted screening effort produced only modest additional reductions in tuberculosis incidence over the 5 year period (≈1.3%) in tuberculosis incidence. In summary, we found that HHCT is an efficient approach for tuberculosis case finding, but has limited population impact. Other screening approaches which target areas of high tuberculosis prevalence are less efficient, and may have limited impact unless very large numbers of individuals can be screened.