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IntroductionThis study evaluated changes in the white matter of the brain and psychological health variables, resulting from a neuroscience-based mindfulness intervention, the Training for Awareness, Resilience, and Action (TARA), in a population of healthy adolescents.MethodsA total of 100 healthy adolescents (57 female, age ranges 14–18 years) were randomized into the 12-week TARA intervention or a waitlist-control group. All participants were imaged with diffusion MRI to quantify white matter connectivity between brain regions. Imaging occurred at baseline/randomization and after 12 weeks of baseline (pre- and post-intervention in the TARA group). We hypothesized that structural connectivity in the striatum and interoceptive networks would increase following the TARA intervention, and that, this increased connectivity would relate to psychological health metrics from the Strengths and Difficulties Questionnaire (SDQ) and the Insomnia Severity Index (ISI). The TARA intervention and all assessments, except for the MRIs, were fully remotely delivered using secure telehealth platforms and online electronic data capture systems.ResultsThe TARA intervention showed high consistency, tolerability, safety, recruitment, fidelity, adherence, and retention. After 12 weeks, the TARA group, but not controls, also demonstrated significantly improved sleep quality (p = 0.02), and changes in the right putamen node strength were related to this improved sleep quality (r = −0.42, p = 0.006). Similarly, the TARA group, but not controls, had significantly increased right insula node strength related to improved emotional well-being (r = −0.31, p = 0.04). Finally, we used the network-based statistics to identify a white matter interoception network that strengthened following TARA (p = 0.009).DiscussionThese results suggest that the TARA mindfulness-based intervention in healthy adolescents is feasible and safe, and it may act to increase structural connectivity strength in interoceptive brain regions. Furthermore, these white matter changes are associated with improved adolescent sleep quality and emotional well-being. Our results suggest that TARA could be a promising fully remotely delivered intervention for improving psychological well-being in adolescents. As our findings suggest that TARA affects brain regions in healthy adolescents, which are also known to be altered during depression in adolescents, future studies will examine the effects of TARA on depressed adolescents.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT04254796.

Background: Women are less physically active, report greater perceived barriers for exercise, and show higher levels of depressive symptoms. This contributes to high global disability. The relationship between perceived barriers for physical activity and depressive symptoms in women remains largely unexplored. The aims of this cross-sectional analysis were to examine the association between physical activity barriers and depressive symptoms, and identify types of barriers in physically inactive community-dwelling women. Methods: Three hundred eighteen physically inactive women aged 25?65 years completed the Barriers to Being Active Quiz (BBAQ) developed by the Centers for Disease Control and Prevention, and the Center for Epidemiological Studies Depression Scale at the baseline visit of the mobile phone-based physical activity education trial. The BBAQ consists of six subscales (lack of time, social influence, lack of energy, lack of willpower, fear of injury, lack of skill, and lack of resources). We used multivariate regression analyses, correcting for sociodemographics. Results: Higher physical activity barriers were associated with greater depressive symptoms scores (linear effect, estimate?=?0.75, 95% confidence interval [CI]: 0.39?1.12, p?0.001). This effect appeared to taper off for the higher barrier scores (quadratic effect, estimate: ?0.02, 95% CI: ?0.03 to ?0.01, p?=?0.002). Exploratory analyses indicated that these associations were most driven by the social influence (p?=?0.027) and lack of energy subscales (p?=?0.017). Conclusions: Higher depression scores were associated with higher physical activity barriers. Social influence and lack of energy were particularly important barriers. Addressing these barriers may improve the efficacy of physical activity interventions in women with higher depressive symptoms. Future research should assess this in a randomized controlled trial. Trial Registration ClinicalTrials.gov#: NCTO1280812 registered January 21, 2011.

AbstractExposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman’s reports of social adversity during the third trimester were associated with their infant’s resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants’ cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

Abstract Background Tuberculosis (TB) preventive treatment (TPT) substantially reduces the risk of developing active TB for people living with HIV (PLHIV). We utilized a novel implementation strategy based on choice architecture (CAT) which makes TPT prescribing the default option. Through CAT, health care workers (HCWs) need to “opt-out” when choosing not to prescribe TPT to PLHIV. We assessed the prospective, concurrent, and retrospective acceptability of TPT prescribing among HCWs in Malawi who worked in clinics participating in a cluster randomized trial of the CAT intervention. Methods 28 in-depth semi-structured interviews were conducted with HCWs from control (standard prescribing approach) and intervention (CAT approach) clinics. The CAT approach was facilitated in intervention clinics using a default prescribing module built into the point-of-care HIV Electronic Medical Record (EMR) system. An interview guide for the qualitative CAT assessment was developed based on the theoretical framework of acceptability and on the normalization process theory. Thematic analysis was used to code the data, using NVivo 12 software. Results We identified eight themes belonging to the three chronological constructs of acceptability. HCWs expressed no tension for changing the standard approach to TPT prescribing (prospective acceptability); however, those exposed to CAT described several advantages, including that it served as a reminder to prescribe TPT and routinized TPT prescribing (concurrent acceptability). Some felt that CAT may reduce HCW´s autonomy and might lead to inappropriate TPT prescribing (retrospective acceptability). Conclusions The default prescribing module for TPT has now been incorporated into the point-of-care EMR system nationally in Malawi. This seems to fit the acceptability of the HCWs. Moving forward, it is important to train HCWs on how the EMR can be leveraged to determine who is eligible for TPT and who is not, while acknowledging the autonomy of HCWs.

Abstract Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.

Crowdsourced platforms provide huge amounts of street-view images that contain valuable building information. This work addresses the challenges in applying Scene Text Recognition (STR) in crowdsourced street-view images for building attribute mapping. We use Flickr images, particularly examining texts on building facades. A Berlin Flickr dataset is created, and pre-trained STR models are used for text detection and recognition. Manual checking on a subset of STR-recognized images demonstrates high accuracy. We examined the correlation between STR results and building functions, and analysed instances where texts were recognized on residential buildings but not on commercial ones. Further investigation revealed significant challenges associated with this task, including small text regions in street-view images, the absence of ground truth labels, and mismatches in buildings in Flickr images and building footprints in OpenStreetMap (OSM). To develop city-wide mapping beyond urban hotspot locations, we suggest differentiating the scenarios where STR proves effective while developing appropriate algorithms or bringing in additional data for handling other cases. Furthermore, interdisciplinary collaboration should be undertaken to understand the motivation behind building photography and labeling. The STR-on-Flickr results are publicly available at https://github.com/ya0-sun/STR-Berlin.

Abstract The impacts of large terrestrial volcanic eruptions are apparent from satellite monitoring and direct observations. However, more than three quarters of all volcanic outputs worldwide lie submerged beneath the ocean, and the risks they pose to people, infrastructure, and benthic ecosystems remain poorly understood due to inaccessibility and a lack of detailed observations before and after eruptions. Here, comparing data acquired between 2015 - 2017 and 3 months after the January 2022 eruption of Hunga Volcano, we document the far-reaching and diverse impacts of one of the most explosive volcanic eruptions ever recorded. Almost 10 km3 of seafloor material was removed during the eruption, most of which we conclude was redeposited within 20 km of the caldera by long run-out seafloor density currents. These powerful currents damaged seafloor cables over a length of >100 km, reshaped the seafloor, and caused mass-mortality of seafloor life. Biological (mega-epifaunal invertebrate) seafloor communities only survived the eruption where local topography provided a physical barrier to density currents (e.g., on nearby seamounts). While the longer-term consequences of such a large eruption for human, ecological and climatic systems are emerging, we expect that these previously-undocumented refugia will play a key role in longer-term ecosystem recovery.

Abstract Background The syndemic effects of poverty, food insecurity and living with HIV are recognized as global health priorities, including through the United Nations Sustainability Goals 1, 2 and 3. Today, women and girls account for 63% of all new HIV infections in eastern and southern Africa, including Kenya. Pregnant and postpartum women living with HIV in this setting face unique challenges including increased financial insecurity as women leave the work force to care for their newborn infants. This contributes to poverty, food scarcity and stress. Methods To address financial insecurity, improve infant feeding and reduce stress among mothers living with HIV in this setting, we developed a multilevel intervention, Supporting Healthy Mothers, consisting of 10 monthly unconditional cash transfers (10,000 KES, ~$75 USD/month) and personalized infant feeding support from pregnancy to 7 months postpartum. We conducted a non-randomized feasibility trial of this intervention among women engaged in HIV care in Kisumu, Kenya. From February 23, 2022 to March 23, 2022, we enrolled a total of 40 women who were 20–35 weeks pregnant—20 women to the intervention group at a public clinic, and 20 women to the control group at a similar clinic. Our aim was to assess feasibility, acceptability, and the potential impact of the intervention on food security, infant feeding and maternal mental health. Results Analyzing data from all 40 participants, we found a significant reduction in food insecurity scores from baseline for the intervention group when compared to the control group at 6 weeks and 6 months postpartum (p = 0.0008 and p

IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

IntroductionA multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern.MethodsConsidering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes.ResultsOur analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation.ConclusionsTaken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients.

Abstract Magnetic resonance imaging (MRI) is widely used for ischemic stroke lesion detection in mice. A challenge is that lesion segmentation often relies on manual tracing by trained experts, which is labor-intensive, time-consuming, and prone to inter- and intra-rater variability. Here, we present a fully automated ischemic stroke lesion segmentation method for mouse T2-weighted MRI data. As an end-to-end deep learning approach, the automated lesion segmentation requires very little preprocessing and works directly on the raw MRI scans. We randomly split a large dataset of 382 MRI scans into a subset (n = 293) to train the automated lesion segmentation and a subset (n = 89) to evaluate its performance. We compared Dice coefficients and accuracy of lesion volume against manual segmentation, as well as its performance on an independent dataset from an open repository with different imaging characteristics. The automated lesion segmentation produced segmentation masks with a smooth, compact, and realistic appearance that are in high agreement with manual segmentation. We report dice scores higher than the agreement between two human raters reported in previous studies, highlighting the ability to remove individual human bias and standardize the process across research studies and centers.

Abstract Background Involvement in caregiving and tailored support services may reduce the risk of mental health symptoms for mothers after their preterm infant’s neonatal intensive care unit (NICU) discharge. We aimed to compare Family-Centered Care (FCC) with mobile-enhanced Family-Integrated Care (mFICare) on post-discharge maternal mental health symptoms. Method This quasi-experimental study enrolled preterm infant (≤ 33 weeks)/parent dyads from three NICUs into sequential cohorts: FCC or mFICare. We analyzed post-discharge symptoms of perinatal post-traumatic stress disorder (PTSD) and depression using intention-to-treat and per protocol approaches. Results 178 mothers (89 FCC; 89 mFICare) completed measures. We found no main effect of group assignment. We found an interaction between group and stress, indicating fewer PTSD and depression symptoms among mothers who had higher NICU-related stress and received mFICare, compared with mothers who had high stress and received FCC (PTSD: interaction β=-1.18, 95% CI: -2.10, -0.26; depression: interaction β=-0.76, 95% CI: -1.53, 0.006). Per protocol analyses of mFICare components suggested fewer PTSD and depression symptoms among mothers who had higher NICU stress scores and participated in clinical team rounds and/or group classes, compared with mothers who had high stress and did not participate in rounds or classes. Conclusion Overall, post-discharge maternal mental health symptoms did not differ between the mFICare and FCC groups. However, for mothers with high levels of stress during the NICU stay, mFICare was associated with fewer post-discharge PTSD and depression symptoms.

Abstract Background Opioid use disorder (OUD) is overrepresented among people with criminal justice involvement; HIV is a common comorbidity in this population. This study aimed to examine how formerly incarcerated men living with HIV and OUD in South Africa experienced HIV and OUD services in correctional facilities and the community. Methods Three focus group discussions were conducted with 16 formerly incarcerated men living with HIV and OUD in Gauteng, South Africa. Discussions explored available healthcare services in correctional facilities and the community and procedural and practice differences in health care between the two types of settings. Data were analyzed thematically, using a comparative lens to explore the relationships between themes. Results Participants described an absence of medical services for OUD in correctional facilities and the harms caused by opioid withdrawal without medical support during incarceration. They reported that there were limited OUD services in the community and that what was available was not connected with public HIV clinics. Participants perceived correctional and community HIV care systems as readily accessible but suggested that a formal system did not exist to ensure care continuity post-release. Conclusions OUD was perceived to be medically unaddressed in correctional facilities and marginally attended to in the community. In contrast, HIV treatment was widely available within the two settings. The current model of OUD care in South Africa leaves many of the needs of re-entrants unmet. Integrating harm reduction into all primary care medical services may address some of these needs. Successful HIV care models provide examples of approaches that can be applied to developing and expanding OUD services in South Africa.

Digital technology brought informational saturation to our lives. In cyberspace, private and business users need help to make valuable pieces of information stand out from the noise of excessive information. With search algorithms, recommender systems, and online advertising, digital platforms specialised in providing relief for this problem. Their technologies arrange digitalised information to make it intelligible and relevant for individuals. But the separation of information from noise did not only become a necessity to comfortably navigate the depths of the web, it also became a commodity. There is a demand for it, a supply, a price, and an exchange on markets which is enabled by private law. The examples of general search, recommender systems, and online advertising illustrate that. At the same time, their commodification can become problematic. This paper argues that in the European Union (EU), the separation of information from noise has become a contested commodity according to M. J. Radin’s framework. The Digital Services Act and the Digital Markets Act purposefully limit the influence of the market price mechanism on the design and allocation of the separation technology to protect legal goods like the democratic process, innovation, and privacy.

Abstract Background Poor adherence and under-utilization of antiretroviral therapy (ART) services have been major setbacks to achieving 95-95-95 policy goals in Sub-Saharan Africa. Social support and mental health challenges may serve as barriers to accessing and adhering to ART but are under-studied in low-income countries. The purpose of this study was to examine the association of interpersonal support and depression scores with adherence to ART among persons living with HIV (PLWH) in the Volta region of Ghana. Methods We conducted a cross-sectional survey among 181 PLWH 18 years or older who receive care at an ART clinic between November 2021 and March 2022. The questionnaire included a 6-item simplified ART adherence scale, the 20-item Center for Epidemiologic Studies Depression Scale (CES-D), and the 12-item Interpersonal Support Evaluation List-12 (ISEL-12). We first used a chi-squared or Fisher’s exact test to assess the association between these and additional demographic variables with ART adherence status. We then built a stepwise multivariable logistic regression model to explain ART adherence. Results ART adherence was 34%. The threshold for depression was met by 23% of participants, but it was not significantly associated with adherence in multivariate analysis(p = 0.25). High social support was reported by 48.1%, and associated with adherence (p = 0.033, aOR = 3.45, 95% CI = 1.09–5.88). Other factors associated with adherence included in the multivariable model included not disclosing HIV status (p = 0.044, aOR = 2.17, 95% CI = 1.03–4.54) and not living in an urban area (p = 0.00037, aOR = 0.24, 95% CI = 0.11–0.52). Conclusion Interpersonal support, rural residence, and not disclosing HIV status were independent predictors of adherence to ART in the study area.

Heartland virus (HRTV) disease is an emerging tickborne illness in the midwestern and southern United States. We describe a reported fatal case of HRTV infection in the Maryland and Virginia region, states not widely recognized to have human HRTV disease cases. The range of HRTV could be expanding in the United States.

BackgroundAdherence to antiretroviral therapy (ART) can substantially reduce morbidity and mortality among women living with HIV (WLWH) and prevent vertical transmission of HIV. However, in sub-Saharan Africa (SSA), more than 50% of new mothers discontinue ART and HIV care after childbirth. The role of water insecurity (WI) in ART adherence is not well-explored. We examined the relationship between WI and ART adherence among pregnant and postpartum WLWH in Greater Accra region of Ghana.MethodsUsing a cross-sectional survey, we recruited 176 pregnant and postpartum WLWH on ART across 11 health facilities. We examined the association between WI (measured using the Household Water Insecurity Experience Scale, and categorized as moderate and severe WI compard to low WI) and poor ART adherence (defined as scoring a below average observed CASE index score). Bivariate analysis was performed using chi-square test followed by multivariate logistic regression models. We included all variables with p-values less than 0.20 in the multivariate analysis.ResultsMost (79.5%) of the pregnant and postpartum WLWH enrolled on ART, were urban residents. Over 2/3 were aged 30 years and older. Overall, 33.5% of respondents had poor ART adherence. Proportion of poor ART adherence was 19.4% among those with low WI, 44.4% in those with moderate WI, and 40.0% among those with high WI. Respondents with moderate household water insecurity had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (adjusted Odds ratio (aOR) = 2.76, 95%CI: 1.14-6.66, p = 0.024), even after adjusting for food insecurity. Similarly, respondents with high WI had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (aOR = 1.49, 95%CI: 0.50-4.48, p = 0.479), even after adjusting for food insecurity.ConclusionWater insecurity is prevalent among pregnant and postpartum WLWH and is a significant risk factor for poor ART adherence. Governments and other stakeholders working in HIV care provision should prioritize water security programming for WLWH along the HIV care continuum.

Introduction We consider an analytical problem of characterising patterns and identifying discrepancies between database systems for longitudinal aggregated healthcare data involving multiple facilities.Methods We used routinely collected data on the registered number of people living with HIV who initiated antiretroviral treatment (ART) in 69 South African facilities in 2019; reported in the Three Interlinked Electronic register (Tier.net) and the District Health Information System. A Bayesian multiplicative interaction model quantified the average time effect as realised through the heterogeneous facility-specific slopes and quantified discrepancies between the two database sources.Results The estimated average trends showed a slight dip in June and a large dip in December. The estimated slopes identified clusters of facilities based on their ranges of fluctuations over time. The differences in average monthly ART initiations between the two database sources had a median of 1.6 (IQR 0.8–3.3), while 3 outlying facilities differed by at least 10 ART initiations between the 2 sources.Conclusion Multiplicative interaction models are a powerful tool for quantifying average trends over time and for evaluating discrepancies between reporting systems for multiple facilities with heterogeneous time slopes. The Bayesian framework enables efficient estimation for a very large number of parameters.

Introduction: Older adult patients (≥65) accessing emergency departments (ED) represent a significant demographic. Recidivism secondary to adverse drug events (ADE) ranges between 6–24% and levels of prescribed medication non-adherence is common among older adults. The ED pharmacist medication reconciliation workflow may mitigate self-management challenges in real time and reduce medication-related harm while potentially impacting recidivism, medication adherence, and patient self-efficacy. The purposes of this evidence-based project were to (1) evaluate the impact of a modified Medication Management for Deficiencies in the Elderly (MedMalDE) intervention on Self-Efficacy for Appropriate Medication Use (SEAMS) and 30-day return to care and (2) identify factors associated with medication self-management challenges (MedMalDE) in the participating institution. Methods: As part of an evidence-based quality improvement (QI) effort to build an accredited geriatric emergency department (GED) and meet State legislated acute care medication history requirements, a new medication reconciliation workflow was deployed. To assess the intervention’s impact on self-efficacy in a pre/post design, 21 older adult patient’s underwent SEAMS assessment at two time points: the intervention and 7–14 days post-discharge from the emergency department. Baseline data and medication self-management challenges for an ED convenience sample of 167 older adult patients completed the MedMalDE. Descriptive statistics and a logistic regression model were used to evaluate the impact of the intervention and factors associated with medication management deficiencies. Wilcoxon Signed Rank was used for pre/post SEAMS score change. Results: The self-efficacy (SEAMS) scores of 21-patients participating in the intervention were significantly improved from 19.88 to 21 (p=0.0077, p10%, included lack of knowledge regarding medication names, ease of opening or manipulating medications, ease of swallowing medications, and affordability. MedMalDE total scores were significantly associated with female gender (OR=2.0, 95%CI=1.14–3.51, p=0.016), and the functional (ability) subscale was associated with female gender (OR=1.88, 95%CI=1.03–3.41, p=0.011) and patient as the informant (OR=0.49, 95%CI=0.27–0.89, p=0.019). Conclusion: Integrating a modified MedMalDE into medication reconciliation can identify common patient medication self-management challenges in real-time, guiding pharmacist’s interventions and potentially reducing medication-related harm. Individualized assessment improves self-efficacy while ensuring the health system has a reliable and accurate medication history at times of transition.

(Series Information) European Papers - A Journal on Law and Integration, 2023 8(1), 17-23 | European Forum Highlight of 12 April 2023 | (Abstract) This Highlight proposes an interpretation of the notion of “fairness” in the context of the EU Digital Markets Act (DMA), and explores whether it could become an evaluative principle for gatekeeper compliance with Articles 5 and 6 of the Act. There are good reasons to believe that fairness refers to equity, i.e. a distribution of legal entitlements that takes into account individual characteristics of the subjects. Gatekeepers have different obligations compared to non-gatekeepers. By imposing that discrimination, the legislator aims for a different allocation of economic rents and opportunities in the platform economy. But apart from the DMA’s vague reference to a “significant disequilibrium in rights and obligations” in certain relationships with platforms, there is no concrete understanding of a fair or equitable distribution. Fairness, as presented in the DMA, is inherently indeterminate. It is not a legal standard, but a “gut feeling”. This is not necessarily a bad thing. The fairness language simply confers power from economists to lawyers in competition agencies and courts, who will be required to find an elusive “disequilibrium in rights and obligations”. Fairness leaves a certain margin of appreciation to any enforcer responsible for deciding the scope of gatekeeper obligations.

The ‘Clash of Civilizations’ hypothesis suggested that global politics would revert to inter-civilizational (inter-religious) conflict with the end of the Cold War. Conceptual and empirical refutations followed, but the idea that pre-Cold War inter-polity interaction was generally characterized by such conflict was not addressed. We consider this a possible historical libel. First, we briefly review the position of major faith traditions toward making and keeping agreements with those of other faith traditions. Most forms of agreements are sanctioned, and there is inconsistent and minimal support for duplicity. Second, using the MATRS database of multilateral treaties, we identify 79 sovereign entities active between 1750 and 1900 (when multilateral treaties were numerous and official state religions were prominent), link states to their official religions, and analyze the pattern of 385 multilateral treaties’ signings. We conclude that there is no tendency among states with one official religion to avoid entering into treaties with those of other official religions. The ‘Clash of Civilizations’ hypothesis is a historical myth.

Abstract Background COVID-19 is an ongoing global health crisis with prevention and treatment recommendations rapidly changing. Rapid response telephone triage and advice services are critical in providing timely care during pandemics. Understanding patient participation with triage recommendations and factors associated with patient participation can assist in developing sensitive and timely interventions for receiving the treatment to prevent adverse health effects of COVID-19. Methods This cohort study aimed to assess patient participation (percentage of patients who followed nursing triage suggestions from the COVID hotline) and identify factors associated with patient participation in four quarterly electronic health records from March 2020 to March 2021 (Phase 1: 14 March 2020–6 June 2020; Phase 2: 17 June 2020–16 September 2020; Phase 3: 17 September 2020–16 December 2020; Phase 4: 17 December 2020–16 March 2021). All callers who provided their symptoms (including asymptomatic with exposure to COVID) and received nursing triage were included in the study. Factors associated with patient participation were identified using multivariable logistic regression analyses, including demographic variables, comorbidity variables, health behaviors, and COVID-19-related symptoms. Results The aggregated data included 9849 encounters/calls from 9021 unique participants. Results indicated: (1) 72.5% of patient participation rate; (2) participants advised to seek emergency department care had the lowest patient participation rate (43.4%); (3) patient participation was associated with older age, a lower comorbidity index, a lack of unexplained muscle aches, and respiratory symptoms. The absence of respiratory symptoms was the only factor significantly associated with patient participation in all four phases (OR = 0.75, 0.60, 0.64, 0.52, respectively). Older age was associated with higher patient participation in three out of four phases (OR = 1.01–1.02), and a lower Charlson comorbidity index was associated with higher patient participation in phase 3 and phase 4 (OR = 0.83, 0.88). Conclusion Public participation in nursing triage during the COVID pandemic requires attention. This study supports using a nurse-led telehealth intervention and reveals crucial factors associated with patient participation. It highlighted the importance of timely follow-up in high-risk groups and the benefit of a telehealth intervention led by nurses serving as healthcare navigators during the COVID-19 pandemic.

Abstract Objective Although targeted approaches have become available in second‐ and third‐line settings, platinum‐based chemotherapy remains the standard first‐line treatment for advanced muscle‐invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance. Methods In this study, we established a routine compatible method for the molecular classification of MIBC samples according to various classification systems and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy. This retrospective study included 191 patients with advanced MIBC (pT≥3 or pN+) who underwent radical cystectomy, with or without adjuvant chemotherapy. A 48‐gene panel and classifier rule set were established to determine molecular subtypes according to TCGA, MDA, LundTax, and Consensus classifications. Additionally, 12 single platinum‐predictive candidate genes were assessed. The results were correlated with patients' clinicopathological and follow‐up data and were validated using independent data sets. Results Our final evaluation of 159 patients demonstrated better survival in the luminal groups for those who received chemotherapy compared with those who did not. In contrast, no such differences were observed in basal subtypes. The use of chemotherapy was associated with better survival in patients with high APOBEC3G expression (p

For millennia, humans have gravitated towards coastlines for their resource potential and as geopolitical centres for global trade. A basic requirement ensuring water security for coastal communities relies on a delicate balance between the supply and demand of potable water. The interaction between freshwater and saltwater in coastal settings is, therefore, complicated by both natural and human-driven environmental changes at the land–sea interface. In particular, ongoing sea-level rise, warming and deoxygenation might exacerbate such perturbations. In this context, an improved understanding of the nature and variability of groundwater fluxes across the land–sea continuum is timely yet remains out of reach. The flow of terrestrial groundwater across the coastal transition zone and the extent of freshened groundwater below the present-day seafloor are receiving increased attention in marine and coastal sciences because they likely represent a significant yet highly uncertain component of (bio)geochemical budgets and because of the emerging interest in the potential use of offshore freshened groundwater as a resource. At the same time, “reverse” groundwater flux from offshore to onshore is of prevalent socio-economic interest, as terrestrial groundwater resources are continuously pressured by over-pumping and seawater intrusion in many coastal regions worldwide. An accurate assessment of the land–ocean connectivity through groundwater and its potential responses to future anthropogenic activities and climate change will require a multidisciplinary approach combining the expertise of geophysicists, hydrogeologists, (bio)geochemists and modellers. Such joint activities will lay the scientific basis for better understanding the role of groundwater in societally relevant issues such as climate change, pollution and the environmental status of the coastal oceans within the framework of the United Nations Sustainable Development Goals. Here, we present our perspectives on future research directions to better understand land–ocean connectivity through groundwater, including the spatial distributions of the essential hydrogeological parameters, highlighting technical and scientific developments and briefly discussing the societal relevance of that connectivity in rapidly changing coastal oceans.

BackgroundPatients with muscle-invasive bladder cancer face a poor prognosis due to rapid disease progression and chemoresistance. Thus, there is an urgent need for a new therapeutic treatment. The tumor microenvironment (TME) has crucial roles in tumor development, growth, progression, and therapy resistance. TME cells may also survive standard treatment of care and fire up disease recurrence. However, whether specific TME components have tumor-promoting or tumor-inhibitory properties depends on cell type and cancer entity. Thus, a deeper understanding of the interaction mechanisms between the TME and cancer cells is needed to develop new cancer treatment approaches that overcome therapy resistance. Little is known about the function and interaction between mesenchymal stromal cells (MSC) or fibroblasts (FB) as TME components and bladder cancer cells.MethodsWe investigated the functional impact of conditioned media (CM) from primary cultures of different donors of MSC or FB on urothelial carcinoma cell lines (UCC) representing advanced disease stages, namely, BFTC-905, VMCUB-1, and UMUC-3. Underlying mechanisms were identified by RNA sequencing and protein analyses of cancer cells and of conditioned media by oncoarrays.ResultsBoth FB- and MSC-CM had tumor-promoting effects on UCC. In some experiments, the impact of MSC-CM was more pronounced. CM augmented the aggressive phenotype of UCC, particularly of those with epithelial phenotype. Proliferation and migratory and invasive capacity were significantly increased; cisplatin sensitivity was reduced. RNA sequencing identified underlying mechanisms and molecules contributing to the observed phenotype changes. NRF2 and NF-κB signaling was affected, contributing to improved cisplatin detoxification. Likewise, interferon type I signaling was downregulated and regulators of epithelial mesenchymal transition (EMT) were increased. Altered protein abundance of CXCR4, hyaluronan receptor CD44, or TGFβ-signaling was induced by CM in cancer cells and may contribute to phenotypical changes. CM contained high levels of CCL2/MCP-1, MMPs, and interleukins which are well known for their impact on other cancer entities.ConclusionsThe CM of two different TME components had overlapping tumor-promoting effects and increased chemoresistance. We identified underlying mechanisms and molecules contributing to the aggressiveness of bladder cancer cells. These need to be further investigated for targeting the TME to improve cancer therapy.

Abstract Background Family Integrated Care (FICare) benefits preterm infants compared with Family-Centered Care (FCC), but research is lacking in United States (US) Neonatal Intensive Care Units (NICUs). The outcomes for infants of implementing FICare in the US are unknown given differences in parental leave benefits and health care delivery between the US and other countries where FICare is used. We compared preterm weight and discharge outcomes between FCC and mobile-enhanced FICare (mFICare) in the US. Methods In this quasi-experimental study, we enrolled preterm infant (≤ 33 weeks)/parent dyads from 3 NICUs into sequential cohorts: FCC or mFICare. Our primary outcome was 21-day change in weight z-scores. Our secondary outcomes were nosocomial infection, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and human milk feeding (HMF) at discharge. We used intention-to-treat analyses to examine the effect of the FCC and mFICare models overall and per protocol analyses to examine the effects of the mFICare intervention components. Findings 253 infant/parent dyads participated (141 FCC; 112 mFICare). There were no parent-related adverse events in either group. In intention-to-treat analyses, we found no group differences in weight, ROP, BPD or HMF. The FCC cohort had 2.6-times (95% CI: 1.0, 6.7) higher odds of nosocomial infection than the mFICare cohort. In per-protocol analyses, we found that infants whose parents did not receive parent mentoring or participate in rounds lost more weight relative to age-based norms (group-difference=-0.128, CI: -0.227, -0.030; group-difference=-0.084, CI: -0.154, -0.015, respectively). Infants whose parents did not participate in rounds or group education had 2.9-times (CI: 1.0, 9.1) and 3.8-times (CI: 1.2, 14.3) higher odds of nosocomial infection, respectively. Conclusion We found indications that mFICare may have direct benefits on infant outcomes such as weight gain and nosocomial infection. Future studies using implementation science designs are needed to optimize intervention delivery and determine acute and long-term infant and family outcomes. Clinical Trial Registration NCT03418870 01/02/2018.

Abstract Background Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. Methods To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. Results We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Conclusions Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

Abstract Background Correctional settings in South Africa have disproportionately high rates of HIV infection; a large number of inmates living with HIV return to the community each year. The transition community adherence club (TCAC) intervention was a differentiated care delivery approach with structural and peer components designed to increase antiretroviral therapy (ART) adherence and HIV care engagement following release from incarceration. The objective of this study was to assess the acceptability of the TCAC intervention among HIV-infected community re-entrants to inform program revisions and future intervention designs. Methods This was a qualitative study set within a randomized controlled trial (RCT) of the TCAC intervention in South Africa. We conducted semi-structured, in-depth interviews with 16 re-entrants living with HIV and assigned to the intervention arm. All interviews were audio-recorded, transcribed, translated, and de-identified. Transcripts were coded and analyzed using content analysis, and acceptability was assessed using the Theoretical Framework of Acceptability (TFA). Results Overall, study participants reported that the TCAC intervention was acceptable. Development of supportive relationships between participants, non-judgmental attitudes from peer-facilitators, and perceived effectiveness of the intervention to support ART adherence and HIV care were noted as the most valued components. An altruistic desire to help other participants facing similar post-incarceration and HIV-related challenges was a key motivator for TCAC attendance. A lack of access to reliable transportation to intervention sites and clinic-based medication collection were described as burdens to program participation. Illicit drug use by other group members and negative social influences were also identified as potential barriers to optimal program engagement. Conclusion The TCAC was a well-accepted model of differentiated care delivery among re-entrants living with HIV in South Africa. To further enhance intervention acceptability for future scale-ups, program revisions should address logistical barriers related to reaching TCAC sites and implementing ART distribution at TCAC group sessions.

Summary: Genome-wide association studies (GWASs) have identified more than 130 genetic susceptibility loci for migraine; however, how most of these loci impact migraine development is unknown. To identify novel genes associated with migraine and interpret the transcriptional products of those genes, we conducted a transcriptome-wide association study (TWAS). We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 53 tissues and migraine susceptibility using FUSION software. Meta-analyzed GWAS summary statistics from 26,052 migraine cases and 487,214 controls, all of European ancestry and from two cohorts (the Kaiser Permanente GERA and the UK Biobank), were used. We evaluated the associations for genes after conditioning on variant-level effects from GWAS, and we tested for colocalization of GWAS migraine-associated loci and expression quantitative trait loci (eQTLs). Across tissue-specific and multi-tissue analyses, we identified 53 genes for which genetically predicted gene expression was associated with migraine after correcting for multiple testing. Of these 53 genes, 10 (ATF5, CNTNAP1, KTN1-AS1, NEIL1, NEK4, NNT, PNKP, RUFY2, TUBG2, and VAT1) did not overlap known migraine-associated loci identified from GWAS. Tissue-specific analysis identified 45 gene-tissue pairs and cardiovascular tissues represented the highest proportion of the Bonferroni-significant gene-tissue pairs (n = 22 [49%]), followed by brain tissues (n = 6 [13%]), and gastrointestinal tissues (n = 4 [9%]). Colocalization analyses provided evidence of shared genetic variants underlying eQTL and GWAS signals in 18 of the gene-tissue pairs (40%). Our TWAS reports novel genes for migraine and highlights the important contribution of brain, cardiovascular, and gastrointestinal tissues in migraine susceptibility.

In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.

Abstract Sustainability in tourism is a topic of global relevance, finding multiple mentions in the United Nations Sustainable Development Goals. The complex task of balancing tourism’s economic, environmental, and social effects requires detailed and up-to-date data. This paper investigates whether online platform data can be employed as an alternative data source in sustainable tourism statistics. Using a web-scraped dataset from a large online tourism platform, a sustainability label for accommodations can be predicted reasonably well with machine learning techniques. The algorithmic prediction of accommodations’ sustainability using online data can provide a cost-effective and accurate measure that allows to track developments of tourism sustainability across the globe with high spatial and temporal granularity.

Abstract Background Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. Methods Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. Results We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. Conclusions Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.

The severity of rare genetic diseases often varies between individuals, but small sample sizes make it difficult to identify contributing factors. Here, the authors use biobank-scale clinical and genetic data to investigate a role for common genetic variation.

Measurement(s) RNA-seq assay • Proteome Technology Type(s) Whole Transcriptome Sequencing • Mass spectrometry intensity based label-free quantification method Factor Type(s) Effect of HDAC5 overexpression in a range of urothelial cancer cells Sample Characteristic - Organism Homo sapiens

Evidence suggests that plant traits, plant functional diversity, and species diversity are linked to ecosystem functions to different extents. However, these relationships are sometimes inconsistent because of the presence of environmental gradients (e.g. climate, topography, land use) and scale mismatches between sampling units and landscape processes. Relationships between satellite data and vegetation parameters seem to be also case-specific, which hinders the creation of generalizable models. We have built predictive models of structural parameters and species composition across a broad range of climatic and topoedaphic conditions and management practices across grasslands and forests in Germany. For that, we use Sentinel multitemporal imagery and neural networks. Our models manage to explain 50% of the data variability for structural parameters, show high stability, and can generalize well across environmental gradients and sites. We also found that prediction models of biodiversity parameters show lower predictive capabilities. Spatially continuous models of grassland and forest attributes provide vital information on ecosystem functions at landscape scale. Thus, they can contribute to studying the feedback mechanisms between biodiversity, ecosystem functions, and land management at the scales to which ecological processes occur.

Abstract Introduction Despite advances in HIV and HIV co‐morbidity service delivery, substantial challenges remain in translating evidence‐based interventions into routine practice to bring optimal care and prevention to all populations. While barriers to successful implementation are often multifactorial, healthcare worker behaviour is critical for on‐the‐ground and in‐clinic service delivery. Implementation science offers a systematic approach to understanding service delivery, including approaches to overcoming delivery gaps. Behavioural economics is a field that seeks to understand when and how behaviour deviates from traditional models of decision‐making, deviations which are described as biases. Clinical policies and implementation strategies that incorporate an understanding of behavioural economics can add to implementation science approaches and play an important role in bridging the gap between healthcare worker knowledge and service delivery. Discussion In HIV care in low‐ and middle‐income countries (LMICs), potential behavioural economic strategies that may be utilized alone or in conjunction with more traditional approaches include using choice architecture to exploit status quo bias and reduce the effects of cognitive load, overcoming the impact of anchoring and availability bias through tailored clinical training and clinical mentoring, reducing the effects of present bias by changing the cost–benefit calculus of interventions with few short‐term benefits and leveraging social norms through peer comparison. As with any implementation strategy, understanding the local context and catalysts of behaviour is crucial for success. Conclusions As the focus of HIV care shifts beyond the goal of initiating patients on antiretroviral therapy to a more general retention in high‐quality care to support longevity and quality of life, there is an increasing need for innovation to achieve improved care delivery and management. Clinical policies and implementation strategies that incorporate elements of behavioural economic theory, alongside local testing and adaptation, may increase the delivery of evidence‐based interventions and improve health outcomes for people living with HIV in LMIC settings.

Background Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.Methods We undertook an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5′-leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.Results Clones carrying proviruses with 5′-leader defects can cause persistent NSV up to approximately 103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope.Conclusion These findings show that proviruses with 5′-leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5′-leader can help in understanding failure to completely suppress viremia.Funding Office of the NIH Director and National Institute of Dental and Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases (NIAID), NIH, to the PAVE, BEAT-HIV, and DARE Martin Delaney collaboratories.

Ta–Al2O3 composite samples with different compositions are prepared using Field Assisted Sintering Technique (FAST). Two different alumina powders are used to investigate the influence of the starting powders particle size on the microstructural features and the resulting electrical conductivity of the prepared composite materials. Percolation threshold of the two material systems is influenced by the metal fraction, as well as the alumina particle size of the starting powder. The percolation threshold for the fine- and the coarse-grained alumina is found to be at 15 vol.-% Ta and 7.5 vol.-% Ta, respectively. Microstructural investigations show significant differences in terms of particle shape of both, Ta and Al2O3 after sintering, most likely being the reason for the different percolation thresholds of the investigated materials. Anisotropy effects resulting from the processing using FAST and the influence on electrical properties are also shown.

A major barrier to the analysis of genotyping and sequencing data is the relative complexity of the tools needed to perform the analysis. We developed shinyGAStool, an open source tool that enables the user to perform a candidate gene association analysis from large datasets in an easy to use tool from a web browser. With a 3-step workflow, shinyGAStool allows the user to (1) identify and explore distributions of the phenotype and covariates, (2) select genes and variants to evaluate, and (3) run an association analysis linking the two.

Abstract Background HIV testing is the entry point into the HIV care continuum and critical for HIV epidemic control. Facility-based HIV testing services (HTS) reach individuals who are already seeking clinical care and engaging with the medical care system. For this reason, individuals diagnosed with HIV during facility-based HIV testing are more likely to continue into HIV care. To increase the number of PLHIV who are diagnosed and initiated on ART, in 2015, the South African Department of Health instituted Provider-Initiated Counselling and Testing (PICT) policy—encouraging healthcare providers to recommend HIV testing, but this strategy remains under-utilized. We aimed to identify key constraints to the normalization of PICT implementation in 10 Ekurhuleni District healthcare facilities in South Africa. Methods In-depth interviews were conducted with 40 healthcare workers (28 clinicians and 12 lay counsellors). Health care workers were purposefully selected to participate in the interviews, stratified by health facility and work category. Interviews were audio-recorded, transcribed, and translated for analysis. Thematic analysis was guided by the normalization process theory (NPT). NPT theory explains how practices are routinely embedded within organizational contexts. We used NVivo 10 software for qualitative data management. Results Both clinicians and lay counsellors exhibited a clear understanding of the PICT policy— acknowledging its purpose and value. The identified barrier to normalization of PICT among clinicians was offering HIV testing based on suspicion of HIV despite understanding that PICT involves offering testing to all clients. Additionally, clinicians perceived PICT as incongruent with their clinical roles and perceived it to be lay counsellors’ responsibility. The main facilitator was the participation of all healthcare workers, specifically the presence of lay counsellors, although they also faced barriers such as a lack of workspace and under-appreciation. Conclusions Use of NPT helped identify barriers that prevent the normalization of PITC and its integration into routine patient care. These barriers can be modified by low-cost interventions that promote congruence of PICT to the roles of clinicians and integrate the role of lay counsellors within the patient flow in the facility.

BackgroundDespite the health benefits of engaging in regular physical activity (PA), the majority of American adults do not meet the PA guidelines for aerobic and muscle-strengthening activities. Self-efficacy, the belief that one can execute specific actions, has been suggested to be a strong determinant of PA behaviors. With the increasing availability of digital technologies, collecting longitudinal real-time self-efficacy and PA data has become feasible. However, evidence in longitudinal real-time assessment of self-efficacy in relation to objectively measured PA is scarce. ObjectiveThis study aimed to examine a novel approach to measure individuals' real-time weekly self-efficacy in response to their personalized PA goals and performance over the 12-week intervention period in community-dwelling women who were not meeting PA guidelines. MethodsIn this secondary data analysis, 140 women who received a 12-week PA intervention were asked to report their real-time weekly self-efficacy via a study mobile app. PA (daily step counts) was measured by an accelerometer every day for 12 weeks. Participants rated their self-efficacy on meeting PA goals (ranging from “not confident” to “very confident”) at the end of each week via a mobile app. We used a logistic mixed model to examine the association between weekly self-efficacy and weekly step goal success, controlling for age, BMI, self-reported White race, having a college education or higher, being married, and being employed. ResultsThe mean age was 52.7 (SD 11.5, range 25-68) years. Descriptive analyses showed the dynamics of real-time weekly self-efficacy on meeting PA goals and weekly step goal success. The majority (74.4%) of participants reported being confident in the first week, whereas less than half of them (46.4%) reported confidence in the final week of the intervention. Participants who met weekly step goals were 4.41 times more likely to be confident about achieving the following week's step goals than those who did not meet weekly step goals (adjusted odds ratio 4.41; 95% CI 2.59-7.50; P

Tuberculosis (TB) causes 1 in 3 deaths among people living with HIV (PLHIV). Diagnosing and treating latent tuberculosis infection (LTBI) is critical to reducing TB incidence and mortality. Blood-based screening tests (e.g., QuantiFERON-TB Gold Plus (QFT+)) and shorter-course TB preventive therapy (TPT) regimens such as 3HP (3 months weekly isoniazid-rifapentine) hold significant promise to improve TB outcomes. We qualitatively explored barriers and solutions to optimizing QFT+ and 3HP among PLHIV in three cities in Brazil. We conducted 110 in-depth interviews with PLHIV, health care providers (HCP) and key informants (KI). Content analysis was conducted including the use of case summaries and comparison of themes across populations and contexts. LTBI screening and treatment practices were dependent on HCP's perceptions of whether they were critical to improving TB outcomes. Many HCP lacked a strong understanding of LTBI and perceived the current TPT regimen as complicated. HCP reported that LTBI screening and treatment were constrained by clinic staffing challenges. While PLHIV generally expressed willingness to consider any test or treatment that doctors recommended, they indicated HCP rarely discussed LTBI and TPT. TB testing and treatment requests were constrained by structural factors including financial and food insecurity, difficulties leaving work for appointments, stigma and family responsibilities. QFT+ and 3HP were viewed by all participants as tools that could significantly improve the LTBI cascade by avoiding complexities of TB skin tests and longer LTBI treatment courses. QFT+ and 3HP were perceived to have challenges, including the potential to increase workload on over-burdened health systems if not implemented alongside improved supply chains, staffing, and training, and follow-up initiatives. Multi-level interventions that increase understanding of the importance of LTBI and TPT among HCP, improve patient-provider communication, and streamline clinic-level operations related to QFT+ and 3HP are needed to optimize their impact among PLHIV and reduce TB mortality.

Metastatic clear cell renal cell carcinomas (ccRCCs) are resistant to DNA-damaging chemotherapies, limiting therapeutic options for patients whose tumors are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCCs were frequently characterized by high levels of endogenous DNA damage and that cultured ccRCC cells exhibited intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage–sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) with the orally administered, potent, and selective drug M4344 (gartisertib) induced antiproliferative effects in ccRCC cells. This effect was due to replication stress and accumulation of DNA damage in S phase. In some cells, DNA damage persisted into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single-agent treatment with M4344 inhibited the growth of ccRCC xenograft tumors. M4344 synergized with chemotherapeutic drugs including cisplatin and carboplatin and the poly(ADP-ribose) polymerase inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

Abstract Background KDM6A, encoding a histone demethylase, is one of the top ten mutated epigenetic cancer genes. The effect of mutations on its structure and function are however poorly characterized. Methods Database search identified nonsense and missense mutations in the N-terminal TPR motifs and the C-terminal, catalytic JmjC domain, but also in the intrinsically disordered region connecting both these two well-structured domains. KDM6A variants with cancer-derived mutations were generated using site directed mutagenesis and fused to eGFP serving as an all-in-one affinity and fluorescence tag to study demethylase activity by an ELISA-based assay in vitro, apoptosis by FACS, complex assembly by Co-immunoprecipitation and localization by microscopy in urothelial cells and apoptosis by FACS. Results Independent of the mutation and demethylase activity, all KDM6A variants were detectable in the nucleus. Truncated KDM6A variants displayed changes in complex assemblies affecting (1) known interactions with the COMPASS complex component RBBP5 and (2) KDM6A-DNA associated assemblies with the nuclear protein Nucleophosmin. Some KDM6A variants induced a severe cellular phenotype characterized by multiple acute effects on nuclear integrity, namely, release of nuclear DNA into the cytoplasm, increased level of DNA damage indicators RAD51 and p-γH2A.X, and mitosis defects. These damaging effects were correlated with increased cell death. Conclusion These observations reveal novel effects of pathogenic variants pointing at new specific functions of KDM6A variants. The underlying mechanisms and affected pathways have to be investigated in future research to understand how tumor cells cope with and benefit from KDM6A truncations.

Hélène Choquet et al. identify novel loci associated with migraine in a large multiethnic genome-wide meta-analysis. They find 79 loci associated with migraine, including 45 which have not been previously reported and 3 that were specific to women, and which may lead to an improved understanding of migraine etiology.

Abstract Objective The global burden of HIV on women and pediatric populations are severe in sub-Saharan Africa. Global child HIV infection rates have declined, but this rate remains quite high in sub-Saharan Africa due to Mother-to-child transmission (MTCT). To prevent MTCT of HIV, postpartum women living with HIV (WLHIV) are required to return to a health facility for HIV care within 60 days after childbirth (Retention in HIV care). Studies suggest that interpersonal support was positively associated with retention in HIV care. However, information on this association is lacking among postpartum WLHIV in Uganda. Therefore, this study investigates the relationship between interpersonal support, measured with the Interpersonal Support Evaluation List (ISEL-12), and retention in HIV care. Results In a total of 155 postpartum WLHIV, 84% were retained in HIV care. ISEL-12 was negatively associated with retention in HIV care. Postpartum WLHIV retained in care (24.984 ± 4.549) have lower ISEL-12 scores compared to the non-retained group (27.520 ± 4.224), t(35.572) = − 2.714, p = 0.01. In the non-income earning sample, respondents retained in care (24.110 ± 4.974) have lower ISEL scores compared to the non-retained group (27.000 ± 4.855), t(20.504) = -2.019, p = 0.049. This was not significant among income earning WLHIV.

The genetic basis of cataract is not well understood. Here, the authors perform a genome-wide association multiethnic meta-analysis of cataract, finding 37 new loci and replicating known and new loci. They additionally perform sex-specific analyses, identifying new associations specific to women.

BackgroundGay and bisexual men are 26 times more likely to acquire HIV than other adult men and represent nearly 1 in 4 new HIV infections worldwide. There is concern that the COVID-19 pandemic may be complicating efforts to prevent new HIV infections, reduce AIDS-related deaths, and expand access to HIV services. The impact of the COVID-19 pandemic on gay and bisexual men’s ability to access services is not fully understood. ObjectiveThe aim of this study was to understand access to HIV services at the start of the COVID-19 pandemic. MethodsOur study used data collected from two independent global online surveys conducted with convenience samples of gay and bisexual men. Both data sets had common demographic measurements; however, only the COVID-19 Disparities Survey (n=13,562) collected the outcomes of interest (HIV services access at the height of the first COVID-19 wave) and only the Global Men’s Health and Rights Survey 4 (GMHR-4; n=6188) gathered pre-COVID-19 pandemic exposures/covariates of interest (social/structural enablers of and barriers to HIV services access). We used data fusion methods to combine these data sets utilizing overlapping demographic variables and assessed relationships between exposures and outcomes. We hypothesized that engagement with the gay community and comfort with one’s health care provider would be positively associated with HIV services access and negatively associated with poorer mental health and economic instability as the COVID-19 outbreaks took hold. Conversely, we hypothesized that sexual stigma and experiences of discrimination by a health care provider would be negatively associated with HIV services access and positively associated with poorer mental health and economic instability. ResultsWith 19,643 observations after combining data sets, our study confirmed hypothesized associations between enablers of and barriers to HIV prevention, care, and treatment. For example, community engagement was positively associated with access to an HIV provider (regression coefficient=0.81, 95% CI 0.75 to 0.86; P