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Abstract Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.

We present a genome assembly from an individual Labrus mixtus (the cuckoo wrasse; Chordata; Actinopteri; Labriformes; Labridae). The genome sequence has a total length of 740.60 megabases. Most of the assembly is scaffolded into 24 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 16.49 kilobases in length.

Objective Aboriginal Elders have supported Aboriginal health and wellbeing for generations. Aboriginal Elders also play an important role in guiding those who work in health systems to work in culturally safe ways. The Cultural Exchange Program was developed to encourage reflexivity among non-Aboriginal researchers (N = 6) through experiential learning and relationship building with local Noongar Elders (N = 5). This paper examines the transformative impacts of this program for both the Aboriginal Elders and non-Aboriginal participants.Method The Cultural Exchange Program was developed through an Aboriginal Participatory Action Research (APAR) approach. The Elders and researchers had active involvement and influence over the research process and interpretation of data. Themes were co-created through the APAR approach, including a reflexive thematic analysis and feedback loop.Results For the Elders, the program promoted a desire to educate and bring about change, facilitated healing through truth-telling, and led to experiences of cultural respect. For the non-Aboriginal participants, the program evoked deep respect for the Elders and their knowledges, surfaced unsettling colonial realities, encouraged an inwards reflection, and motivated social justice change.Conclusions These results highlight the transformative and healing experiences which can exist at the intersection of reflexivity, truth-telling, truth-witnessing, and relationship building.

This systematic review aims to explore published research on the use of ChatGPT in language learning between November 2022 and November 2023, outlining the types of papers, methodologies adopted, publishing journals, major research trends, topics of interest, and existing gaps demanding attention. The PRISMA framework was utilized to capture the latest published articles, selecting 36 articles that met the inclusion criteria. Findings extracted from this review include (1) authors worldwide contribute to this topic, with Asia and North America leading; (2) the wide distribution across various journals underscores the interdisciplinary nature of this research topic, such as computer science, psychology, linguistics, education, and other social sciences; (3) empirical research dominates the literature that is published, with the majority focusing on higher education and ethical considerations. Other findings include that ChatGPT plays multifaceted roles, supporting self-directed language learning, content generation, and teacher workflows. Research gaps include the need for diversified scopes, longitudinal studies, exploration of stakeholders’ perceptions, and assessments of feedback quality.

AbstractObjectives Lifestyle promotion during follow-up consultations may improve long-term health and quality of life in endometrial cancer patients. This study aimed to identify barriers and facilitators to improve and sustain a healthy lifestyle that can be translated to behavioral methods and strategies for lifestyle counseling.Methods Endometrial cancer patients from three hospitals were recruited to participate in a semi-structured interview. The data were transcribed and coded. Thematic analysis was applied to identify themes and the behavior change wheel was used as a theoretical framework. Data saturation was confirmed after 18 interviews.Results Barriers included knowledge gaps as well as lack of motivation and environmental opportunities to engage in health-promoting behavior. Facilitators included applying incremental lifestyle changes, social support, positive reinforcements, and the ability to overcome setbacks.Conclusions We propose the following intervention functions: education, persuasion, training, environmental restructuring, and enablement. Suitable behavior change techniques to deliver the intervention functions include information about the consequences of certain behavior, feedback on behavior, credible source, graded tasks, habit formation, restructuring of the environment, prompts/cues, goal setting, action planning, and social support. Including these recommendations in lifestyle counseling could aid lasting lifestyle change since it suits the needs and preferences of patients.

BackgroundGlobally, transgender women have been disproportionately affected by the HIV epidemic, including in Malaysia, where an estimated 11% of transgender women are living with HIV. Available interventions designed specifically to meet transgender women’s needs for HIV prevention are limited. Mobile health, particularly smartphone mobile apps, is an innovative and cost-effective strategy for reaching transgender women and delivering interventions to reduce HIV vulnerability. ObjectiveThis study aims to adapt a theory-based mobile health HIV prevention smartphone app, HealthMindr, to meet the unique needs of transgender women in Malaysia. We conducted theater testing of the HealthMindr app with transgender women and key stakeholders and explored barriers to transgender women’s uptake of HIV pre-exposure prophylaxis (PrEP). MethodsFrom February to April 2022, a total of 6 focus group (FG) sessions were conducted with 29 participants: 4 FG sessions with transgender women (n=18, 62%) and 2 FG sessions with stakeholders (n=11, 38%) providing HIV prevention services to transgender women in Malaysia. Barriers to PrEP uptake and gender-affirming care services among transgender women in Malaysia were explored. Participants were then introduced to the HealthMindr app and provided a comprehensive tour of the app’s features and functions. Participants provided feedback on the app and on how existing features should be adapted to meet the needs of transgender women, as well as any features that should be removed or added. Each FG was digitally recorded and transcribed. Transcripts were coded inductively using Dedoose software (version 9.0.54; SocioCultural Research Consultants, LLC) and analyzed to identify and interpret emerging themes. ResultsSix subthemes related to PrEP barriers were found: stigma and discrimination, limited PrEP knowledge, high PrEP cost, accessibility concerns, alternative prevention methods, and perceived adverse effects. Participants suggested several recommendations regarding the attributes and app features that would be the most useful for transgender women in Malaysia. Adaptation and refinement of the app were related to the attributes of the app (user interface, security, customizable colors, themes, and avatars), feedback, and requests for additional mobile app functional (appointment booking, e-consultation, e-pharmacy, medicine tracker, mood tracker, resources, and service site locator) and communication (peer support group, live chat, and discussion forum) features. ConclusionsThe results reveal that multifaceted barriers hinder PrEP uptake and use among transgender women in Malaysia. The findings also provide detailed recommendations for successfully adapting the HealthMindr app to the context of Malaysian transgender women, with a potential solution for delivering tailored HIV prevention, including PrEP, and increasing accessibility to gender-affirming care services.

Background: Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. Scope of Review: Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. Major Conclusions: We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.

Summary: Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

As tomorrow’s leaders, adolescents are navigating coming-of-age tasks in the context of both the fast-growing promises of technology and the burdens of overwhelming global challenges. The Climate Leaders Fellowship (CLF) is an extracurricular program that supports adolescents interested in environmental sustainability. Program participants are connected with like-minded peers and mentors across the globe who help them develop and implement community-based volunteer projects (CLF, 2022). This study focuses on whether and how participation in CLF shaped adolescents’ development. A directed content analysis approach was utilized to conduct and analyze semi-structured interviews with adolescent CLF participants (n = 9, 89% female). Results indicate that engagement in the program is associated with civic purpose development. Specifically, participants reported experiencing civic reflection, motivation, and action through their CLF involvement. Findings offer supporting evidence that the development of civic purpose may be associated with burgeoning critical consciousness. Recommendations for future programming, study limitations, and implications are discussed.

Summary: Background: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. Methods: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. Findings: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. Interpretation: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. Funding: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children’s. BRACE trial funding is detailed in acknowledgements.

IntroductionA developing theoretical framework for the investigation of tight cultures’ reaction toward members who violate communal norms is societal conditional regard (SCR).MethodsUsing a qualitative interpretive approach, in the current study we investigated the way the Ultraorthodox Jewish community uses SCR to cope with substance use disorders (SUDs), which considered to be a norms violation in closed religious communities. We did so by drawing on in-depth interviews with 14 young men from the Ultraorthodox community in Israel who were diagnosed as having an SUD and were in recovery.Results(a) The community’s socialization process, educating its members to lead a life that is the only right one; (b) The community’s use of God as the one whose love and regard are conditional; (c) The SCR emotional and behavioral practices used by the community toward individuals who violate norms, and (d) How, paradoxically, the use of SCR may eventuate in the initiation of drug use, and within the community itself.DiscussionFindings are discussed in the context of self-determination theory and SCR, and shed light on how tight cultures cope with the threat of deviation of communal norms. Implications for intervention and policy are outlined.

Specialty coffee, comprising a tenth of the global coffee trade, is distinguished by its strict quality requirements and traceable origins. The diverse flavor profiles of specialty coffee raise demands on providers to serve individual taste preferences. Prior research has not sufficiently explored how to predict customer preferences for specific flavor profiles or how these preferences influence behavioral intentions such as revisiting or recommending a café. This study hypothesized that customer involvement, the extrinsic factors of coffee experience, and culinary risk-taking would predict flavor preference, which would in turn affect behavioral intentions. In an experiment involving 47 participants, individuals tasted and evaluated two espresso flavor profiles in a counterbalanced order. Results showed that taking pleasure in buying coffee, an aspect of involvement, significantly predicted preference for a distinctly acidic single-origin flavor profile over a more conventional blend. However, factors such as interest in involvement, sensory and service quality aspects of the café experience, and culinary risk-taking in coffee consumption were not significant predictors of coffee preference. Furthermore, there was no significant relationship between coffee preference and the intention to revisit or recommend the establishment, though individual evaluations of each coffee were predictive of these behavioral intentions. These results refine the existing theory linking specialty coffee consumption and consumer behavior, particularly highlighting the role of acidity in flavor preferences. They also confirm the link between the sensory experience of tasting specialty coffee and subsequent behavioral intentions, applicable across diverse flavor profiles.

Background: Bladder cancer (BCa) is the second most common genitourinary malignancy and has a mortality of 165,000 deaths p.a. The diagnosis of BCa is mostly carried out using cystoscopy - the visual examination of the urinary bladder with an endoscope. White light cystoscopy is currently considered as gold standard for the diagnosis. Nevertheless, especially flat, small or weakly textured lesions, are very difficult to detect and diagnose. Objective: With the advent of deep learning and already commercially available systems for the detection of adenomas in colonoscopy, it is investigated how such a system - for colonoscopy - performs if retrained and tested with cystoscopy images. Methods: A deep neural network with a YOLOv7-tiny architecture was pre-trained on 35,699 colonoscopy images (partially from Mannheim), yielding a precision = 0.92, sensitivity = 0.90, F1 = 0.91 on public colonoscopy data collections. Results: Testing this adenomadetection network with cystoscopy images from three sources (Ulm, Erlangen, Pforzheim), F1 scores in the range of 0.67 to 0.74 could be achieved. The network was then retrained with 12,066 cystoscopy images (from Mannheim), yielding improved F1 scores in the range of 0.78 to 0.85. Conclusion: It could be shown that a deep learning network for adenoma detection in colonoscopy is ad-hoc able to detect approximately 75% of the lesions in the urinary bladder in cystoscopy images, suggesting that these lesions have a similar appearance. After retraining the network with additional cystoscopy data, the performance for urinary lesion detection could be improved, indicating that a domain-shift with adequate additional data is feasible.

Abstract Background High dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy. Methods 3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs ( $$1\times {10}^{6}$$ 1 × 10 6 cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 $$\mu$$ μ M Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining. Results ADSC treatment significantly increased body lean mass (10–20%), muscle wet weight (15–30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45–65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo. Conclusions ADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Abstract Background Desmoid‐type fibromatosis (DTF) has a highly variable clinical course with varying intensity of symptoms. The objectives of this study were to identify subgroups of DTF patients based on physical symptom burden and to compare symptom burden subgroups on health‐related quality of life (HRQoL) and healthcare use (univariate and multivariate). Methods Desmoid‐type fibromatosis patients from the United Kingdom and the Netherlands received cross‐sectional questionnaires on HRQoL (EORTC QLQ‐C30), DTF‐specific HRQoL (DTF‐QoL) and healthcare utilisation. Latent class cluster analysis was performed to identify subgroups based on patients' symptom burden using EORTC QLQ‐C30 and DTF‐QoL physical symptom items. Multivariate linear and logistic regression analyses were conducted to examine associations of symptom burden with HRQoL and healthcare utilisation, respectively. Results Among 235 DTF patients, four symptom burden clusters were identified, with low symptom burden (24%), intermediate symptom burden‐low pain (20%), intermediate symptom burden‐high pain (25%) and high symptom burden (31%). DTF patients with high symptom burden had clinically relevant lower HRQoL scores compared to patients with low and intermediate symptom burden (p

Abstract Background The progressive deterioration of tissue–tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from Ginkgo biloba, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice. Methods Muscle injury models were established by barium chloride induction into the hind limb of 20‐month‐old mice (aged mice) and into C2C12‐derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 μg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings. Results GB administration in aged mice improved muscle regeneration (muscle mass, P = 0.0374; myofiber number/field, P = 0.0001; centre nucleus, embryonic myosin heavy chain‐positive myofiber area, P = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, P = 0.0002; twitch force, P = 0.0005) and exercise performance (rotarod performance, P = 0.002), and reduced muscular fibrosis (collagen deposition, P

Mind–body interventions (MBIs) include mindfulness-based interventions (MiBIs), meditation- and mantra-based interventions (MMIs), and movement-based interventions (MoBIs). These approaches have demonstrated preliminary efficacy in improving posttraumatic stress disorder (PTSD) symptoms. However, previous systematic reviews and meta-analyses have noted that this area of research is limited by inadequate comparator conditions, heterogeneity of measurement, and absence of objective outcome measures. For these reasons, an updated review of the highest-quality evidence available is warranted. We used the Agency for Healthcare Research and Quality (AHRQ)-funded evidence tables for the PTSD-Repository to identify relevant studies and assess the risk of bias as follows: The search was conducted between June 2018 and June 2022, and databases included PTSDpubs (formerly PILOTS), Ovid® MEDLINE®, Cochrane CENTRAL, Embase®, the Cumulative Index to Nursing and Allied Health Literature (CINAHL®), SCOPUS, and PsycINFO®. Twenty-six randomized controlled trials met our inclusion criteria. After identifying studies and retrieving risk of bias information from the PTSD-Repository evidence tables, we extracted additional data and synthesized the evidence. The strength of evidence was rated as low for MiBIs and MMIs, largely due to contradicting results, inconsistent use of active versus passive comparators, and high risk of bias. The strength of evidence for MoBIs was rated as moderate due to individual studies consistently favoring the intervention and a relatively large number of studies and participants. Of the 26 included studies, only two included objective outcome measures. Implications for future MBI research and clinical applications for treating PTSD are discussed.

ABSTRACTEnterococcus faecalis is the leading Gram-positive bacterial species implicated in urinary tract infection (UTI). An opportunistic pathogen, E. faecalis is a commensal of the human gastrointestinal tract (GIT), and its presence in the GIT is a predisposing factor for UTI. How E. faecalis colonizes and survives in the urinary tract (UT) is poorly understood, especially in uncomplicated or recurrent UTI. The UT is distinct from the GIT and is characterized by a sparse nutrient landscape and unique environmental stressors. In this study, we isolated and sequenced a collection of 37 clinical E. faecalis strains from the urine of primarily postmenopausal women. We generated 33 closed genome assemblies and 4 highly contiguous draft assemblies and conducted a comparative genomics analysis study to identify genetic features enriched in urinary E. faecalis with respect to E. faecalis isolated from the human GIT and blood. Phylogenetic analysis revealed high diversity among urinary strains and a closer relatedness between urine and gut isolates than blood isolates. Plasmid replicon (rep) typing further underscored possible UT-GIT interconnection, identifying nine shared rep types between urine and gut E. faecalis. Both genotypic and phenotypic analyses of antimicrobial resistance among urinary E. faecalis revealed infrequent resistance to the front-line UTI antibiotics nitrofurantoin and fluoroquinolones and no vancomycin resistance. Finally, comparing gene presence and absence among urinary and gut strains, we identified 19 candidate genes enriched among urinary strains. These genes are involved in the core processes of sugar transport, cobalamin import, glucose metabolism, and post-transcriptional regulation of gene expression.IMPORTANCEUrinary tract infection (UTI) is a global health issue that imposes a substantial burden on healthcare systems. Women are disproportionately affected by UTI, with >60% of women experiencing at least one UTI in their lifetime. UTIs can recur, particularly in postmenopausal women, leading to diminished quality of life and potentially life-threatening complications. Understanding how pathogens colonize and survive in the urinary tract is necessary to identify new therapeutic targets that are urgently needed due to rising rates of antimicrobial resistance. How Enterococcus faecalis, a bacterium commonly associated with UTI, adapts to the urinary tract remains understudied. Here, we generated a collection of high-quality closed genome assemblies of clinical urinary E. faecalis isolated from the urine of postmenopausal women that we used alongside detailed clinical metadata to perform a robust comparative genomic investigation of genetic factors that may be involved in E. faecalis survival in the urinary tract.

Background: Primary sarcopenia is usually known as age-related skeletal muscle loss; however, other factors like endocrine, lifestyle and inflammation can also cause muscle loss, known as secondary sarcopenia. Although many studies have used different sarcopenia animal models for exploring the underlying mechanism and therapeutic approaches for sarcopenia, limited study has provided evidence of the relevance of these animal models. This study aims to investigate the similarity and difference in muscle qualities between primary and secondary sarcopenia mice models, using naturally aged mice and dexamethasone-induced mice. Methods: 21-month-old mice were used as naturally aged primary sarcopenia mice and 3-month-old mice received daily intraperitoneal injection of dexamethasone (20 mg/ kg body weight) for 10 days were used as secondary sarcopenia model. This study provided measurements for muscle mass and functions, including Dual-energy X-ray absorptiometry (DXA) scanning, handgrip strength test and treadmill running to exhaustion test. Besides, muscle contraction, muscle fibre type measurements and gene expression were also performed to provide additional information on muscle qualities. Results: The results suggest two sarcopenia animal models shared a comparable decrease in forelimb lean mass, muscle fibre size, grip strength and muscle contraction ability. Besides, the upregulation of protein degradation genes was also observed in two sarcopenia animal models. However, only primary sarcopenia mice were identified with an early stage of mtDNA deletion. Conclusion: Collectively, this study evaluated that the dexamethasone-induced mouse model could be served as an alternative model for primary sarcopenia, according to the comparable muscle mass and functional changes. However, whether dexamethasone-induced mice can be used as an animal model when studying the molecular mechanisms of sarcopenia needs to be carefully evaluated. The translational potential of this article: The purpose of sarcopenia research is to investigate appropriate treatments for reversing the loss of skeletal muscle mass and functions. Using animal models for the preclinical study could predict the safety and efficacy of the treatments. This study compared the typical age-related sarcopenia mice model and dexamethasone-induced secondary sarcopenia mice to provide evidence of the pathological and functional changes in the mice models.

Summary: Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2−8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27–2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32–0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69–3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26–0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3–2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

IntroductionGambling is a public health concern. Problem gambling is related to a range of psycho-social risk factors including ethnonational affiliation. Israel is an insightful case to probe problem gambling, given the socio-economic marginalization of Israeli Arabs, the continued exposure of Israelis to stress and the conservative Israeli gambling market. This study aimed to estimate problem gambling severity in Israeli society, characterize the sociodemographic, environmental, mental health, and gambling-related risk factors associated with problem gambling severity, and examine the role of ethnonational affiliation (Israeli Jewish/Arab) as a moderating factor in the associations between these risk factors and problem gambling severity.MethodsA cross-sectional study based on a representative sample of 3,244 Israelis was conducted in 2022, of whom 1,626 had gambled in the previous year. Measurements included Problem Gambling Severity Index, Gambling Behaviors, Perceived Neighborhood Cohesion, Stress, the Patient Health Questionnaire-4, and sociodemographic variables.ResultsLow-risk, moderate-risk and problem gambling were reported by 16.7% of the total sample. The main risk factors for problem gambling were being an Israeli Arab, traditional, residing in a low socio-economic cluster, reporting anxiety symptoms, and higher gambling behaviors, specifically in legal/illegal online gambling. Ethnonational affiliation (Israeli Jewish/Arab) moderated the associations between gambling, illegal online gambling, and problem gambling severity. Higher neighborhood cohesion emerged as a risk factor for problem gambling solely for Israeli Arabs.DiscussionAs an excluded minority, Israeli Arabs may turn to gambling as a method to access the core republican community, thus, exposing themselves to a higher risk of developing problem gambling.

This paper proposes a generalized predictive control (GPC) with constraints and orthonormal Laguerre functions using the simplified model of the primary system (reactor core and intermediate heat exchanger (IHX)) of a prototypical sodium fast reactor (SFR). This paper develops a multiple-input multiple-output (MIMO) GPC with input constraints able to track polynomial references of any degree applied in coolant temperature difference across the core and fractional power. The manipulated variables of the GPC-SFR are the reactivity and the sodium flow rate of the primary and secondary pipes. Moreover, orthonormal Laguerre functions and step down condition number techniques were also applied to avoid the numerical ill-conditioning issue in quadratic programming of large systems. Thus, a GPC type-2 was designed to control fractional power, coolant temperature difference across the core and sodium tank temperature of the SFR primary system when temperature references change according to a linear ramp after reaching their steady-state operation, sustaining 100% power operation on the reactor. In order to analyze the load tracking capability of the GPC-SFR type-2, the load following from 100% fractional power (FP) to 60% FP at 0.8% FP/min rate is simulated. Constraints on the rate of coolant temperature difference across the core and reactivity were applied for the design safety. For comparison criteria, this paper compares the GPC-SFR type-2 with the GPC-SFR type-1, i.e, standard model predictive control (MPC), to verify the viability and superior performance of the proposal regarding: (a) ramp-tracking capability of temperature and load; (b) the rejections of a reactivity disturbance of -1 cent and a secondary sodium inlet temperature disturbance of $+10 ^{o}F$ ; and (c) a simulation with uncertainty in reactor design. The simulations show that the GPC-SFR type-2 overcome the GPC-SFR type-1 robustness and performance.

To comprehensively support national and international initiatives for sustainable development, land cover products need to be reliably and routinely generated within operational frameworks. Coupled with consistent semantics and taxonomies, ensuring confidence in mapping land cover for multiple time periods, facilitates informed decision-making at scales appropriate to multiple policy domains. The United Nations Food and Agriculture Organisation (FAO) Land Cover Classification System (LCCS) provides a taxonomy that comparable at different scales, level of detail and geographic location. The Open Data Cube (ODC) initiative offers a framework for operational continental-scale land cover mapping using analysis-ready Earth Observation data. This study utilised the FAO LCCS framework and the Landsat sensor data through Digital Earth Australia (DEA; Australia’s ODC instance) to generate consistent and continent-wide land cover mapping (DEA Land Cover) of the Australian continent. DEA Land Cover provides annual maps from 1988 to 2020 at 25 m resolution. Output maps were validated with ∼12,000 independent validation points, giving an overall map accuracy of 80%. DEA Land Cover provides Australia with a nationally consistent picture of land cover, with an open-source software package using readily available global coverage data and demonstrates a pathway of adoption for national implementations across the world.

Abstract Background Patient reported outcome measures (PROMs) may be useful for patients with benign liver tumours and cysts (BLTC) to evaluate the impact of treatment and/or guide shared decision making. Yet, a set of PROMs relevant to patients with BLTC is currently unavailable. In this study, we selected a PROMs set for patients with BLTC. Methods Potentially relevant patient reported outcomes (PROs) were selected by psychologist-researchers based on keywords used or suggested by participants of two virtual focus groups meetings consisting of thirteen female BLTC patients with a median age of 50 years. Subsequently, patients were asked to report their most relevant PROs. PROMs identified by systematic literature review and computerized adaptive tests (CATs) in the Patient-Reported Outcomes Measurement Information System (PROMIS) were considered in selecting the final PROMs set to assess relevant outcomes. Results The most important PROs were: insecurity/anxiety (11/12 patients), pain (9/12 patients), fatigue (8/12 patients), and limitations in daily life (5/12 patients). The literature review included 23 studies, which used various generic and disease-specific PROMs, often not measuring (all) relevant PROs. The final selected PROMs set included numerical rating scales for pain, two questions on overall health and quality of life and four PROMIS CATs. Conclusions A PROMs set generically and efficiently measuring outcomes relevant for patients with BLTC was developed and may be used in future research and clinical practice.

Introduction: Early detection of adenomas and polyps is one central goal of colonoscopic screening programs. As the adenoma detection rate (ADR) depends on the experience of the endoscopist, AI-based polyp detection systems can be used for real-time assistance. Hence, to support the physicians such AI-based systems using deep-convolutional neural networks (DCNNS) have been introduced in the past years. One disadvantage of these techniques is the need of a huge amount of labeled training data. Method: We investigate a "human-in-the-loop approach" to minimize the required time to generate labeled training data. The approach is evaluated within the training a YOLOv4 neural network to detect polyps in colonoscopic image data. The performance metrics of the neural network are evaluated on three public datasets. Results: The performance of the YOLO network increased from a precision of 0.88, recall of 0.83, F1 score of 0.86, and a F2 score of 0.86 to a precision of 0.91, recall of 0.87, F1 = of 0.89, and F2 = of 0.88. The interactive labelling of 1,000 images only takes one hours. Conclusion: The proposed "human-in-theloop approach" is capable of generating labelled image data in a minimum of time while increasing the performance metrics as well. For higher performance increase more data can now be labeled within this new approach.

Summary: Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality. Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41. Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations. Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution. Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC.

Introduction: The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described. Objectives: To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires. Methods: sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes. Results: sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered “medicinal signaling lncRNAs”; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered “licensing-responsive lncRNAs”. Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding. Conclusion: In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics.

Cannabis is among the most widely consumed psychoactive drugs around the world and cannabis use disorder (CUD) has no current approved pharmacological treatment. Nicotine and cannabis are commonly co-used which suggests there to be overlapping neurobiological actions supported primarily by the co-distribution of both receptor systems in the brain. There appears to be strong rationale to explore the role that nicotinic receptors play in cannabinoid dependence. Preclinical studies suggest that the ɑ7 nAChR subtype may play a role in modulating the reinforcing and discriminative stimulus effects of cannabinoids, while the ɑ4β2 * nAChR subtype may be involved in modulating the motor and sedative effects of cannabinoids. Preclinical and human genetic studies point towards a potential role of the ɑ5, ɑ3, and β4 nAChR subunits in CUD, while human GWAS studies strongly implicate the ɑ2 subunit as playing a role in CUD susceptibility. Clinical studies suggest that current smoking cessation agents, such as varenicline and bupropion, may also be beneficial in treating CUD, although more controlled studies are necessary. Additional behavioral, molecular, and mechanistic studies investigating the role of nAChR in the modulation of the pharmacological effects of cannabinoids are needed.

Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.

ABSTRACT Vancomycin-resistant E. faecium (VREfm) is a significant public health concern because of limited treatment options. Genomic surveillance can be used to monitor VREfm transmission and evolution. Genomic analysis of VREfm has not been reported for the Dallas/Fort Worth/Arlington, TX, area, which is currently the 4th largest metropolitan area in the United States. Our study aimed to address this gap in knowledge by analyzing the genomes of 46 VREfm strains and 1 vancomycin-sensitive comparator collected during routine fecal surveillance of high-risk patients upon admission to a Dallas, TX, hospital system (August to October 2015). Thirty-one complete and 16 draft genome sequences were generated. The closed VREfm genomes possessed up to 12 extrachromosomal elements each. Overall, 251 closed putative plasmid sequences assigned to previously described and newly defined rep family types were obtained. Phylogenetic analysis identified 10 different sequence types (STs) among the isolates, with the most prevalent being ST17 and ST18. Strikingly, all but three of the VREfm isolates encoded vanA-type vancomycin resistance within Tn1546-like elements on a pRUM-like (rep17) plasmid backbone. Relative to a previously reported typing scheme for the vanA-carrying Tn1546, new variants of the Tn1546 were identified that harbored a combination of 7 insertion sequences (IS), including 3 novel IS elements reported here (ISEfa16, ISEfa17, and ISEfa18). We conclude that pRUM-like plasmids are important vectors for vancomycin resistance in the Dallas, TX, area and should be a focus of plasmid surveillance efforts. IMPORTANCE Vancomycin is an antibiotic used to treat infections caused by multidrug-resistant Gram-positive bacteria. Vancomycin resistance is common in clinical isolates of the Gram-positive pathogen Enterococcus faecium. Among E. faecium strains, vancomycin resistance genes can be disseminated by plasmids with different host ranges and transfer efficiencies. Surveillance of resistance plasmids is critical to understanding antibiotic resistance transmission. This study analyzed the genome sequences of VREfm isolates collected from the Dallas, TX, area, with particular focus on the mobile elements associated with vancomycin resistance genes. We found that a single plasmid family, the pRUM-like family, was associated with vancomycin resistance in the majority of isolates sampled. Our work suggests that the pRUM-like plasmids should continue to be studied to understand their mechanisms of maintenance, transmission, and evolution in VREfm.

Autosomal dominant polycystic kidney disease (ADPKD) is part of a spectrum of inherited diseases that also includes autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, and an expanding group of recessively inherited disorders collectively termed hepatorenal fibrocystic disorders. ADPKD is the most common monogenic disorder frequently leading to chronic kidney failure with an estimated prevalence of 12 million people worldwide. Currently, only one drug (tolvaptan) has been approved by regulatory agencies as disease-modifying therapy for ADPKD, but, given its mechanism of action and side effect profile, the need for an improved therapy for ADPKD remains a priority. Although significant regulatory progress has been made, with qualification of total kidney volume as a prognostic enrichment biomarker and its later designation as a reasonably likely surrogate endpoint for progression of ADPKD within clinical trials, further work is needed to accelerate drug development efforts for all forms of PKD. In May 2021, the PKD Outcomes Consortium at the Critical Path Institute and the PKD Foundation organized a PKD Regulatory Summit to spur conversations among patients, industry, academic, and regulatory stakeholders regarding future development of tools and drugs for ADPKD and autosomal recessive polycystic kidney disease. This Special Report reviews the key points discussed during the summit and provides future direction related to PKD drug development tools.

Abstract Background Determining factors correlated with protective measures against COVID-19 is important to improve public health response. This study describes student opinions related to university COVID-19 preventive measures. Methods In fall 2020, 643 US university students completed an online survey on perception, awareness, and adherence to COVID-19 preventive measures. Outcomes included protocol effectiveness (self or others), protocol adherence (self or others), consequences of protocol violation, knowledge of violations, and level of concern for COVID-19. Multiple linear regression models determined correlates of outcome variables. Covariates included gender, race, residence, area of study, class, and knowledge of someone with a positive COVID-19 test. Results Overall, students agreed with protective measures (equivalent to higher scores). In adjusted linear models, females (versus males) had significantly higher scores for protocol effectiveness (self) (p

ChatGPT is a state-of-the-art generative artificial intelligence (AI) chatbot released by OpenAI in 2022. It simulates human conversation and has the capability to generate different texts at various levels of sophistication in near real time depending upon the user’s skill in creating prompts. While concerns have been raised about academic dishonesty and cheating among students, ChatGPT has significant academic potential for education, particularly in the field of language learning. This research explores the potential of ChatGPT in supporting and empowering Chinese language learners (CLLs) whose first language is English to enhance their writing skills, mainly focusing on the research question: Is there a functional relation between Chinese language learners from low‐income families using ChatGPT after school twice a week and improvements in their Chinese writing? Four participants with varying language proficiency levels were recruited, and their data were analyzed using an ABA design. Over three weeks, they utilized ChatGPT twice a week for approximately 20 min each after school. The students’ writing scores, writing samples, and learning reflections were used to triangulate the data and enhance the data’s trustworthiness. The findings indicate that (1) each participant made a noticeable improvement in their Chinese writing scores during the intervention and reversal phases; (2) ChatGPT played a crucial role in correcting errors and facilitating the development of complete sentence structures; and (3) the students expressed a sense of empowerment through their interactions with ChatGPT. These findings highlight that ChatGPT shows promise as a supportive tool for CLLs from low-income families, reducing educational inequality and promoting equitable access to language learning opportunities.

Abstract Background In palliative care, sleep and circadian rhythm problems are common symptoms. Nonpharmacological interventions are available; however, health care providers are not aware of these or lack the knowledge to effectively implement in practice. This study reports the content and design development of the PRIME™ (Program for Improving & Managing Environments for Sleep) sleep online educational intervention as well as the evaluation of the intervention by practicing nurses with a focus on perceived acceptability and satisfaction. Methods Development of the education employed a multi-step process that assesses the current state of the science in this area (literature reviews), the needs of regional target recipients (hospice/palliative care staff), expert recommendations and views of a national pool of hospice/palliative workers. A cross-sectional, descriptive study with key staff informants evaluated the acceptability and usability of the modules using both scale-response items to rate the content and design of the modules and overall satisfaction and five open-response questions to suggest changes to the educational intervention. Results Among 31 palliative care professionals, most rated the content and design favorably. A total of 20 participants provided suggestions to improve the educational intervention. Their comments were categorized into six themes: Integration into Practice; Content, Exercises and Material Provided by Modules; User Interface and Design; and Adapt and Expand Modules for Public, Family and Caregivers. Conclusions The data suggest that the PRIME™ educational intervention can be an effective tool to train direct-care palliative care professionals on interventions for use in their daily practice. We also demonstrated that the educational intervention is feasible to deliver online and that the online modules appealed to respondents, suggesting that future delivery of the educational intervention can use the same or similar modes of presentation.

Abstract While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF 0.5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.

The relevance of the study lies in the fact that in modern competitive environment for effective business management, the analysis of settlements, namely the state of accounts receivable and accounts payable, which are an integral part of monetary relations and play an important role for risk assessment of the impact on the development of agribusiness is important. The purpose of this study is to improve the methodological support for the analysis of debt security in agribusiness and measures to improve its level as an effective way to manage settlements. Methodological techniques for comparing indicators and ratio analysis techniques were used to analyse calculations. The approaches of scientists to organise the analysis of settlements and debt security assessment in agribusiness are summarised and two phases are highlighted: 1) providing analysis; 2) organising the analytical process. Provisions are determined for the organisation of settlements analysis in terms of tasks, objects, subjects, frequency and stages which include: analysis of structure and dynamics of settlements, analysis of turnover of accounts receivable and payable; analysis of quality of settlements and assessment of debt security. A model of settlement analysis methodology has been proposed with the separation of debt security assessment, accounting and evaluation based on an integral indicator which includes: debt load indicators, structure indicators, quality indicators, and turnover indicators. It has been found that the improvement of methodological support through the introduction of the debt security assessment methodology provides ample opportunities for a comprehensive analysis of agribusiness calculations, enables the identification of threats and is the result of a detailed analysis of calculations. A matrix of measures to improve debt security is considered. The practical value of scientific work lies in the introduction of methods of analysis of settlements with the assessment of debt security, which will control the status of settlements with counterparties, reduce the risk of non-repayment of receivables, determine the need for additional resources to cover accounts payable and contribute to risk reduction