Incorporating the knowledge of people who use/have used drugs into academic research presents the possibility of new ways of understanding drug use, increasing opportunities for equitable outcomes. Community Advisory Boards (CAB) are part of the community-engaged research continuum offering community members clearly defined roles and a structure to advise academic researchers. Acting in an advisory capacity, CAB members have a platform for sharing community-informed knowledge with researchers. The concept of knowledge democracy suggests that not all knowledge is valued equally, with scientific knowledge often considered neutral or more valuable than community knowledge which is sometimes understood as subjective opinion. Transformative change requires an embrace of knowledge that extends beyond the sole perspective of academic research to embrace multiple ways of knowing. We used directed content analysis to analyze minutes from 43 monthly CAB meetings, focusing on member knowledge about opioid use and overdose. We centre the expertise of people who use/have used drugs and propose that academic researchers should listen to and embrace knowledge that is held by the communities and people being studied. (1) identify and describe the knowledge Massachusetts CAB members shared with academic researchers and each other during a federally-funded study to reduce opioid overdose fatalities and (2) centre the contributions of community knowledge for the study. Three themes were identified: (1) CAB members generously shared their knowledge; (2) Members brought attention to root causes of opioid overdose fatalities; and (3) Honest and challenging meeting discussions created solidarity and trust among members and with staff. This case study makes an important contribution to the literature by highlighting the knowledge that a Community Advisory Board, including people with lived and living experience of drug use, can bring to substance use research. By centreing the voices of people with lived and living experience, front line staff, and family members, the study confirms that a substance use research-focused CAB can be an important source of valuable knowledge, contributing to the development of knowledge democracy. The HEALing Communities Study Massachusetts Community Advisory Board members - people with lived and living experience with their own or family member drug use, harm reductionists, recovery coaches, and public health advocates committed to saving the lives of people who use drugs - were active participants in the HEALING Communities Study. They were involved in local, statewide and national levels of the study, including community coalitions, study cores, the national steering committee, and dissemination, acting as advisors and consultants with staff throughout the 4 years of the study and beyond. Eighteen months after the study officially ended, members continue to stay in frequent contact with each other and staff and many chose to be co-authors of this manuscript.
Out-of-hospital cardiac arrest is a leading cause of death in Europe, with most events occurring at home. Early recognition and initiation of resuscitation improve survival and neurological outcomes, yet they are not consistently performed by bystanders. School-based initiatives such as "Kids Save Lives" promote basic life support (BLS) training and encourage schoolchildren to disseminate this knowledge within their families. However, evidence on how this transfer occurs and how it can be assessed remains limited. To map how BLS knowledge transfer from schoolchildren to family members and friends has been implemented and evaluated, and to identify potential key limitations for measurement and reporting. A scoping review was conducted following PRISMA-ScR. Searches were performed in PubMed, Scopus, and Web of Science in February 2026. Studies involving adolescents (10-19 years) trained in BLS at school who subsequently taught family members and friends were included. Evidence was synthetized descriptively, focusing on training characteristics, transfer processes, and reported outcomes. Four quasi-experimental studies and one prospective observational study were included. Training was mainly based on self-instruction kits, and knowledge transfer was typically conducted without supervision. Outcomes focused primarily on theoretical knowledge, with limited assessment of practical skills or long-term retention. The reported multiplier effect ranged from 0.33 to 4.9, with substantial variability and inconsistent measurement. Schoolchildren may act as transmitters of BLS knowledge to family members and friends, but current evidence is limited, heterogeneous, and largely based on indirect or self-reported outcomes. More structured and standardized approaches are needed to better understand, evaluate, and optimize this potentially relevant knowledge transfer process.
The insulin superfamily constitutes a phylogenetically conserved hormonal system that critically regulates growth, metabolism, and reproduction in Metazoa. However, the functional diversification and the architecture of its regulatory networks of this superfamily remains poorly characterized in crustaceans. Here, we identify and characterize two little-studied insulin superfamily genes in the Pacific white shrimp Litopenaeus vannamei, gonadulin (LvGon) and insulin-related peptide (LvIRP). LvGon is predominantly expressed in neural tissues (brain and thoracic ganglia), while LvIRP is specifically enriched in the ovary. Notably, both of them show significantly elevated expression during the D3-D4 pre-molt stages of the molting cycle. Integrated RNA interference (RNAi) and transcriptomic analysis revealed that knockdown of either LvGon or LvIRP induces elevated hemolymph glucose levels and retarded somatic growth. Furthermore, silencing of either gene significantly increased cumulative molting rates, accompanied by activated ecdysone signaling and enhanced glycogenolysis, highlighting the central role of insulin signaling in balancing energy allocation and developmental homeostasis. Transcriptomic analysis revealed that LvGon knockdown remodeled lipid metabolism pathways in both the hepatopancreas and ovary, including PPAR, cAMP, and eicosanoid signaling, causing lipid dysregulation and oocyte developmental suppression. Based on integrated RNAi-transcriptomic data, we propose a hierarchical regulatory model in which LvGon functions as an upstream modulator that positively regulates a downstream functional module comprising LvIRP and LvILP1. This study provides mechanistic insight into crustacean insulin signaling organization, offering valuable perspectives on arthropod endocrine evolution and potential molecular targets for the genetic improvement of shrimp growth and reproduction.
Ethics committees (ECs) play a central role in ethical oversight and in protecting research participants. However, empirical evidence on their composition and practices in Portugal remains limited. The aim of this study was to characterize members of ECs, assess their activity and main constraints, and explore their views on the assessment of informed consent (IC) in research. A cross-sectional observational study was conducted between March and June 2025 using an anonymous online questionnaire distributed to ECs in healthcare institutions, higher education institutions and research centers. The survey collected sociodemographic data, information on EC composition and functioning, and perceptions regarding IC documents. Eighty-one EC members participated. Most respondents were women (63.0%), aged 51 - 60 years (33.3%) or 61 years and older (30.9%), and nearly half had more than five years of EC experience (49.4%). The ECs represented were mainly based in healthcare institutions (50.6%) and higher education institutions (42.0%). The most frequently reported constraints were lack of training (87.7%) and insufficient time allocated to EC work (79.0%). Respondents reported no previous training in bioethics (56.8%) or data protection (47.0%). However, requests for revisions to the consent form were frequent, primarily due to unclear language (91.4%). Twenty-one percent rated the IC as poor or average, identifying lack of investigator training as the main reason. Regarding withdrawal of consent, 35.8% stated that it would depend on compliance with certain formalities, whereas 5,0% reported not knowing. In addition, nearly half of the respondents (45.7%) indicated that they had no personal experience in obtaining IC. Variability emerged regarding the importance attributed to certain consent components, particularly study conditions and procedures related to the communication of new information, the format of data retention, and contact details for the EC and the data protection officer. Portuguese EC members recognize informed consent as a central ethical safeguard, but their responses reveal heterogeneity in the assessment of some informational components, together with structural constraints related to training and time allocated to EC activities. Strengthening training, harmonizing guidance and improving institutional support may enhance the consistency and pedagogical value of EC review. Introdução: As comissões de ética (CE) desempenham um papel central na supervisão ética e na proteção dos participantes em investigação. Porém, os dados sobre a sua composição e atividade em Portugal permanecem limitados. Este estudo teve como objetivos caracterizar os membros das CE, avaliar a sua atividade e constrangimentos percecionados, e explorar as suas perspetivas sobre a avaliação do consentimento informado (CI) na investigação. Métodos: Foi realizado um estudo entre março e junho de 2025, com recurso a um questionário anónimo online distribuído a CE em instituições de saúde, ensino superior e centros de investigação. O questionário recolheu dados sociodemográficos, informação sobre a composição e o funcionamento das CE e perceções relativas aos documentos de CI. Resultados: Foram obtidas 81 respostas. A maioria dos inquiridos era do sexo feminino (63,0%), tinha 51 - 60 anos (33,3%) ou ≥ 61 anos (30,9%) e mais de cinco anos de experiência em CE (49,4%). As CE que responderam pertenciam sobretudo a instituições de saúde (50,6%) ou ensino superior (42,0%). Os principais constrangimentos identificados foram a falta de formação (87,7%) e a ausência de tempo de trabalho dedicado (79,0%), sendo frequente a ausência de formação em bioética (56,8%) e em proteção de dados (47,0%). A maioria referiu utilização de modelo padrão de CI (74,1%), mas os pedidos de revisão por linguagem pouco clara foram frequentes (91,4%). Vinte e um por cento classificaram os CI como fracos ou medianos, atribuindo-o à falta de formação dos investigadores. Quanto à revogação do CI, 35,8% consideraram-na dependente de formalidades e 5,0% não souberam responder. Além disso, 45,7% indicaram não ter experiência pessoal na obtenção de CI. Verificou-se variabilidade na importância atribuída a componentes como condições do estudo e procedimentos para novas informações, formato de conservação dos dados e contactos da CE e do encarregado da proteção de dados. Conclusão: O CI é reconhecido como central, mas as respostas revelam heterogeneidade na avaliação de alguns componentes, a par de constrangimentos estruturais relacionados com a formação e o tempo dedicado no horário de trabalho. O reforço da formação, a harmonização de orientações e maior apoio institucional poderão aumentar a consistência e o valor pedagógico da revisão ética.
Inadequate access to clinical bacteriology testing in low-resource settings compromises individual patient care and contributes to antimicrobial resistance. Funders, policy makers, and health administrators working to expand bacteriology testing in sub-Saharan Africa require evidence-based guidance. The aim of this study was to assemble a costed consensus list of minimum equipment and consumables required to implement and operate a functional clinical bacteriology laboratory in secondary and tertiary care hospitals in sub-Saharan Africa, to guide funders and health administrators. A consensus list of minimum materials for diagnosing bloodstream infections was assembled by experts from Africa, North America, and Europe, representing academia, funders, and implementers. A modelling study was performed to estimate costs across several testing scenarios developed using a formal framework for forecasting testing volumes and reagent usage. Outcomes assessed were consumable costs per hospital admission and per investigation of septic episode and costs of non-recurring items at the time of establishment of a laboratory. Data from two accredited bacteriology laboratories providing individual patient care in Benin and Ethiopia were used to inform expected positivity rates, reagent usage, and testing volumes. Supplier quotes from North America and Europe were used to provide average unit costs and 95% uncertainty ranges. The estimated mean consumable cost per hospital admission was, in 2023 USD, $6·23 (95% uncertainty range 5·42-7·54) in the strict minimum scenario and $10·86 (9·82-12·31) in the standard scenario. The mean cost for the minimal equipment list at the time of establishment of a laboratory was estimated at $30 763 (28 403-33 043; plus an annual equipment maintenance cost of $3076 [2840-3304]), which includes purchase of commercial quality control strains and other non-recurring consumables. Available data suggest that costs from national distributors in sub-Saharan Africa could be three-fold higher than those described. Finally, we provide a transparent and adaptable basis for estimating minimal testing volumes and reagent usage, enabling tailored procurement planning in regions currently without clinical bacteriology laboratories. These results inform national antimicrobial resistance action plans on supply procurement, costing, and the ability to benchmark and forecast minimal acceptable testing volumes for the diagnosis of bloodstream infections for individual patient care. Fonds de recherche du Québec - Santé.
Selective lipophagy requires cargo recognition and recruitment of autophagy receptors to lipid droplets (LDs), yet the molecular mechanisms that couple LDs to the core autophagy machinery remain poorly defined. Here, we identified the small GTPase RAB18 (RAB18, member RAS oncogene family) as an upstream initiator of lipophagy that directly recruited the macroautophagy/autophagy receptor OPTN (optineurin) to LDs in osteoblasts. Lipid stress induced RAB18 activation and its localization to LDs, where RAB18 engaged OPTN enabling OPTN-LC3 bridging and lysosomal degradation of LDs. Loss of either RAB18 or OPTN impaired lipophagic flux, resulting in lipid accumulation and defective osteogenic differentiation, whereas OPTN overexpression partially rescued RAB18 deficiency, supporting a hierarchical RAB18-OPTN pathway. Thus, while OPTN acted as a critical effector downstream of RAB18, it did not feed back to promote RAB18 recruitment. In vivo, perturbation of this axis compromised bone regeneration under hyperlipidemic conditions. Together, these findings establish RAB18-dependent recruitment of OPTN as a molecular mechanism for selective lipophagy and reveal lipophagy as a critical metabolic adaptation that sustains osteoblast function during lipid stress.Abbreviations: AAV: adeno-associated virus; ALP: alkaline phosphatase; Baf A1: bafilomycin A1; CC domain 1: coiled-coil domain 1; CCK-8: cell counting Kit-8 kit; Co-IP: co-immunoprecipitation; ER: endoplasmic reticulum; HE: hematoxylin and eosin; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; LDs: lipid droplets; Micro-CT: microscopic computerized tomography; OE: overexpression; OPTN: optineurin; qRT-PCR: quantitative real-time polymerase chain reaction; RAB18: RAB18, member RAS oncogene family; ROI: region of interest; SD: standard deviations; TBK1: TANK binding kinase 1; TEM: transmission electron microscopy; WB: western blot.
This study aimed to develop consensual definitions and semiquantitative scoring for structural damage on ultrasound and to test the reliability of individual components of a global Outcome Measures in Rheumatology ultrasound joint damage score (GLODS) in rheumatoid arthritis (RA). A Delphi survey including statements on normal ultrasound appearance of joint features, scanning technique, new definitions, and scoring systems for 3 components of structural damage (bone erosions, cartilage change, and joint malalignment) was circulated among task force members. After agreement (≥75% of grades 4-5 on a 1-5 Likert scale) was achieved on the statements, datasets of ultrasound images representing various grades of the above-mentioned structural damage components were created and used in 2 web-based exercises. Finally, the metacarpophalangeal joints 1 to 5 of 7 patients with RA were scanned with ultrasound, twice on the same day by 7 task force members for detecting and scoring the 3 components using the consensus-based semiquantitative GLODS. Intraobserver and interobserver reliability of the new scoring system was measured by weighted kappa. Agreement on a total of 9 statements was reached in 4 Delphi rounds. Intraobserver and interobserver reliability for the individual components ranged from good to excellent in both the web-based (0.72-0.97) and the live exercises (0.68-0.89). Intraobserver and interobserver reliability of the total GLODS was shown to be excellent (0.92) and good (0.69), respectively. Ultrasound is a reliable tool for evaluating bone erosions, cartilage change, and joint malalignment in the hand joints of patients with RA. These features can be reliably integrated into a global ultrasound score.
This report investigates the role of creative health assets in addressing health inequalities across Stoke-on-Trent and Staffordshire. The project aimed to map and align arts-based interventions delivered by voluntary, community, faith and social enterprise (VCFSE) organisations with public health priorities and to explore how these assets respond to hyperlocal needs and contribute to community health and wellbeing. A scoping exercise was conducted from January to May 2024 as part of a Transdisciplinary Placement (TDP) within the National Institute for Health and Care Research (NIHR) School for Public Health Research (SPHR). The methodology included a literature and strategy review, analysis of public health data and two online engagement sessions with the NIHR SPHR's Public Health RESearch for Health (PHRESH) Public Advisory Committee (PAC). Through desk-based research and network engagement, over 100 creative health assets were identified, with Stoke Creates being a key partner and stakeholder. Findings revealed the prevalent but under-recognised and underutilised landscape of creative health assets, including arts organisations, charities and cultural networks. PAC members highlighted the benefits and barriers to engagement, including financial constraints, cultural competency gaps and limited visibility of opportunities. Strategic disconnects between cultural and public health policies were identified, alongside opportunities for future integration. Overall, these assets play a vital role in promoting mental and physical wellbeing, fostering social cohesion and addressing social determinants of health. Creative health assets and arts-based interventions offer significant potential to reduce health inequalities and improve public health outcomes in Stoke-on-Trent and Staffordshire. Greater recognition, investment and strategic alignment are needed to embed creative public health approaches within local governance and health systems. Future work will focus on comprehensive asset mapping including associated health outcomes and impact, research on the role of heritage and green-blue infrastructure, and the development of a creative health network for the region. Creativity and community for better health in StaffordshireThis project looked at how creativity and the arts can help improve people’s health and wellbeing in Staffordshire and Stoke-on-Trent, areas where many people face serious health challenges. It focused on organisations and places, like community centres, theatres, museums and charities that use creative activities to support health. These are called creative health assets. The research was part of a placement funded by the National Institute for Health and Care Research (NIHR). It involved reviewing local health data, public health and cultural strategies, and identifying over 100 creative health organisations across the region. The project also included two group sessions with members of the public, where people shared their experiences of creative activities and how these helped their mental and physical health. People described creative health as empowering, calming and a way to connect with others. Activities like gardening, music, walking and crafts were seen as important for wellbeing. However, many also said that cost, lack of awareness of activities and cultural barriers made it hard to access these opportunities. The findings show creative health assets are a valuable but often overlooked part of public health. They can help reduce health inequalities and support people in ways that traditional healthcare might not. The next phase of the project will focus on mapping these assets more fully, exploring how nature and green spaces, and heritage, can be part of creative health, and working with local organisations to build a stronger network. Creativity is about arts, health and community towards better health for everyone.
Introduction The growing use of digital technologies in medical education has increased the demand for faculty proficiency in video editing and multimedia content creation. Video-based learning enhances student engagement and understanding. However, many educators lack formal training in video production and editing tools. This study aimed to evaluate the effectiveness of a national-level workshop designed to improve video-editing skills among medical faculty members from across India. Methods A hands-on national-level workshop on video editing and digital content creation was conducted for medical educators representing various institutions across India. The training covered essential video-editing techniques, including clip trimming, sound optimization, green screen removal, text addition, transitions, and AI-assisted content creation. Participants undertook pretest and posttest assessments to evaluate their knowledge gain. In addition, structured feedback questionnaires were used to assess participant satisfaction, confidence, and the perceived usefulness of the training. Results A total of 75 faculty members participated in the workshop, of whom 70 (93.3%) completed both the posttest and feedback evaluation. The mean test score increased from 4.8/10 in the pretest to 8.9/10 in the posttest, representing an 85.4% improvement in performance. Marked gains were observed across all assessed skill domains, including identification of video formats, use of editing tools, audio optimization, green screen removal, trimming and merging clips, text and transition effects, and color correction. Statistical analysis using a paired t-test demonstrated a significant improvement in participant performance following the workshop (p < 0.001). Feedback analysis revealed a high level of participant satisfaction, with all respondents (70/70, 100%) reporting improvement in their video-editing skills and 62/70 (88.6%) expressing confidence in applying the acquired techniques in their teaching practice. Furthermore, most participants rated the workshop highly for its relevance, clarity of instruction, and hands-on learning approach. Conclusions The workshop significantly enhanced participants' video-editing knowledge, skills, and confidence. Structured hands-on training programs are effective in enhancing digital competencies among medical educators and facilitating the integration of innovative multimedia resources into medical education.
The aim of this systematic review was to synthesize current evidence on end-of-life (EOL) communication in surgical and neurocritical care settings. While effective EOL communication is essential to support patient-centered decision-making and ethical care, its implementation in surgical and neurosurgical contexts remains inconsistent and insufficiently characterized. Using advanced search terms, a systematic review of the literature was conducted, comprising PubMed and Scopus. Studies published from January 2016 to January 2026 were included if they involved adult patients, family members, or clinicians engaged in EOL communication within surgical, neurosurgical, or oncological settings and reported empirical data on communication practices, barriers, ethical issues, family involvement, or training interventions. Observational, interventional, and qualitative studies were eligible. Due to substantial heterogeneity in study design and outcomes, findings were synthesized qualitatively. Twenty-six studies met the inclusion criteria. Across studies, EOL communication was characterized by significant challenges related to time constraints, emotional burden, prognostic uncertainty, and variability in clinician communication skills. Structured training interventions, particularly simulation-based programs, were associated with improved clinician confidence and perceived competence, although their implementation was inconsistent. Neurosurgical and neuro-oncological settings presented distinct challenges, including rapid disease progression, early cognitive impairment, and increased reliance on family members for surrogate decision-making. Ethical dilemmas surrounding medical futility, autonomy, and conflict resolution were recurrent. The available evidence highlights persistent gaps between recommended and actual EOL communication practices in surgical and neurocritical care. Improving outcomes will require earlier and structured communication, formal training embedded in surgical education, and multidisciplinary collaboration. Future research should prioritize prospective designs and standardized outcome measures to strengthen the evidence base and support more informed clinical decision-making for patients, families, and clinicians. Systematic review registration no.: CRD420261320726 (www.crd.york.ac.uk/prospero/).
Fibroblast growth factor 21 (Fgf21) is a member of the endocrine subfamily of fibroblast growth factors. In mammals, FGF21 regulates glucose and lipid metabolism, and energy balance. Fgf21 was recently demonstrated to stimulate feed intake and regulate energy balance in zebrafish. The physiological mechanisms that regulate energy balance are tightly interlinked with reproduction. As a first step to extend our original findings on Fgf21 and energy balance, this research aimed to determine whether Fgf21 regulates the reproductive axis in zebrafish. Using quantitative PCR, we demonstrate the expression of fgf21, its receptor fgfr1c, and co-receptor β-klotho; and FGF21-like immunoreactivity (immunohistochemistry) in the zebrafish ovary and liver cells. These results suggest local production of FGF21 and possible actions within the ovary. Single intraperitoneal (IP) injection of 1, 10, or 100 ng/g bodyweight FGF21 significantly (ANOVA, P < 0.05) upregulated reproductive hormone genes in the brain; gonadotropin-releasing hormone isoforms (sgnrh/cgnrh-III) and kisspeptin (kiss1), and gonads; aromatase (cyp19a1a) and gonadotropin receptors (fshr, lhr) that are critical for reproductive success. FGF21 significantly (ANOVA, P < 0.05) upregulated vitellogenin transcript levels and total vitellogenin concentration (ELISA) in zebrafish liver cells at 1 h and 24 h post-incubation, respectively. Lastly, at 100 ng/mL, FGF21 induced (ANOVA P < 0.05) oocyte maturation in vitro (determined by germinal vesicle breakdown quantification). These results support a very strong positive role for Fgf21 in the reproductive endocrine axis of zebrafish.
To explore the experiences, evolving needs, key pain points, and service touchpoints of patients with temporary ostomies during the dual transition, and develop a patient journey map to guide nursing practice and enhance patient experience. A descriptive qualitative study following the Standards for Reporting Qualitative Research (SRQR). Between December 2025 and March 2026 in Shanghai, China, 19 patients with temporary ostomies were recruited. Data were collected via semi-structured interviews, analysed using framework analysis, and synthesized into a visual patient journey map. Thirty-two initial codes were identified and, guided by the Fitch supportive care needs framework, synthesized into four dimensions and 16 subthemes. Mapped across four stages of the patient journey: (1) preoperative phase, characterized (survival-driven decision-making and limited understanding); (2) early postoperative phase, marked (tangible impacts and a knowledge-action gap in skill acquisition); (3) transitional care phase, (trial-and-error adaptation and lifestyle reconstruction); and (4) stoma reversal waiting phase, (tension between the desire for "normalcy" and uncertainty regarding bowel function). The visual patient journey map reconstructs the patient experience, highlighting stage-specific behaviours, emotions, needs, and key pain points from initial stoma creation to the stoma reversal waiting phase. This study highlights the phase-specific supportive care needs of patients with temporary ostomies across the identified journey phases. The resulting patient journey map offers insights into key pain points, the progression of needs, and the complex interplay among behaviours, emotions, and service touchpoints. Future research and clinical practice could explore digitally supported follow-up systems, family-centered dyadic empowerment strategies, and front-loaded risk communication as potential avenues to enhance care. Participants contributed to this study by sharing their lived experiences through semi-structured interviews. Three participants also participated in member checking to validate the interpretation of the findings and provide feedback to refine the final map.
The current state of respiratory physical therapy for adult pneumonia in Japan is insufficiently characterized. This study aimed to elucidate the current practices of respiratory physical therapy in Japan, including its implementation specifics, clinical frameworks, and medical reimbursement, with the aim of optimization respiratory physical therapy for adult pneumonia. A cross-sectional questionnaire survey comprising 21 questions was administered to members of the Japanese Society of Respiratory Physical Therapy. The survey items encompassed basic institutional information, existence of protocols, timing of rehabilitation prescriptions, clinical and educational systems for respiratory physical therapy (such as training systems), and content of respiratory physical therapy. The timing of rehabilitation prescriptions for adult pneumonia "varies depending on clinical decision-making by attending physicians" in 35.4% of institutions, and only 8.3% of facilities had established rehabilitation protocols. Furthermore, the most pressing issue concerning respiratory physical therapy for adult pneumonia was identified as "the lack of guidelines for respiratory physical therapy (pulmonary rehabilitation) for pneumonia," with 92 institutions citing this as the most significant problem. The practice of respiratory physical therapy for adult pneumonia in Japan varies across institutions, with a lack of reference materials, including clinical practice guidelines, potentially contributing to this variability. These findings highlight the need for further research and the development of optimized clinical guidance.
Does NR5A2 (nuclear receptor subfamily 5 group A member 2) play a role in the dysregulation of granulosa cells in polyendocrine metabolic ovarian syndrome (PMOS), which is a common endocrine disorder and a leading cause of anovulatory infertility, and what are its underlying regulatory mechanisms? The mRNA expression levels of NR5A2 and related genes were assessed in human granulosa cells (HGCs) isolated from patients with or without PMOS. To investigate the effects of NR5A2 on inflammation and proliferation of granulosa cells, as well as the underlying molecular mechanisms, in-vitro experiments were conducted using the KGN human granulosa-like cell line. Overexpression of NR5A2 promoted cell proliferation and induced G1-to-S phase transition in KGN cells, at least in part by upregulating cyclin D1 (CCND1) expression. NR5A2 acted as a co-activator of NF-κB p65 (also known as RelA) by increasing its phosphorylation and nuclear localization, thereby increasing CCND1 expression through transcriptional regulation. Furthermore, NR5A2 regulated the IL-1β positive self-regulatory loop via the NF-κB p65 signalling pathway. Up-regulated NR5A2 may contribute to chronic inflammation and aberrant proliferation of granulosa cells by increasing NF-κB p65 activity. These findings highlight NR5A2 as a potential therapeutic target for ameliorating ovarian dysfunction in patients with PMOS.
Cyclin-dependent kinase 9 (CDK9), a key member of the CDK family, plays a crucial role in transcriptional regulation. As its expression is dysregulated in various cancers, CDK9 is regarded as a promising therapeutic target. However, the clinical efficacy of traditional CDK9 inhibitors is limited by potential on-target toxicity, and degradation-based strategies face similar challenges. In recent years, dual-target inhibitors against CDK9 have gradually become a research focus. Our group previously reported a CDK9/EZH2 dual inhibitor, D16, though its activity still required further improvement. Furthermore, to validate the general applicability of this design strategy, we designed a series of new CDK9/EZH2 dual-target inhibitors by conjugating a self-designed CDK9-targeting fragment with a selective EZH2 inhibitor. Among them, compound A9 demonstrated excellent inhibitory activity, with IC50 values of 19.3 nM in U2932 cells and 9.1 nM in KARPAS-422 cells. Compared to single-target inhibitors, its dual inhibitory action significantly increased the apoptosis rate and induced substantial DNA damage in DLBCL cells.
Benthic foraminiferal assemblages are widely used as bioproxy for coastal environment monitoring. The present study investigated seasonal variation in benthic foraminiferal assemblages and their co-occurrence patterns in response to freshwater influx and nutrient dynamics along the northeast coast of the Bay of Bengal. Over a one-year period (2021-2022), benthic foraminiferal communities, sediment total organic carbon and dissolved nutrient concentrations in surface and porewater were analyzed from intertidal zones spanning Junput and Tajpur. The benthic foraminiferal abundance varied seasonally, with Junput showing increased abundance during the post-monsoon, followed by a decline in the pre-monsoon. In Tajpur, the benthic foraminiferal abundance decreased from post-monsoon 2021 to pre-monsoon 2021, then increased in monsoon 2021 samples. The benthic foraminiferal assemblages were dominated by Asterorotalia pulchella, Ammonia sp.1, and Ammonia sp.2. Notably, Asterorotalia pulchella showed a significant positive correlation with monsoonal rainfall and sediment total organic carbon, suggesting its potential as bioproxy for monsoon-influenced environments. Network analysis revealed the negative association between Asterorotalia pulchella and members of Ammonia spp., while Asterorotalia pulchella positively co-occurred with Trochammina inflata and Quinqueloculina seminula during the monsoon. Pearson correlation and multivariate analyses revealed that surface and porewater concentrations of dissolved nitrate and ammonia, along with precipitation, were key environmental variables associated with the spatio-temporal dynamics and co-occurrence patterns within the foraminiferal communities. These findings highlight the responses of benthic foraminifera to episodic nutrient enrichment and freshwater input and underscore their utility in ecological monitoring and paleoenvironmental reconstructions across tropical estuarine systems.
This study aimed to evaluate the use of Indonesian Self-MNA (Mini Nutritional Assessment) as a modest and simple tool to screen the risk of malnutrition in the elderly in the community-based care setting. This formative study involved 20 females, aged 60 and above, who were chosen from a local community health post-elderly program in Depok-West Java, Indonesia. Self-MNA was administered by a health cadre and compared to Full MNA administered by a trained nutritionist as the gold standard. All respondents were female, the mean age was 65.35 years (SD = 4.71), the mean BMI was 24.34 (SD = 2.87), and the mean, median, and mode of the Self-MNA score were 11.6, 12, and 13, respectively. While for the Full MNA, the mean, median, and mode score were 25.35, 25.50, and 22.50, respectively. The sensitivity of Self-MNA compared to Full MNA was 100%, while the specificity was 78.9%. Linear regression test between Self-MNA and MNA showed the r value was 0.675 showing a moderate correlation between Self-MNA and full MNA. The total Healthy Eating Index (HEI) of the respondents was 62.25 or included in the category that needed improvement. Self-MNA is a simple tool that can be administered independently by health cadre or family members, and has shown high level of inter tools reliability and validity compared to the full MNA as a standard. Thus, further development of app-based Self-MNA for elderly nutritional status monitoring maybe feasible.
The unregulated toxic drug supply has had a disproportionate impact on rural communities across Canada, yet most health and social interventions target urban settings. Drawing on the Care Collective's (2020) work on universal care, families often provide care within the larger context of "careless" communities and governments that prioritize economic productivity over relational wellbeing. Although there is a growing body of research on care and caregiving experiences, little is known about the experiences of family caregivers of people who use drugs (PWUD) in rural settings. Using a community-engaged qualitative research design, we conducted semi-structured one-on-one interviews with 31 family members caregiving for a person who uses drugs in rural Prairie communities across Canada. Data were analyzed using reflexive thematic analysis to generate themes. Families of PWUD in rural settings provide robust care as a result of the increasing "carelessness" of communities and governments. Neoliberal policy decisions on public service funding and delivery, combined with systemic stigma and racism, create conditions that shift care responsibilities to families. Caregiving for family and, at times, the wider community can result in significant personal impacts. Despite this, caregivers are vocal about the need for structural reforms to foster communities and governments that are more "caring" for PWUD. The unregulated toxic drug supply has deeply impacted rural communities, placing the burden of care on families. An urgent comprehensive response to the crisis is needed; one that includes rural communities and families. This response should focus on structural changes that reduce sole reliance on family care, enhance resources and infrastructure for community care, adequately addresses families' grief and trauma, and ultimately place care as a central organizing principle in society.
Cultural capital is theorized to comprise both a declarative (i.e., deliberate/conscious) and a nondeclarative (i.e., automatic/unconscious) element, also referred to as "embodied." While the latter is considered crucial in everyday health-related choices and in explaining why members of the higher strata more often make healthier ones, extant quantitative research has been unable to empirically measure it. This study implemented a novel method that measures nondeclarative cultural capital using implicit association tests and embedded it within a high-quality panel drawn randomly from the official Dutch population register (N = 2,436). Both declarative and nondeclarative cultural capital prove to be independently associated with adherence to dietary guidelines and contribute to the relationship between educational attainment and adherence to dietary guidelines. This analysis more validly tests common theorizing on cultural capital's role in stratified health patterns and suggests it is larger than assumed based on research solely relying on measures of declarative cultural capital.
Histone lysine methyltransferases (HKMTs) are a class of enzymes capable of catalyzing the methylation modification of lysine residues on histones. Members of the lysine methyltransferase family, such as EZH2, G9a, DOT1L, NSD2, NSD3, and ASH1L, show overexpression, abnormal activation, or mutations in various diseases. HKMT inhibitors are under intense development, but most have drawbacks such as poor efficacy. Targeted protein degraders (TPDs) offer the benefit of controlling both the enzymatic and non-enzymatic activities of the target protein, serving as a method to offset the limitations of inhibitors. This manuscript presents 31 degraders targeting six lysine methyltransferases, offering insights into their development potential and serving as a valuable reference for pharmacologists and researchers.