Entrepreneurial activity is shaped by the structure and functioning of the entrepreneurial ecosystem, yet there is limited consensus on how entrepreneurial resilience is defined or measured. This study protocol outlines the development of a novel, empirically grounded measure of entrepreneurial resilience, conceptualised as a multidimensional and dynamic capability that enables adaptation under contextual hardship and resource constraints. Guided by a capability-based framework, the study draws on prior literature and employs qualitative methods, including a multi-round Delphi study and stakeholder interviews and focus groups. The study components will identify context-specific mechanisms and translate expert consensus into measurable and policy-relevant indicators. By setting out a transparent and reproducible methodology, this protocol contributes to the entrepreneurship and behavioural economics literature and provides a foundation for future empirical work and targeted policy interventions to support business continuity in volatile environments.
Recent advances in text-to-image (T2I) generation have led to impressive visual results. However, these models still face significant challenges when handling complex prompts-particularly those involving multiple subjects with distinct attributes. Inspired by the human drawing process, which first outlines the composition and then incrementally adds details, we propose Detail++, a training-free framework that introduces a novel Progressive Detail Injection (PDI) strategy to address this limitation. Specifically, we decompose a complex prompt into a sequence of simplified sub-prompts, guiding the generation process in stages. This staged generation leverages the inherent layout-controlling capacity of self-attention to first ensure global composition, followed by precise refinement. To achieve accurate binding between attributes and corresponding subjects, we exploit cross-attention mechanisms and further introduce a Centroid Alignment Loss at test time to reduce binding noise and enhance attribute consistency. Extensive experiments on T2I-CompBench and a newly constructed style composition benchmark demonstrate that Detail++ significantly outperforms existing methods, particularly in scenarios involving multiple objects and complex stylistic conditions.
Atherosclerosis is a chronic inflammatory vascular disease in which dyslipidemia, endothelial dysfunction, and maladaptive innate immunity jointly drive plaque initiation, progression, and rupture. Among the innate immune mechanisms involved, neutrophil extracellular traps (NETs) have emerged as important amplifiers of endothelial injury, macrophage activation, necrotic core expansion, and immunothrombosis. These findings suggest that restoration of NET homeostasis may help attenuate atherosclerotic progression. Accordingly, plant-derived metabolites have attracted increasing attention because some of them reduce NET-associated readouts in cellular and preclinical models. However, the current evidence base remains uneven. For many polyphenols and flavonoids, the reported anti-NET activity is derived mainly from simplified in vitro systems and may be confounded by pan-assay interference compounds (PAINS)-like assay interference. Therefore, statistically significant reductions in extracellular DNA, reactive oxygen species (ROS), or myeloperoxidase (MPO)-related signals should not be overinterpreted as evidence of selective NET inhibition or clinically relevant efficacy in humans. At present, most plant-derived metabolites should be regarded as hypothesis-generating candidates rather than validated therapeutics. This review summarizes the contribution of NETs to atherosclerosis, critically appraises the pharmacological and translational strength of the available literature on these metabolites, and outlines future directions based on orthogonal NET assays, disease-relevant models, pharmacokinetic grounding, and biomarker-guided clinical studies.
African district-level health facilities and services face many interconnected challenges including infectious disease outbreaks, conflict and insecurity, fiscal austerity, population displacement and climate-related hazards such as heat, flooding and drought. Emergency preparedness and disaster risk reduction plans have often not included the challenges from climate hazards. In this article, we outline six practical steps that a facility can take to assess its vulnerabilities, capacities and climate-related risks, and develop a plan to improve climate resilience and environmental sustainability: (1) a desktop review of the facility and services; (2) contextualisation and planning; (3) an audit of the facility; (4) a focus group discussion; (5) integration and analysis; (6) creation of an action plan. Environmental sustainability needs to be considered simultaneously with climate resilience as the key domains are the same (workforce; energy; water, waste and sanitation; infrastructure and equipment). In addition, the article outlines how to perform a carbon footprint and integrate the findings into one action plan for the facility. The article provides a practical roadmap for evaluating and improving the climate resilience and environmental sustainability of primary care or primary hospital facilities, and readers can access the referenced resources if they need additional details and support.
Due to high morbidity and mortality rates, colorectal cancer (CRC) poses the significant global health challenge, thus early screening is essential to improve patient outcomes. DNA methylation biomarkers have become pivotal tools for detection of CRC, moving from research to clinical use. Key methylation loci (SEPT9, BMP3, and NDRG4) have been identified through genome-wide association studies and candidate gene approaches, then validated with high-throughput technologies, such as methylation arrays and next-generation sequencing. This advancement has led to the creation of clinically approved assays. Notably, the sensitivity of the Cologuard assay for detection of CRC is 92%, while that of the Epi proColon assay is 70%-80%, both outperforming traditional methods like fecal immunochemical testing, which has a sensitivity of 74%. These assays offer non-invasive screening for both average- and high-risk groups, and aid in postoperative monitoring. However, significant challenges remain. Key issues include technical difficulties for detection of low-abundance methylation signals and standardization of sample processing methods. Clinically, managing false results and validating long-term efficacy are problematic. Ethical concerns about overdiagnosis and data privacy also require attention. Future efforts should prioritize technological advancements, like single-molecule sequencing and liquid biopsy integration, along with large-scale prospective studies to validate biomarker utility in diverse populations. Updated guidelines for standardized implementation are also crucial. This review underscores the pivotal role of methylation biomarkers to revolutionize screening of CRC, while stressing the need for interdisciplinary collaboration, and outlines a strategy to address current limitations, ultimately aiming to reduce the global impact of CRC.
Commercial content moderators (CCMs) serve as the hidden first responders of the internet, sifting through flagged user-generated content to keep online platforms safe. In their work, they have repetitive, frequent exposure to traumatic content, including child sexual abuse material, graphic violence, death, hate rhetoric, and more. Yet, relative to other occupations in which trauma exposure is common, the mental health effects of content moderation have received little study. This is in large part because it is a newer profession that arose with the widespread adoption of social media. In this paper, we describe the work and working conditions typical of CCMs and how these contribute to potential mental health impacts. Global labor inequities are discussed with regard to how outsourcing moderation to low- and middle-income countries with stressful working conditions may exacerbate the risk of posttraumatic stress. Research on the mental health effects of content moderation is synthesized. We propose a research agenda for preventing and mitigating the negative mental health impacts of trauma exposure that CCMs experience. Finally, the paper outlines principles for trauma-informed, psychologically safe moderation systems and discusses implications for clinicians, employers, and occupational health professionals.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and prevalent malignancy challenged by early detection, frequent presentation at advanced stages, and high likelihood of postoperative recurrence and metastasis. Despite ongoing research efforts, the 5-year survival rate for PDAC has only marginally improved. Although pharmacotherapy remains the cornerstone of multidisciplinary management strategies for PDAC, treatment options for advanced disease have historically been limited. In recent years, an increasing number of clinical trials have identified novel agents and combination therapies with promising efficacy for advanced PDAC. Immunotherapy has demonstrated significant success across various solid tumors, yet application for PDAC has so far yielded limited clinical benefit. Combination approaches integrating immune checkpoint inhibitors with chemotherapy, radiotherapy, and other therapeutic modalities have shown preliminary evidence of efficacy, although further investigation is necessary. Emerging immunotherapeutic strategies, such as adoptive cell transfer, oncolytic virotherapy, and tumor vaccines, have exhibited potential for PDAC treatment, albeit accompanied by inherent limitations. Hence, a more thorough understanding of the complex tumor microenvironment in PDAC is essential to improve the effectiveness of immunotherapeutic interventions. Personalized and precision-driven combination immunotherapies represent a promising frontier in the future of PDAC treatment. This review outlines recent advances and future perspectives in immunotherapy for PDAC, aiming to inform and enhance therapeutic strategies for this devastating malignancy.
Free Open Access Medical Education (FOAMed) has rapidly transformed emergency medicine learning by offering accessible, on-demand educational resources such as blogs, podcasts, and social media content. However, for physicians, the vast and unregulated nature of FOAMed may be overwhelming and difficult to navigate. This brief report introduces FOAMed as a movement, outlines high-quality starting points for newcomers, and offers guidance on evaluating educational quality and managing conflicting information. By critically engaging with FOAMed and applying it critically and appropriately in clinical contexts, emergency physicians can enhance their ongoing education and professional development.
Generative AI platforms such as ChatGPT, Claude, and Gemini have become de facto mental health resources for millions of users worldwide, driven by accessibility, low cost, anonymity, and growing gaps in professional care. This rapid, unregulated adoption raises urgent concerns: misinformation from AI hallucinations, erosion of data privacy, algorithmic bias, emotional dependency, and the undermining of user autonomy. At the same time, these tools offer real promise as low-barrier entry points to psychoeducation, self-reflection, and support for underserved populations. This policy brief synthesizes the current evidence on public use of general-purpose GenAI for mental health support, outlines both opportunities and risks, and provides actionable recommendations for users, clinicians, developers, and regulators.
Recent research has highlighted the pivotal role of RNA metabolism-related stress responses in the pathophysiology of cardiovascular diseases, particularly atherosclerosis, stroke, atrial fibrillation (AF), and heart failure (HF). Stress granules (SGs) are dynamic, membraneless organelles that arise during RNA metabolism via liquid-liquid phase separation (LLPS), in which mRNA associates with RNA-binding proteins (RBPs). SGs form following translation arrest in response to various external stimuli, resulting in cytoplasmic accumulation of mRNA and RBPs, which subsequently aggregate into membraneless messenger ribonucleoprotein (mRNP) granules, including Cajal bodies, SGs, P bodies, RNA transport granules, and germinal bodies. This review focuses specifically on SGs. SG formation is typically a transient and protective cellular response to stress; however, the dysregulation or persistence of SG formation has been implicated in a range of diseases, including cardiovascular conditions, neurodegenerative disorders, cancers, immune responses, and viral infections. Thus, this review examines the physiology and pathology of SGs, detailing the associated formation, composition, regulation, and function, with a particular focus on the involvement of SGs in cardiovascular diseases (CVDs) and potential therapeutic strategies targeting SGs. Moreover, this review outlines the complete life cycle of SGs and the associated implications in CVD. SGs originate near the endoplasmic reticulum (ER) and mitigate apoptosis by curbing mitochondrial production of reactive oxygen species. SGs can also disrupt the trafficking of specific cargo from the ER to the Golgi apparatus. Furthermore, SGs can repair damaged lysosomes and eventually undergo self-clearance via the autophagy-lysosome pathway. This model provides new perspectives for researchers in cardiovascular medicine, physicians, and translational medical researchers, and may advance our understanding of SG-related pathophysiology and facilitate the identification of novel therapeutic targets for CVDs.
With the advancement of high-resolution techniques and multi-omics strategy, health implications of probiotics are investigated more profoundly, with the focus shifting from live microbial functions to their non-viable, health-beneficial byproducts, referred to as postbiotic components. Emerging evidence suggests these compounds are promising for non-invasive strategies to prevent and treat chronic diseases. Nonetheless, the understanding of their in vivo effects and mechanisms of action still awaits deeper and holistic exploration. This review presents an up-to-date overview of research on the bioactivities of postbiotic components, elucidating how they orchestrate intestinal homeostasis and systemic health via multi-directional communications. It further highlights the downstream metabolic consequences of typical bioactives by fostering crosstalk between gut and the liver, cardiovascular, and neural system. Finally, it outlines current challenges and future directions of research. These intricate interactions underscore that the gut serves not only as a digestive organ but also a nexus influencing physiological and pathological processes through the body. Compounds derived by probiotics are key drivers of intestinal homeostasis and powerful regulators of the physiology of distant organs. With further clinical investigations, they hold promise for establishment of novel postbiotic-targeted therapies to address health challenges in the future.
Climate-related hazards are impacting community health and healthcare provision across the African continent, resulting in increased vulnerability and reduced capacity to withstand further impacts. While it is important to recognise that not all climate-related hazards result in disaster, this is often the case in populations that are already vulnerable, creating a vicious cycle that further increases risk. However, with appropriate multisectoral collaboration, planning and preparedness, community resilience can be strengthened, thereby reducing the likelihood and severity of disasters. Situated at the interface between health systems and communities, primary care providers are uniquely placed to identify climate-related vulnerabilities and emerging risks. Sharing these insights through disaster risk management platforms can inform planning processes and strengthen preparedness and resilience. With this purpose in mind, this article outlines key concepts and approaches in disaster risk management, supported by a real-life case study that illustrates lessons learned and their implications for primary health care, with the aim of better equipping providers to participate in and support resilience-building efforts.
Endometrial receptivity (ER) serves as a critical determinant for successful embryo implantation, yet its molecular complexity and limited clinical assessment methods pose significant challenges. Despite advancements in assisted reproductive technology (ART), recurrent implantation failure (RIF) linked to ER abnormalities persists, creating a need for precise, non-invasive diagnostics. This review outlines ER research, from the biology of the window of implantation (WOI) to the roles of immune components and the microbiome in shaping the receptive microenvironment. Multi-omics integration reveals regulatory networks across transcriptomic, epigenomic, proteomic, and metabolomic levels, with uterine fluid biomarkers emerging as promising non-invasive candidates. The analysis further covers how chronic endometritis (CE), adenomyosis, and polycystic ovary syndrome (PCOS) impair ER: through mechanisms including inflammatory imbalance, microbial dysbiosis, abnormal extracellular matrix remodeling, and hormonal dysregulation. Commercial ER tests face limitations, including insufficient evidence and inconsistent results, which undermine their clinical reliability. A significant translational gap remains between biomarker discovery and clinical application. Current challenges involve technical standardization and data integration, and poor model generalizability. Future progress requires combining multi-omics with artificial intelligence (AI) to establish standardized clinical pathways, advancing ER assessment into precision medicine, and improving global infertility management.
Extracellular vesicles (EVs) are nano-sized vesicles secreted by living cells and ubiquitously present in body fluids. They carry molecular cargo-including proteins, nucleic acids, and lipids-that accurately mirrors the physiological and pathological state of their parent cells, offering a highly promising novel source of biomarkers for liquid biopsy. This review systematically summarizes the progress in biomarker discovery and application of EVs in major diseases such as cancer, neurological disorders, and cardiovascular diseases. It provides an in-depth analysis of the key technical bottlenecks in current EV isolation, characterization, and detection methodologies, and discusses the challenges related to standardization and clinical translation. Finally, the review outlines the broad future prospects in this field, including integrated multi-omics analysis based on EVs, and their potential for early diagnosis, real-time therapeutic monitoring, and prognostic assessment.
Cyclists present with a broad range of musculoskeletal and neurologic injuries, both traumatic and overuse. The Spaulding Cycling Medicine Clinic is a cycling-specific multidisciplinary sports medicine clinic, employing a collaborative approach to management of cycling injury. This paper outlines the clinic structure and the demographics, training habits, injuries, and biomechanics of 323 adult patients across the first 9 years. The most common areas of chronic discomfort in this group were the knee, hip, and lumbar spine, and knee pain was the most frequent complaint that motivated patients to seek care. Neck pain was noted as an area of discomfort more frequently than as a chief complaint. Patients with a chief complaint of low back pain were more likely to demonstrate posterior pelvic tilt and lumbopelvic asymmetry on the bicycle. This is the first work we know of to comprehensively evaluate demographics, clinical presentation, and bicycle fit for a large sample of cyclists.
The dissemination of skills acquired by master surgeons remains an unmet need within the surgical community. Live surgical workshops (LSWs) are envisaged as comprehensive initiatives to foster ongoing learning and skill enhancement for surgeons across all surgical sub-specialties. With advances in technology, these workshops are now being conducted worldwide and are commonly featured in major scientific meetings. A public interest litigation filed in the Supreme Court of India has sparked controversies, raising questions about the utility of LSW and the ethical considerations surrounding their conduct. We provide a comprehensive review of the existing literature pertaining to LSWs. A body of literature related to LSWs was identified, outlining the perceived benefits and risks associated with such workshops. Overall, LSWs were perceived by surgeons to have immense educational potential. However, concerns regarding the perceived benefits for the audience and anticipated issues related to ethics and safety need to be addressed. These appear to be predominantly rooted in qualitative studies that explore the perspectives of surgeons and attendees, rather than in objective quantitative studies that investigate patient safety and outcomes. Recognizing the potential for underreporting adverse events from LSWs, reliance on published figures of equality between groups is at best subject to further studies. Field experts have proposed several interventions to conduct LSWs safely, based on their experience.
The COVID-19 pandemic has significantly affected global respiratory health, with a notable rise in severe and recurrent respiratory infections. Irrational antibiotic use and limited public health measures during the pandemic were perceived by Physicians to have worsened post-COVID respiratory morbidity and to have contributed to the emergence of antimicrobial resistance (AMR). To explore physicians' experiences and perspectives on the rise in post-COVID respiratory infections in Pakistan, with a focus on contributing factors, treatment challenges, and the impact of irrational antibiotic use and antimicrobial resistance on respiratory disease management. A qualitative explorative study was conducted from September to December 2025 with 20 physicians in public and private healthcare settings in Islamabad and Rawalpindi. In-depth interviews using a semi-structured guide explored post-COVID respiratory trends, contributing factors, treatment challenges, and AMR. Data were transcribed, translated, and analyzed through inductive thematic analysis until saturation, following the COREQ reporting guidelines. Physicians reported increased frequency and severity of upper and lower respiratory tract infections including asthma, COPD, and pneumonia, physicians characterized them as often severe, recurrent, and prolonged. Key contributing factors cited by physicians included perceived post-viral immune compromise, comorbidities, environmental factors, behavioral changes, and reduced adherence to preventive measures. Challenges such as irrational antibiotic prescribing, over-the-counter use, and self-medication were cited by physicians as drivers of AMR. Respondents emphasized the need for strengthened diagnostics, antimicrobial stewardship, vaccination, public awareness, and systemic interventions. The increase and severity of post-COVID respiratory infections in Pakistan is due to a combination of factors including lack of immune compromise, socio-environmental and behavioral factors, and irrational antibiotics prescriptions fueling the rising antimicrobial resistance (AMR) perceived by Physicians. It is crucial to integrate public health measures, vaccination, and antimicrobial stewardship to strengthen diagnostics and mitigate the long-term respiratory morbidity and potential future crises of infectious disease. Not applicable.
Clinical medical physics is a profession that intersects with various groups as part of a broader healthcare team, including dosimetrists, radiation therapists, radiologic and MRI technologists, IT specialists, and physicians. Success in this field requires academic and technical excellence as well as comprehensive skills for working effectively within an interdisciplinary healthcare team. When hiring medical physics residents, the selection of well-rounded and highly qualified candidates can be facilitated through a holistic review process that ensures consideration of traditional metrics such as academic performance while also accounting for the importance of various experiences, personal attributes, and intrinsic motivations that impact clinical performance and patient care. The Association of American Medical Colleges (AAMC) emphasizes an overall consideration of Experiences, Attributes, Competencies, and Metrics (EACM) as important for the search process. As part of the healthcare community, medical physics shares the same commitment to high-quality patient care. By adopting the AAMC's EACM framework, medical physics residency programs can strengthen the fairness, rigor, and overall effectiveness of their application review processes-ultimately benefiting applicants, the medical physics community, and the patients we serve. This Society of Directors of Academic Medical Physics Programs (SDAMPP) task report aims to provide information and resources for applying holistic review to the applicant selection process for medical physics residency programs. Our objective is to enable program directors to reevaluate their selection methods in the context of institutional and program missions and goals and to improve the quality and specificity of recruitment by integrating holistic review concepts into their residency recruitment processes. This initiative can inspire change in recruitment practices, aid programs in hiring well-rounded and well-qualified residents, and support the professional growth of our trainees in healthcare. This report provides an overview of holistic reviews and its core principles. We review the current literature and provide evidence from successful implementations of holistic review in other medical fields to illustrate how it can benefit our field. Furthermore, we outline actionable recommendations to facilitate transitioning to a holistic review framework and address potential barriers with practical solutions. A supplemental workbook is provided to guide residency programs in developing their own holistic application review and interview processes. With this report, we aim to provide practical implementation guidelines that will allow residency program directors to implement a selection methodology that comprehensively assesses the full qualifications of individual candidates and ultimately fosters the development of versatile and competent clinical medical physicists who are best equipped to advance the field, meet patient needs, and improve patient care.
Sunvozertinib has emerged as one of the most promising tyrosine kinase inhibitors (TKIs) for previously treated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations, a molecular subset with limited sensitivity to conventional EGFR TKIs and a persistent unmet need especially in the second-line setting. Regulatory approvals have occurred at different doses - 300 mg daily in China based on WU-KONG6 and 200mg daily in the United States based on WU-KONG1B - raising an important question regarding optimal dose selection in clinical practice. In this editorial, we outline the preclinical and clinical evidence supporting sunvozertinib's approval, compare the efficacy and tolerability at 200mg versus 300mg, and discuss other emerging TKIs in this evolving treatment landscape. Finally, we highlight a critical paradox: despite FDA approval, sunvozertinib remains largely inaccessible to patients in the United States.
Levosimendan is a calcium-sensitizing inodilator that has attracted renewed attention for a potential role in the management of cardiogenic shock (CS). The pharmacological profile of levosimendan differs markedly from that of adrenergic inotropes: levosimendan augments contractile force without increasing intracellular calcium or myocardial oxygen demand and, through activation of ATP-sensitive (KATP) potassium channels, produces systemic and coronary vasodilation. Experimental and clinical data also suggest additional protective effects, including modulation of inflammatory pathways, anti-apoptotic activity, and improved mitochondrial function. Although these mechanisms translate into consistent hemodynamic improvement across several studies, large, randomized trials have not demonstrated a consistent survival advantage, likely due to differences in patient selection, treatment timing, and concomitant therapies. Nevertheless, certain clinical groups, such as patients who fail to respond to catecholamines, individuals on chronic β-blockers, and selected perioperative or mechanically supported patients, appear more likely to benefit. Therefore, current guidance favors an individualized rather than universal approach to levosimendan use. Several ongoing investigations, including trials in extracorporeal membrane oxygenation (ECMO)-supported patients and those with septic cardiomyopathy, may help clarify the optimal indications and timing for levosimendan use. This review integrates mechanistic, clinical, and safety data to identify patient profiles most suited to levosimendan therapy and to outline areas where further study is needed.