Game-based learning (GBL) is increasingly used in healthcare education, but educators must choose among diverse modalities (e.g., quiz platforms, apps, serious games and metaverse environments). Comparative evidence on which modalities perform best across learning domains (knowledge, attitudes, and practice) remains limited. To compare the effects of distinct GBL modalities on knowledge, attitudes, and practice outcomes in nursing and medical education and to explore whether comparative effects differ by learner group (pre-licensure students and in-service professionals). PRISMA-NMA-aligned systematic review and Bayesian network meta-analysis. We searched eight databases and trial registries through September 2, 2024, for randomized controlled trials comparing GBL with traditional teaching (TT). Outcomes were transformed to a 0-100 scale and analysed as change from baseline in Bayesian consistency models; random-effects models were selected using deviance information criterion (DIC). Risk of bias was assessed using RoB 2. We report mean differences (MDs) with 95% credible intervals (CrIs) versus TT, ranking probabilities, and subgroup NMAs by learner group. Thirty-one RCTs (n = 3439) were included; 15 contributed complete data to the network. Risk of bias was low in 15 trials and raised some concerns in 16. The network was modest for knowledge (11 trials) and sparse for attitudes (3) and practice (4). Compared with TT, metaverse-based learning showed improved attitudes (MD 15; 95% CrI 12 to 18), based on a single trial. For knowledge and practice, Kahoot-based quizzes (MD 9.1; 95% CrI -8.9 to 27) and app-based learning (MD 4.6; 95% CrI -4.4 to 14) had the highest estimated mean improvements, but credible intervals were wide and included the null for most comparisons. Subgroup rankings differed by learner group, but several comparisons were imprecise and uncertainty was substantial, particularly in sparse networks. GBL modalities may improve learning outcomes compared with TT, but relative effects appear domain-specific and the certainty of rankings is limited by sparse evidence and imprecision. Future trials should prioritise head-to-head comparisons, robust outcome measurement, and longer-term retention and transfer outcomes in both student and in-service populations.
Solid-state spin defects are promising qubits for quantum network nodes. A key challenge toward larger networks is creating defects with high yield into nanophotonic devices while maintaining good optical and spin properties. Here, we demonstrate the creation of single V2 centers in nanopillars fabricated from commercial bulk-grown 4H-silicon carbide using a pulsed above-bandgap (UV) laser. We observe an 11-fold increase in the V2 center occurrence after UV laser illumination. These laser-induced V2 centers exhibit narrow optical line widths and spectral diffusion rates comparable to naturally occurring V2 centers in nanopillars of the same material. Furthermore, we measure a spin coherence time of T2DD=3.6(3)ms under dynamical decoupling, consistent with dephasing by the nuclear-spin bath. This demonstration of the in situ, postfabrication generation of coherent V2 centers in nanostructures in widely available bulk-grown 4H-SiC shows the potential for above-bandgap laser illumination for scalable defect creation in integrated photonic devices.
Fossils of the Ediacara Biota preserve the oldest macroscopic communities that include animals. Classification of many of these taxa has proved contentious. Instead, studies of ecological characters reveal key insights. Here we examine the Ediacaran fossil Spriggina floundersi from the Ediacara Member, Flinders Ranges and surrounding region. Specimens from Nilpena Ediacara National Park (NENP) and the South Australia Museum (SAM) present significant morphological variation. Fossils found in situ on discrete bedding planes at NENP reveal no systematic orientation of features, suggesting variable morphologies formed via biological processes, rather than external forces. Our results support motility in Spriggina, which involved bending about the long axis, propagation of pedal waves, vertical adjustment of the anterior region and horizontal manipulation of repeated body units. A significant number of fossil specimens are bent to the left (right in life). The nature of these bends does not match expectations of anatomical asymmetry and instead constitutes the oldest described evidence of behavioural handedness. Results are consistent with Spriggina as a bilaterally symmetrical, possibly segmented, benthic organism. These characters are unique compared with known Ediacaran ecologies but are common in various extant bilaterian groups, indicating major animal innovations prior to the Phanerozoic.
To examine whether the oncologic adequacy of resection type differs according to biologic risk in small invasive lung adenocarcinoma. We performed a multi-hospital retrospective study of patients who underwent resection for pathologic node-negative lung adenocarcinoma with invasive size ≤2 cm from 2010 to 2022. Tumors were classified as low-risk, high-risk, or very high-risk according to the presence of 0, ≥1, or ≥2 adverse pathologic features including spread through air spaces, lymphovascular invasion, visceral pleural invasion, and high-grade histology. Locoregional recurrence (LR) was evaluated using competing-risk cumulative incidence functions and multivariable Fine-Gray models. Overall survival (OS) and recurrence-free survival (RFS) were assessed using overlap-weighted Cox models. Among 1,436 patients (494 lobectomy, 316 segmentectomy, 626 wedge; median follow-up 45.5 months), 5-year LR remained low across resection types in the low-risk cohort but increased stepwise in the high-risk cohort from lobectomy to segmentectomy to wedge resection. In Fine-Gray models, wedge resection was associated with higher LR than lobectomy in the overall (sHR=3.39, 95% CI 1.86-6.20) and the high-risk cohort (sHR=2.71, 95% CI 1.35-5.47). Hilar N1 station sampling was independently associated with lower LR in the high-risk cohort. In overlap-weighted analyses, OS and RFS favored lobectomy overall. In high-risk tumors, wedge resection was associated with worse RFS (HR=1.62, 95% CI 1.03-2.56). The oncologic adequacy of resection extent varies according to tumor biology in node-negative invasive ≤2 cm lung adenocarcinomas. Low-risk tumors demonstrated low absolute LR across resection types, whereas high-risk tumors showed progressively less favorable outcomes with lesser resection extent.
Travel-related fatigue and circadian disruption (i.e., jet lag) are well-established factors limiting performance in elite men's sport and are recognized contributors to home advantage. Yet evidence from women's professional leagues remains scarce. This study examined temporal trends in home-court advantage and assessed how cumulative travel burden and directional jet lag relate to performance in the Women's National Basketball Association (WNBA). Game location, timing, and performance data from 3489 regular season WNBA games spanning 18 seasons (2007-2024) were analyzed using mixed-effects models adjusted for game time, team and opponent strength, and season. We quantified cumulative travel distance over the preceding seven days and directional jet lag based on eastward or westward travel adjusted for circadian resynchronization. Home-court advantage declined significantly over time (β =  - 0.67, p = .002), from 64.3% in 2009 to 52.3% in 2024, coinciding with improved league-wide travel conditions. Greater recent travel distance was associated with worse performance among away teams (β = -0.04, p = .020), primarily driven by increased points conceded (β = 0.04, p = .018). Eastward jet lag was significantly associated with worse home team performance (β = -0.15, p = .049), with no such associations observed for westward jet lag or among away teams (all p ≥ .399). These findings provide the first large-scale evidence linking travel and circadian disruption to performance in the WNBA. Although home-court advantage has declined, travel-related challenges persist. Incorporating circadian principles into travel and recovery protocols may help improve performance, particularly as game schedules grow more congested with league expansion.
To determine if patients with early rheumatoid arthritis (RA), an inadequate response to methotrexate (MTX-IR), dual seropositivity for anticitrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), plus shared epitope (SE) human leukocyte antigen risk allele would show a superior response to abatacept vs adalimumab. The AMPLIFIED trial (NCT04909801) was a global, phase 3, head-to-head, randomised, single-blind study designed to evaluate treatment response with abatacept vs adalimumab in patients with early RA and MTX-IR, with ACPA, RF, and SE positivity. The primary endpoint was a 50% improvement in the American College of Rheumatology criteria (ACR50) at week 24 in the SE-positive subgroup. Exploratory analyses included biomarkers, immune cell subsets, and patient-reported outcomes (PROs). In all, 338 patients were randomised. Most patients (96%) completed treatment. Baseline demographics, disease characteristics, and glucocorticoid use were balanced between arms. The primary endpoint was not met. ACR50 at week 24 was 59% with abatacept and 60% with adalimumab (adjusted odds ratio [95% CI]: 1.0 [0.6-1.6]). Levels of anti-cyclic citrullinated peptide 2, C-reactive protein, and RF decreased with both treatments. Abatacept and adalimumab had differential impacts on immune modulation, including B-cell homeostasis. Both treatments improved PROs, including pain. Abatacept and adalimumab demonstrated similar rates of adverse events (AEs; 58.0% vs 59.2%) and serious AEs (2.4% vs 3.6%). Patients responded well to both treatments, with no clear advantage of abatacept vs adalimumab. Most patients tolerated their assigned therapies.
Gender inequality shapes women's cancer outcomes through social, economic, and health system factors. This study disaggregated the Gender Inequality Index (GII) to identify which dimensions-reproductive health, educational attainment, workforce participation, and political empowerment-independently influence global female cancer outcomes. We conducted an ecologic, cross-national analysis using data from 185 countries. Age-standardized female cancer mortality-to-incidence ratios (MIRs) were derived from GLOBOCAN 2022. Independent variables included the composite GII and its five components: maternal mortality ratio, adolescent birth rate, female secondary education, labor force participation, and parliamentary representation. Univariable (Bonferroni-corrected significance threshold α = .01) and multivariable (α = .05) linear regressions assessed associations between these indicators and MIR, adjusting for health system variables including universal health coverage (UHC) index, gross domestic product (GDP) per capita, workforce availability, health spending, and radiotherapy access. Univariable analyses showed that GII and all components associated with higher MIR (P < .001 for all except labor participation, P = .026). Upon examining GII components in a multivariable model, higher adolescent birth rate (β = .0014, P < .001), lower female secondary education (β = -.0020, P < .001), and lower women's parliamentary representation (β = -.0022, P < .001) were independently associated with higher female MIR (N = 168, R2 = 0.70). In fully adjusted models accounting for national wealth and system capacity (N = 124, R2 = 0.88), higher UHC index (P < .001) and GDP per capita (P = .007) predicted lower MIR, while adolescent birth rate may be positively associated (P = .084). Structural gender inequalities, particularly those related to reproductive burden, education, and political representation, are linked to poorer female cancer outcomes. Advancing gender equity through reproductive health access, girls' education, and women's leadership is integral to improving cancer outcomes globally.
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Inconsistent and variably interpreted definitions of spasticity, alongside evolving mechanistic understanding, highlight the need for a clear, clinically relevant consensus definition. An international expert panel used a modified Delphi process to develop a concise, clinically applicable definition that reflects current understanding and supports consistent assessment and management. Participants reviewed existing definitions, completed a pre‑meeting survey, and engaged in structured discussions, with draft definitions iteratively refined through successive rounds of voting to achieve consensus. Key components identified included disordered sensorimotor control, central nervous system involvement, and velocity‑ and length‑dependent resistance to passive stretch, while existing definitions were considered either overly narrow or insufficiently relevant to clinical practice. The consensus definition characterizes spasticity as "A disorder of sensorimotor control resulting from upper motor neuron disease. It is characterized by velocity- and length-dependent involuntary muscle overactivity, which is intermittent or sustained, during passive stretch." This definition integrates contemporary mechanistic concepts with clinical applicability and is intended to improve conceptual clarity, facilitate communication, and promote consistency in diagnosis, measurement, and treatment.
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Emerging epidemiological evidence indicates that groups in low socioeconomic positions exhibit more pronounced health benefits from nature exposure compared to more privileged groups. We have previously posited one possible mechanism underlying this phenomenon through our framework: (susceptibility to stress) groups in low socioeconomic positions are often exposed to more early-life stressors, which can induce a lifelong susceptibility to stress through various neurobiological pathways; (environmental sensitivity) susceptibility to stress, traditionally understood as heightened reactivity to stressors, could also encompass enhanced responsivity to health-protective exposures, inducing greater risks in adverse environments, but also greater benefits in protective environments. Examine the moderation effect of early life stress on the association between residential nature exposure and fasting glucose. We assessed the impact of residential nature exposure (Normalized Difference Vegetation Index) on glucose dysregulation (elevated levels of fasting blood glucose) with a specific focus on the moderation effect of early life stress (Stress and Adversity Inventory for Adults) using baseline data from a cohort of 340 nursing students. An initial analysis did not support our linear dose-response hypothesis. However, a theory-guided exploration revealed a significant curvilinear trend wherein participants with higher but also lower exposure to early-life stressors both exhibited lower levels of fasting glucose when living in greener neighborhoods. By contrast, for participants with relatively moderate early-life stressor exposure, there was no association between neighborhood greenness and fasting glucose. Our findings contribute to growing evidence and further support the idea that increasing access to nature within disadvantaged neighborhoods could be an effective strategy to mitigate metabolic risks and attenuate health disparities among vulnerable populations. As the evidence for this framework expands, it could inform more targeted interventions that leverage individual differences in environmental sensitivity to promote health equity, ultimately providing more nuanced and socioeconomically attuned approaches to public health.
Prion protein (PrP) lowering is a validated therapeutic hypothesis in prion disease. To identify small molecules that reduce PrP levels, we performed phenotypic screening in cultured cells. To prioritize PrP specificity in our primary screen, we generated mouse N2a cells stably expressing GFP and used high content imaging analysis to select compounds that lowered PrP without affecting GFP signal or cell viability. Screening a curated library of 3492 compounds with annotated mechanisms of action identified two small molecules, EYH (PubChem CID: 71678945) and LCZ (PubChem CID: 24970350), that selectively and dose-dependently lowered PrP. Proteomics on whole cell lysates identified PrP as the #1 or #2 most potently downregulated out of 8722 proteins detected. Both compounds minimally affected Prnp mRNA, reduced expression of exogenously transfected PrP, and remained potent in non-dividing primary cells, consistent with a post-translational mechanism. Co-treatment with the proteasome inhibitor MG132 yielded accumulation of unglycosylated PrP, demonstrating proteasome clearance of PrP. However, both compounds showed limited or no activity in human cell lines, and failed to reduce PrP in vivo after 14 days of treatment. These findings highlight the challenges associated with mechanism-agnostic phenotypic screening for PrP-lowering compounds and support prioritizing compounds with known mechanisms of action.
Digital biomarkers offer promising avenues for enhancing the identification, prognosis, and phenotyping of Alzheimer's Disease (AD). This study evaluates the feasibility and utility of the MIND GamePack©, a digital game platform designed to measure leisure cognitive activity over time. Gameplay data were collected from 60 participants across two cohorts over 3-6 months: Cohort I (no cognitive complaints) and Cohort II (subjective complaints, mild cognitive impairment, mild dementia). Analyses focused on compliance, correlation with validated neuropsychological instruments (Montreal Cognitive Assessment [MoCA], Repeatable Battery for the Assessment of Neuropsychological Status [RBANS], and Trail Making Test [TMT]), test-retest reliability, and known groups comparison. The MIND GamePack© displayed high compliance and excellent test-retest reliability within 1 week (ICC=0.81-0.95) for most selected features. Several game features displayed moderate to strong correlations with standardized neuropsychological test performance. Features related to memory tasks across select games (Normalized Accuracy and Normalized Redundant Move Variability of Memory Match and Word Repetition Rate of Word Scramble) exhibited significant associations with RBANS Sum of Index Score, TMT Part A, and MoCA, respectively. Participants without cognitive impairment exhibited improvement in features over 3 months compared to those with cognitive impairment. Baseline game features differentiated cognitively normal [CN] from cognitively impaired [CI] participants across nearly all domains after controlling for age, sex, and education (p<.01). The MIND GamePack© offers a sensitive, engaging approach to cognitive monitoring and screening, with potential use for dense tracking in longitudinal research and interventional clinical trials.
Elder mistreatment is common, underreported, and associated with significant morbidity and mortality. Emergency department (ED) visits provide an important opportunity to identify elder mistreatment and initiate intervention, but the evidence for the impact of screening or intervention strategies in this clinical setting is not well characterized. Our goal was to conduct systematic literature reviews to describe the impact of ED-based screening tools and ED-initiated interventions for elder mistreatment. We conducted two systematic reviews following PRISMA 2020 guidelines using predefined Patient Intervention Comparator Outcome (PICO) frameworks. PICO 1 evaluated ED based screening tools for patients aged 60 years and older. PICO 2 evaluated ED initiated interventions for patients with known or suspected elder mistreatment. Searches were performed in MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from December 2018 through December 2024 and supplemented by prior scoping reviews. For PICO 1 (ED screening) the prior scoping review identified 5 studies and the updated search identified 208 additional articles, of which 5 studies underwent full-text review. For PICO 2 (ED intervention), the prior scoping review identified 5 studies and the updated search identified 191 additional articles, of which 2 studies underwent full-text review. No studies were identified that met full inclusion criteria for either PICO. Existing studies described multiple screening tools and multidisciplinary intervention models, but lacked comparator groups, standardized reference standards, or clinically meaningful outcome measures required for inclusion. These empty systematic reviews emphasize the large existing knowledge gaps about ED elder mistreatment screening and intervention. These gaps affect the ability to make practice recommendations and highlight opportunities for future rigorous research to inform guideline development.
While community volunteers are increasingly recognized for addressing supply-side gaps in healthcare delivery (e.g., provider shortages), their role in mitigating demand-side barriers (e.g., stigma) remains underexplored. This qualitative study investigated the experiences, knowledge, and roles of community volunteers in Goa, India. We examined barriers and facilitators to community-based work, and strategies for integrating community participation and outreach in demand-side interventions. We conducted semi-structured, in-depth interviews with 35 community volunteers who deliver health and socio-developmental programs (e.g., "social workers", village council members, lay health providers). Thematic analysis revealed that volunteers' work encompassed demand-related tasks such as connecting community members to government welfare schemes, organizing educational events, and providing informational or material resources via contextually-relevant, relationship-driven strategies, such as leveraging influential community leaders and social connections (including via WhatsApp). Participants demonstrated awareness of the social origins of distress (e.g., unemployment), especially post-COVID-19, and expressed willingness to vertically integrate mental health in their work. Facilitators included social recognition, personal satisfaction, and family and political backing. Lack of community support and resources (e.g., insufficient government funding) were significant barriers in continuation of work for community volunteers. These findings suggest the potential of community volunteers as demand-side change agents for mental health interventions, underscoring the necessity of integrating local knowledge, social networks, and non-monetary community-based incentives into scalable global health programs.
The use of artificial intelligence (AI) is anticipated to transform mental health care. However, the rapid research growth in this field has outpaced coordinated frameworks, leaving research efforts fragmented, standards inconsistent, and safeguards for safety and ethics largely absent. This Position Paper outlines a coordinated roadmap to guide the responsible evaluation and implementation of AI in mental health, structured across four overarching priority domains that define near-term actions and longer-term strategic goals. Domain 1 (Strengthen safety and evidence standards) addresses deficits in clinical evidence and safety oversight, emphasising the need for robust comparative trials, standardised safety testing, and adaptive regulatory frameworks. Domain 2 (Centre ethics, equity, and patient voices) focuses on aligning AI development with real-world care contexts through transparent reporting, integration of patient perspectives throughout the AI lifecycle, and the development of representative datasets and equitable governance structures. Domain 3 (Evolve the role of the clinician) addresses challenges in clinical integration, including defining core competencies, clarifying clinical oversight and accountability, and conceptualising and trialling new workforce models. Domain 4 (Facilitate sustainable implementation and systems integration) targets barriers to real-world adoption, including the importance of interoperability with clinical infrastructure and the development of sustainable financing and implementation pathways. This roadmap should support coordinated action across stakeholders and ensure that AI-based mental health systems are developed and implemented in line with principles of safety, equity, evidence, and clinical accountability.
Long-chain fatty acid oxidation disorders (LcFAODs) are rare inherited disorders associated with impaired energy metabolism and increased risk of metabolic decompensation during catabolic stress. With improved diagnosis and care, affected women reach reproductive age, making pregnancy management an emerging clinical challenge. We conducted an international, web-based survey among 55 metabolic centers from 21 countries to assess clinical management of pregnancies in women with lcFAODs focusing on management strategies rather than pregnancy outcomes. The 23-item questionnaire addressed preconception counseling, monitoring strategies, dietary management, peripartum care, postpartum follow-up, and neonatal management. Among respondents, 65% had managed pregnancies in women with lcFAODs, reporting 131 cases, most commonly in CPT2 (n = 52) and VLCAD (n = 44) deficiencies. Preconception counseling and genetic consultation were widely recommended (>85%). Core management principles included dietary adaptation with restriction of long-chain fatty acids, supplementation with medium-chain triglycerides, and prevention of catabolism. Marked inter-center variability was observed in monitoring frequency, biochemical parameters, and follow-up intensity. Creatine kinase was the most used biochemical marker for monitoring metabolic stability. Multidisciplinary care was endorsed but inconsistently implemented, with approximately half of the centers reporting structured multidisciplinary meetings. Individualized peripartum plans were nearly universal, and delivery in specialized centers was generally recommended. Pregnancy in women with lcFAODs is generally considered feasible and safe under specialist metabolic and obstetric care. However, management remains highly heterogeneous, particularly regarding monitoring and multidisciplinary structures. These findings highlight the need for international consensus and standardized care frameworks to optimize maternal and neonatal outcomes.
Current CRISPR-Cas9 methods are restricted to small genomic edits. We developed a CRISPR-guided approach that enables direct insertion of large genomic sequences into mouse zygotes. We deleted the murine 2.4-Mb immunoglobulin heavy-chain (IgH) variable (VH) locus and then precisely inserted a bacterial artificial chromosome (BAC) containing a 155-kb human VH DNA fragment flanked by 20-kb homology arms. Full-length, single-copy BAC integration occurred without ectopic recombination. Human sequences were stably transmitted and expressed VH segments that recombined with endogenous mouse sequences, and mice exhibited normal B cell development. Upon immunization, human VH-expressing B cells underwent class-switch recombination and somatic hypermutation, secreting antigen-specific antibodies. We demonstrated modular IgH humanization by replacing endogenous mouse diversity and joining (DH-JH) segments with human sequences, producing V(D)J recombination and diverse antibodies. Unlike traditional methods requiring more than a year, this approach enables the generation and validation of mice carrying large genomic insertions within 8 weeks.
Drug development in rare metabolic diseases is frequently limited by the lack of validated clinical trial endpoints, particularly for chronic disease modification. Propionic acidemia (PA) is an intoxication-type inherited metabolic disorder with significant morbidity and mortality that begins in early life, for which there are no approved disease-modifying therapies. While regulatory pathways such as accelerated approval permit the use of surrogate endpoints that are reasonably likely to predict clinical benefit, their acceptance requires strong biological rationale and evidence linking biomarker change to meaningful clinical outcomes. This review builds on prior work describing candidate biomarkers in PA by critically evaluating their suitability for use as surrogate- or response endpoints. We assess biomarkers derived from disrupted propionate metabolism, including methylcitric acid, propionylcarnitine, ammonia, and 13C-propionate oxidation, as well as biomarkers reflecting secondary mitochondrial dysfunction such as fibroblast growth factor 21. For each biomarker, we examine biological plausibility, empirical and clinical evidence, durability of response, and limitations relevant to regulatory decision making. Although several biomarkers are routinely used in clinical practice, most lack sufficient specificity, stability, or demonstrated linkage to clinically meaningful outcomes to support use as surrogate endpoints for chronic disease modification. Among those reviewed, fibroblast growth factor 21 and 13C-propionate oxidation show the strongest potential as response biomarkers within defined contexts of use, particularly for therapies that restore or augment enzymatic activity. However, substantial gaps remain, including prospective validation, standardized measurement, and direct correlation with clinical outcomes. This review outlines a framework for evaluating biomarker readiness in PA and defines the evidence required to advance selected biomarkers toward surrogate endpoint qualification for future clinical trials.
Public health depends on trust with the communities it seeks to serve, and yet this trust has historically been difficult to establish within conservative-leaning communities and individuals. Much of the current mistrust of public health professionals is a partisan phenomenon, one that may reflect the progressive slant of programming and policy development within modern public health. In response, we discuss why it would be beneficial to include more conservatives within the profession of public health. We further discuss 6 conservative values-the importance of religious communities and moral narratives, the rich varieties of community expression, the role of the family and other social orders in promoting health, an emphasis on local decision-making, an appreciation for procedural justice, and a cautious approach to large-scale social change-that could help enrich public health theory, research, and practice. We propose several practical strategies for expanding the representation of conservatives within the profession, including surveys of political affiliation, institutions of civil discourse, and intentional recruitment. Public health's mission of serving all people demands a pluralistic, trust-centered approach that explicitly welcomes conservative voices, communities, and ideas. (Am J Public Health. Published online ahead of print July 9, 2026:e1-e8. https://doi.org/10.2105/AJPH.2026.308532).