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1,4-Dioxane is a widespread groundwater contaminant frequently co-occurring with chlorinated solvents. The group-6 propane monooxygenase (PRM) from Mycobacterium dioxanotrophicus PH-06 degrades dioxane efficiently, yet the molecular determinants underlying its broad substrate spectrum and inhibition behavior remain unresolved. Here, we combined AlphaFold2-based structure prediction, molecular docking, and alchemical free energy calculations to systematically characterize ligand binding in PH-06 PRM. The catalytic center (residues 87-265), coordinated by two histidines and four glutamates, exhibited calculated binding free energies for five substrates (C2-C4 alkanes and cyclic ethers) that significantly correlated with experimentally determined degradation rates (p < 0.05), supporting the ability of ligand binding thermodynamics to capture major substrate-recognition trends in PH-06 PRM. In addition, we identified a remote binding site (residues 329-446) approximately 30 &#xc5; from the catalytic center. Thermodynamic analysis indicates that this remote site can attract methane and ethane, potentially limiting their access to the catalytic center. Comparative binding analyses of three common chlorinated solvent inhibitors (i.e., trichloroethylene [TCE], 1,1-dichloroethylene [DCE], and 1,1,1-trichloroethane [TCA]) revealed distinct site preferences consistent with their experimentally observed inhibition modes. Noncompetitive inhibitors (DCE and TCA) displayed stronger affinity for the remote site, whereas the competitive inhibitor TCE exhibited comparable affinity for both binding regions. Sequence conservation, contact probability analysis, and Gene Ontology enrichment further suggest the structural relevance of the remote site and its possible role in ligand recognition and inhibitor selectivity. These findings demonstrate that the AlphaFold-guided free energy calculations can capture experimentally observed substrate and inhibitor trends in PH-06 PRM, while identifying a remote ligand-binding pocket that warrants further mechanistic investigation.

This study aimed to describe rural data from the Australian National Study of Mental Health and Wellbeing survey (2020-2022) to assess strengths-based questions, differences by rurality, and factors associated with excellent social connectedness. Survey questions were mapped to the Rural Strengths Socioecological Framework. Descriptive and logistic analyses assessed rural adults' use of strengths by remoteness and presence of affective/anxiety disorders in the past 12&#x2009;months. Logistic regression explored factors associated with social connectedness. Survey questions reflected some strengths within the Framework including self-management techniques, family and friend support, social connectedness, and health care personnel. However, questions were primarily framed using a deficit perspective and many strengths from the Framework (i.e. nature, rural norms, culture, and lay personnel) were absent. Most strengths did not differ significantly between levels of rurality, though making healthy diet choices (as a self-management technique) was significantly lower in remote areas. Adults without affective/anxiety disorders more often reported good social support and self-efficacy. Conversely, those with affective/anxiety disorders were more likely to self-manage and access consultations for mental health. Excellent social connectedness was associated with better mental health. The survey questions reflected limited strengths. Future surveys should include a broader range of strengths-based questions spanning the extent of the Rural Strengths Socioecological Framework. Healthy diet choices as a self-management tool in remote areas may need to be prioritised. Findings also suggest the need for targeted approaches to protect, improve, or leverage social connectedness for those with more severe illness in rural areas.

All 17 of Nevada's counties carry a federal Health Professional Shortage Area (HPSA) designation, straining the state's capacity to deliver care remotely. This narrative review examines four dimensions of that capacity. It asks how telehealth is regulated and used, how far health information exchange and electronic health records have spread, whether broadband can support remote care, and what role artificial intelligence (AI) and remote patient monitoring (RPM) now play. Throughout, it considers how the state's workforce shortages, geography, and demographic diversity shape both demand for digital health and the barriers to it, with attention to equity. Four databases (PubMed/MEDLINE, CINAHL, Scopus, Google Scholar) were searched alongside federal, state, and policy grey literature for English-language sources from January 2015 to March 2026, yielding 88 sources, 40 peer-reviewed. Nevada has enacted comparatively expansive telehealth legislation, including conditional payment parity made permanent under Senate Bill 119 (2023); however, the limited utilization evidence shows uptake varying by race, ethnicity, and language. The sole statewide HIE operates under an opt-in consent model that constrains data availability, and roughly 100,000 Nevadans lack wireline broadband at the federal benchmark speed, concentrated in rural areas. AI and RPM are being deployed in rural settings without published evaluation, and nearly all peer-reviewed evidence on Nevada's digital health derives from a single study. Nevada's policy framework has outpaced its infrastructure and equity conditions; closing that gap requires coordinated action across HIE consent reform, broadband-telehealth alignment, Medicaid RPM reimbursement, and community-level investment in digital literacy and language access.

Health-related quality of life (HRQoL) is frequently impaired in cirrhosis. Among the most critical components of reduced HRQoL in cirrhosis is disturbed sleep. Despite the importance of sleep in cirrhosis and overall health, sleep is rarely clinically assessed and the specific aspects of sleep which drive reduced wellbeing are understudied. Remote monitoring with wearable technology may facilitate sleep assessment and targeted intervention. We enrolled 119 participants with cirrhosis across two academic medical centers and collected baseline clinical, cognitive and laboratory assessment and 6 months of longitudinal wearable tracking with an Oura Ring. HRQoL was assessed with the Chronic Liver Disease Questionnaire (CLDQ) and subjective sleep quality with the Pittsburgh Sleep Quality Index. Association of sleep metrics with HRQoL and subjective sleep was assessed in multivariable mixed effects model, with mediation analysis further analyzing the relationship. Across analysis of 12516 sleep episodes in 88 participants who completed all assessments and &#x2265;14 valid sleep nights, there was a strong association between measured sleep and reported sleep quality as well as HRQoL, with reduction in sleep efficiency, overall sleep time, and sleep regularity index (SRI). In adjusted mediation analyses, SRI was the strongest mediator (49.9% total mediation effect, ACME = - 0.093, p<0.001) of the relationship between liver disease severity (as measured by Child-Turcotte-Pugh Score) and CLDQ. In a large prospective study of remote sleep monitoring in liver disease, we found that sleep regularity had a strong association with patient-reported sleep quality and wellbeing, and was the strongest sleep metric mediating the relationship between progressive liver disease and overall HRQoL. These findings suggest the potential for circadian-targeted interventions in patients with cirrhosis. Sleep impairment is a major contributor to reduced wellbeing in cirrhosis, but existing sleep assessments often are too cumbersome to be used clinically and fail to capture long-term sleep patterns and circadian disruption. Using six months of wearable-derived sleep data, this study identifies sleep irregularity, as captured by the Sleep Regularity Index, as the sleep metric most strongly associated with patient reported sleep and overall wellbeing impairment. These findings suggest that sleep regularity, a marker of circadian rhythm dysfunction, may be an important digital biomarker for progressive worsening in cirrhosis and highlight a possible target for future interventions. If validated in future studies, wearable monitoring of sleep could provide clinicians and researchers a scalable approach for identifying patients with cirrhosis at increased risk for impaired wellbeing through sleep disturbance and monitor response to treatment.

This study presents a comprehensive 15-year (2009-2023) assessment of persistent organic pollutants (POPs) in the Spanish atmosphere to evaluate the Stockholm Convention's effectiveness. Polyurethane foam passive samplers were deployed across 23 sites to monitor legacy pesticides and industrial chemicals. Results reveal a concentration hierarchy dominated by hexachlorobenzene (HCB), which accounted for a median of 41% of the &#x2211;POP concentrations and displayed a remote-enriched spatial pattern characteristic of global distillation. In contrast, legacy pesticides and indicator polychlorinated biphenyls (iPCBs) were influenced by temperature-dependent secondary volatilization from historically contaminated soils, as indicated by Clausius-Clapeyron analyses. These compounds frequently exhibited an unexpected urban enrichment likely associated with heat island effects, while polybrominated diphenyl ethers (PBDEs) displayed a pronounced urban gradient (a 35-fold increase from remote baselines) driven by the late-regulated BDE-209. Long-term temporal analyses underscore a sharp regulatory dichotomy. Early-banned compounds, such as endosulfan, HCB and dichlorodiphenyltrichloroethane (DDT), and lighter PBDEs, are experiencing rapid environmental depletion, with significant annual declines of up to -33%. Conversely, pentachlorobenzene (PeCB), iPCBs, and BDE-209 show stalled or locally increasing trends (up to +20%), sustained by unintentional combustion, active consumer goods, and regulatory lag times. Altitudinal profiling across Tenerife sites highlights this divergence: coastal areas reflect local secondary emissions, whereas high-altitude observations confirm the progressive clearance of the global free troposphere. Overall, these findings provide new insights into the spatial and temporal dynamics of atmospheric POPs, reaffirming the role of long-term monitoring in guiding international abatement strategies.

Plastic pollution is an ever-growing concern around the globe, with current research portraying the presence of contaminants even in previously pristine regions. Especially small particles, micro- and nanoplastics, can be dispersed over long stretches by atmospheric transport, reaching even the most remote areas of the planet. This study aims to portray current levels of nanoplastic contamination (<&#x2009;1&#xa0;&#x3bc;m) by analyzing snow samples from high-altitude glaciers in the European Alps (2300-3800&#xa0;m) via TD-PTR-MS. We were able to detect six common plastic pollutants, with PE and PP contributing over 60% of the total mass concentration measured across all sites. On average, nanoplastic concentrations of 85 ng mL-&#x2009;1 (range: 3.6&#x2009;&#xb1;&#x2009;12 ng mL-&#x2009;1 - 470&#x2009;&#xb1;&#x2009;76 ng mL-&#x2009;1) were detected at sampled glacier surfaces. Access to these remote regions was enabled through a citizen-science initiative, involving trained mountaineers for sample collection. The results were applied to atmospheric modelling, highlighting possible point sources of contamination. While agriculture and local plastic factories were revealed as potential sources of nanoplastics, spatial and temporal limitations complicated comparison inside the sample cluster.

Mitochondrial oxidative damage is one of the factors that contributes to the pathological process of intestinal ischemia/reperfusion (II/R) injury. Glutaredoxin (GRX2), which serves as a crucial protein in maintaining mitochondrial redox homeostasis, affects the activity of downstream proteins through its deglutathionylation effect. Silent information regulator (SIRT3), a crucial deacetylase in mitochondria, has regulatory effects on the activity of various mitochondrial antioxidant enzymes. However, the precise regulatory mechanism underlying SIRT3 enzymatic activity is unknown. Our research is designed to explore GRX2-mediated SIRT3 deglutathionylation's role and mechanism in II/R injury. GRX2 levels decreased after II/R injury, and GRX2 overexpression alleviated II/R-induced intestinal mucosal injury, mitochondrial oxidative damage, damage to mitochondrial structure and function, remote organ injury, and the systemic inflammatory response. GRX2 overexpression substantially decreased the S-glutathionylation of SIRT3 and increased its activity. The results of the incubation of recombinant SIRT3 with glutathione and H2O2 indicated that the S-glutathionylation of SIRT3 inhibited SIRT3 activity. Subsequently, SIRT3 mutant plasmids with cysteine-to-serine substitutions were constructed to screen for the S-glutathionylation sites of SIRT3 among the four cysteine residues in its amino acid sequence. The results demonstrated that C280 and C283 are the SIRT3 S-glutathionylation sites. The results of experiments using ischemic intestines from clinical cases confirmed the relationship between GRX2 and SIRT3. This study demonstrates that GRX2 alleviates mitochondrial oxidative damage following II/R by reversing the S-glutathionylation of SIRT3. GRX2 is an important protective factor against II/R injury, and GRX2-mediated deglutathionylation of SIRT3 alleviates II/R-induced mitochondrial injury and intestinal damage. Antioxid. Redox Signal. 00, 000-000.

Infective endocarditis (IE) due to Proteus mirabilis is rare, particularly in the absence of an identifiable primary source. We report a case of a woman in her 50s with a history of remote IE&#xa0;and polysubstance use disorder who presented with progressive gait slowing and weakness over one month. Neuroimaging revealed an acute-to-subacute infarct in the right anterior cerebral artery territory. Further evaluation demonstrated mitral valve abnormalities with suspected vegetation, and subsequent blood cultures grew Proteus mirabilis in all four blood culture bottles. Notably, the initial blood cultures obtained during admission were negative despite subsequent high-grade bacteremia. Extensive evaluation failed to identify a primary genitourinary, gastrointestinal, or respiratory source of bacteremia. The patient was treated with a six-week course of IV ceftriaxone, resulting in microbiologic clearance and clinical improvement, with a residual mild neurologic deficit. Follow-up echocardiography demonstrated persistent valvular abnormalities, likely representing fibrotic sequelae. This case highlights a rare etiology of native valve endocarditis, the diagnostic challenges of subacute presentations, and the importance of comprehensive investigation in patients with stroke of unclear etiology.

Spatiotemporal control over cell fate and behavior within bioprinted constructs remains a key challenge in tissue engineering. Optogenetics offers versatile potential for non-invasive regulation of biological processes. Yet, its integration within large-scale, cell-laden bioprinted materials is still limited, especially considering the spatial constraints of existing light delivery methods. In this study, we introduce a novel approach that repurposes tomographic volumetric bioprinting to enable post-printing stimulation of photosensitive protein-switches and optogenetic circuits in cells deep within hydrogel constructs. By converging different bioprinting approaches, computer vision, context-aware model generation, and synthetic biology and cell engineering, we demonstrated selective activation of a fluorescent, light-responsive protein probe within multi-material centimeter-scale constructs. Moreover, leveraging a multi-wavelength volumetric bioprinter, we further demonstrate this concept by selectively stimulating cells expressing a near-infrared optogenetic system that triggers gene expression and the induction of pancreas-specific transcription factors. The described methods provide platforms for remote, repeatable, and localized control of biological events in volumetric constructs, opening new possibilities for advanced tissue models, and dynamic tuning of cell-mediated protein production in engineered living systems.

Little is known about dementia incidence and its risk factors in people older than 90 years, particularly in heterogeneous populations. We evaluated dementia incidence and examined the associations of sex, race and ethnicity, and APOE genotype with dementia risk after age 90 years using data from LifeAfter90, an ongoing prospective cohort study. LifeAfter90 is a prospective cohort study that enrolled Kaiser Permanente Northern California members, who were at least 90 years old, from the San Francisco Bay Area and Sacramento, USA. Participants were clinically evaluated every 6 months from July 17, 2018, to Nov 9, 2024, in person or remotely. Incident all-cause dementia was diagnosed by a combination of physician assessment, Clinical Dementia Rating, and a Functional Activities Questionnaire. Sex, race and ethnicity, and education were captured during in-person assessments; APOE genotyping was performed using salivary DNA. We estimated age-standardised dementia incidence rates and used age-adjusted Cox and Fine-Gray competing-risk models to study the association between sex, race and ethnicity, APOE genotype, and dementia. The Fine-Gray subdistribution hazard ratio (sHR) models treated death as a competing risk. Models were adjusted for age (time-scale) and individuals were followed until dementia diagnosis or end of follow-up. Of 1120 individuals initially available, 96 with prevalent dementia and 219 with only one clinical evaluation were excluded; 805 participants were included. Median age was 92 years (range 90-103), 494 (61%) were female, 209 (26%) Asian, 191 (24%) African American or Black, 157 (20%) Hispanic or Latinx, 228 (28%) White, and 20 (2%) from other racial or ethnic groups; 413 had APOE data. During mean follow-up of 2 years (SD 1&#xb7;7), 138 (17%) developed dementia and 295 (37%) died. The age-standardised incidence rate was 116&#xb7;82 cases per 1000 person-years (95% CI 93&#xb7;69-139&#xb7;96). In Fine-Gray models, dementia risk was higher in female than in male participants (subdistribution hazard ratio [sHR] 1&#xb7;89, 95% CI 1&#xb7;30-2&#xb7;76) and Black than Asian participants (sHR 1&#xb7;75, 1&#xb7;07-2&#xb7;88), lower in APOE &#x3b5;2 carriers than in non-carriers (sHR 0&#xb7;39, 0&#xb7;17-0&#xb7;88), and not significantly higher in APOE &#x3b5;4 carriers than in non-carriers (sHR 1&#xb7;51, 0&#xb7;92-2&#xb7;47). No significant differences were found by education. Ethnoracial disparities in dementia risk appear to persist after 90 years, and the association between APOE &#x3b5;4 and dementia might differ by sex. These findings reinforce the importance of dementia screening and surveillance, even among people with exceptional longevity. National Institute on Aging.

Patient portals are essential infrastructure, reinforced by the 21st Century Cures Act, yet adoption remains inequitable. The COVID-19 pandemic accelerated portal adoption as telehealth expansion and remote test-result delivery made electronic access integral to care, but racial and ethnic disparities persisted. Understanding activation determinants is critical for addressing digital health disparities, particularly among neurology patients, for whom cognitive, speech, and mobility impairments can complicate portal use. We examined the demographic, geographic, and neighborhood-level factors associated with patient portal activation among neurology patients in the Washington, DC metropolitan area. We conducted a cross-sectional study of 72,417 patients with at least one outpatient neurology encounter (including telehealth) at two academic medical centers sharing a common electronic health record in Washington, DC. The primary outcome was portal activation, defined as having logged into the portal at least once (a manual patient step). We examined associations using multivariable logistic regression (reporting adjusted odds ratios [aORs]) adjusting for age, sex, race/ethnicity, visit counts, and year of most recent encounter, and we assessed geographic patterning at multiple scales (the DC metropolitan catchment area, DC's eight wards, census tracts via geocoded addresses, and residential zip codes) using Pearson and Spearman correlations between ward- and tract-level American Community Survey indicators and activation. Portal activation was 64.7% overall (46,851/72,417); patients averaged 9.7 visits (SD 18.9). Activation varied by race/ethnicity: Non-Hispanic White 76.1% (21,420/28,154), Non-Hispanic Asian 57.6% (1,109/1,925), Non-Hispanic Black 57.0% (13,057/22,900), and Hispanic 55.0% (1,979/3,600). In adjusted models, odds of activation were lower for Non-Hispanic Black (aOR 0.46, 95% CI 0.44-0.48), Hispanic (aOR 0.34, 95% CI 0.31-0.37), and Non-Hispanic Asian (aOR 0.47, 95% CI 0.42-0.52) patients versus Non-Hispanic White patients, and each SD increase in age was associated with lower odds (aOR 0.60, 95% CI 0.59-0.61; all P<.001). Activation differed across DC wards, from 48.0% (Ward 7) to 82.0% (Ward 2). Ward-level activation correlated strongly with educational attainment (r=0.95, P<.001), broadband access (r=0.89, P=.003), and median income (r=0.81, P=.02); educational attainment was the strongest independent neighborhood predictor in joint models. Within individual wards, Non-Hispanic White patients activated at 85.7%-91.2% versus 50.5%-63.6% for Non-Hispanic Black patients, and disparities persisted in a sensitivity analysis restricted to 2024-2026 encounters (Non-Hispanic Black aOR 0.37, 95% CI 0.35-0.39). To our knowledge, this is the first multi-scale geographic analysis of patient portal activation. Activation was shaped by demographic, socioeconomic, and geographic factors, yet racial disparities persisted within individual wards regardless of socioeconomic advantage, indicating that neighborhood resources alone do not explain the digital divide. Health systems should pair targeted measures, such as ward-level enrollment support and digital literacy assistance, with culturally tailored, clinic-based activation support to achieve digital health equity.

Anxiety and depression impose substantial clinical and economic burdens worldwide, with high prevalence, impaired functioning, and elevated health care costs. Digital self-help interventions offer scalable and potentially cost-effective strategies; however, evidence from rigorously controlled economic evaluations remains sparse. This trial aims to evaluate the effectiveness and cost-effectiveness of 2 Norwegian mental health apps: Tankevirus (cognitive behavioral therapy-based) and Grubl (metacognitive therapy-based), compared with a digital placebo in reducing anxiety and depression symptoms, improving health-related quality of life, and generating quality-adjusted life years. The Mental Health Intervention With Digital Applications (MIND-APP) trial is a 3-arm randomized controlled trial (1:1:1 allocation) conducted fully remotely via a bespoke smartphone research platform. A total of 1000 Norwegian residents aged 16 years or older with mild to moderate symptoms of anxiety and/or depression will be recruited through national digital outreach. Coprimary outcomes are changes in anxiety (Generalized Anxiety Disorder-7) and depression (Patient Health Questionnaire-9) scores from baseline to postintervention (2-4 weeks). Secondary outcomes include health-related quality of life (EQ-5D-5L), quality-adjusted life years accrued over 6 months, functional impairment (Work and Social Adjustment Scale), health care resource use, and adverse events. Incremental cost-effectiveness ratios for Tankevirus and Grubl relative to placebo will be estimated from the perspective of public health services. Funding was secured in April 2025, with ethical approvals, licensing, and app development planned through 2026. Recruitment will commence in 2027, with follow-up through 2027 and early 2028. An extension of the timetable has been approved by the funding agent to allow inclusion of an updated version of the Tankevirus app, which will be ready for testing around May 2027. Results are expected to be published in autumn 2028 and will provide robust evidence on the clinical and economic value of scalable app-based interventions for common mental health disorders. This trial will be among the first large-scale registered reports to combine rigorous clinical and economic evaluation of digital mental health interventions. Findings will inform health policy and resource allocation by determining whether low-cost, app-based programs represent cost-effective solutions for reducing the burden of anxiety and depression. ClinicalTrials.gov NCT07627204; https://clinicaltrials.gov/study/NCT07627204. PRR1-10.2196/84096.

The global population is ageing at an unprecedented rate, creating substantial pressures on healthcare systems to deliver personalised, proactive, and cost-effective care for older adults. Digital twin (DT) technology, where dynamic virtual replicas of physical entities are continuously updated through real-time data, has emerged as a transformative tool in precision medicine. Despite its growing application across clinical specialties, its specific utility within geriatrics and gerontology remains underexplored in the academic literature. This narrative review aims to synthesise existing evidence on the applications of digital twin technology in geriatric and gerontological care, examine associated challenges and identify future research priorities. A narrative review methodology was employed, with a systematic search of PubMed, Scopus, Web of Science, and IEEE Xplore databases covering publications from January 2014 to December 2025. Studies were selected based on relevance to digital twins, ageing populations, or geriatric clinical domains, with data synthesised thematically. Digital twins demonstrate significant potential benefit across multiple geriatric domains, with use in cardiovascular monitoring, fall prevention, dementia management, polypharmacy optimisation, and chronic disease self-management. Key enablers include advances in Internet of Things (IoT), artificial intelligence, and electronic health records. Persistent challenges include data privacy concerns, interoperability deficits, computational costs, and ethical questions surrounding autonomy and consent in cognitively impaired populations. Digital twin technology holds considerable promise for revolutionising geriatric and gerontological care, by enabling hyper-personalised clinical decision-making, predictive risk management, and remote patient monitoring. Translating this potential into practice requires focused investment in regulatory frameworks, equitable access infrastructure, and interdisciplinary collaboration. Future research should prioritise standardisation, caregiver integration, and longitudinal validation studies within older adult populations.

Extended Reality (XR) technologies offer unprecedented opportunities to redefine physical rehabilitation experiences through embodied telepresence and full-body motion tracking. Realizing meaningful XR in physical rehabilitation requires stakeholder input addressing remote embodied therapy's unique design challenges. This study presents one of the first stakeholder co-design workshops on embodied telehealth for physical rehabilitation, engaging participants [N = 24 total including ten clinicians, eight patients, three designers, and three engineers] across five focus groups with stakeholders from clinical, academic, and industry settings. Through structured usability testing and a four-axis framework analysis, we evaluated immersive Virtual Reality (VR) applications supporting synchronous clinician-led embodied appointments and asynchronous clinician-authored patient home exercise programs with full-body tracked avatars and biomechanical assessments. Stakeholder feedback reinforced the need for embodied agency with adaptive input modalities for diverse patient needs, ensuring clinical authenticity through real-time full-body tracking for accurate movement correction and scaling interaction complexity from minimal interfaces for VR novices (78% of participants) to customizable clinical dashboards. Crossstakeholder prioritization identified minimalist XR interface navigation (19 votes) and flexible clinical assessment capabilities (17 votes) as the highest-priority design requirements, while exit surveys suggested high patient comfort (M = 4.50/5) and strong clinician adoption interest (M = 4.14/5). We propose six design principles for meaningful XR telehealth in physical rehabilitation: 1) embodied guidance with real-time feedback, 2) progressive complexity with minimalist defaults, 3) adaptive accessibility through multi-modal input, 4) clinical authenticity via domain-specific assessments, 5) biomechanical precision for trust and safety, and 6) contextual onboarding to improve therapeutic competency. These findings offer design considerations for developing embodied XR telehealth systems that support sustained therapeutic engagement and meaningful rehabilitation outcomes.