Recent advances in coherent spin shuttling have made sparse semiconductor spin-qubit arrays an appealing solid-state platform to realize quantum processors1-7. The dynamic and long-range connectivity enabled by shuttling is also essential for many quantum error-correction schemes8-10. Here we demonstrate a silicon spin-qubit device comprising a shuttling bus for coherently transporting qubits that can interact at four isolated locations that we call bus stops. We dynamically populate the array and tune all single- and two-qubit operations using shuttling and quantum non-demolition spin measurements, without access to charge sensing in most of the device. We achieve universal control of the effective five-qubit processor and select the connectivity required to form a surface-code stabilizer plaquette that supports X- and Z-type parity checks up to weight four. We use the parity checks to generate multi-qubit entanglement between all qubit combinations in the array and report the genuine entanglement of a five-qubit Greenberger-Horne-Zeilinger state, constituting one of the largest such states constructed with gate-defined semiconductor spins. The protocols developed here lay the groundwork for modular calibration and operation of sparse spin-qubit arrays, and we highlight the feasibility of near-term quantum error-correction experiments with mobile spin qubits.
Although shared decision making (SDM) is considered the standard within mental health care, literature shows that its implementation remains limited. The lack of practical guidelines how to implement SDM in psychiatric practice may contribute to this gap. To develop a pragmatic model for SDM in psychiatric practice and training purposes. We conducted a literature review of existing SDM models. We examined which psychiatry-specific elements were missing from these models, while also considering didactic aspects. The resulting model was further refined through interdisciplinary focus groups with five different panels consisting of healthcare professionals, patients, relatives and students (n=48). We opted for a linear stepwise model incorporating aspects characteristic of mental health care, such as the explicit formulation of treatment goals, the establishment of a ‘decision team’, assessment of decision-making capacity, and risk evaluation. Given that psychiatric care requires a stable and trusting therapeutic relationship, we also included an explicit evaluation of the collaboration between patient and clinician. We present an initial pragmatic and didactic SDM model (‘Shared Steps & Checks’) that explicitly addresses the complexity of shared decision-making in mental health care. The model is designed for application in psychiatric clinical practice as well as for educational purposes within mental health services.
De-implementation of low-value clinical practices requires changes in both documentation and clinician behaviour, yet documentation may not accurately reflect bedside practice. We conducted a multifaceted quality improvement de-implementation initiative in a level III neonatal intensive care unit that combined education, electronic medical record workflow modification and reinforcement of symptom-based feeding assessment to eliminate routine gastric residual (GR) checks in infants with birth weight <1500 g. Following implementation, documented GR checks declined to zero, with no increase in necrotising enterocolitis or feeding intolerance and no improvement in time to full enteral feeds.To evaluate behavioural adoption, we performed a secondary analysis of an anonymous nursing survey. Of 56 nurses, 24 responded to the item assessing ongoing practice; 7 of 24 (29%) reported continuing GR checks without documentation. While most nurses supported the protocol change, some reported anxiety and perceived increases in emesis, abdominal imaging and feeding interruptions despite stable clinical outcomes. Less-experienced nurses were more likely to report concern about potential disciplinary consequences (OR 7.33; 95% CI 1.2 to 45; p<0.05). In sensitivity analysis, nurses who did not report continued checks demonstrated higher anxiety (OR 152; 95% CI 3.0 to 7600; p<0.001) although this post hoc finding should be interpreted cautiously.These findings demonstrate discordance between documented and actual practice following de-implementation. Documentation alone may overestimate implementation fidelity, particularly when discontinuing practices perceived as protective, highlighting the need for measurement strategies that capture true bedside behaviour.
Academic probation is a common institutional response to poor academic performance, yet limited experimental evidence exists on whether the content and framing of probation notifications influence student outcomes. This study examined the impact of an embellished academic probation email on reenrollment and academic performance among community college students placed on academic probation. A randomized controlled trial was conducted at a large, multi-campus community college. Students placed on academic probation at the end of the Fall term (n = 3,109) were randomly assigned to receive either the standard probation notification or an embellished version designed to increase salience and clarity through enhanced formatting, a graphic of sanctions progression, and encouragement to use support resources. Primary intent-to-treat outcomes were reenrollment in the subsequent Winter term and academic recovery, defined as reenrollment with a Winter GPA of at least 2.0. A secondary outcome, Winter GPA, was analyzed among students who reenrolled. Impacts were estimated using covariate-adjusted linear regression models, with logistic regression models estimated as robustness checks. The embellished email produced modest positive estimated effects. Reenrollment and academic recovery increased by approximately 2 to 3 percentage points, although estimates were accompanied by statistical uncertainty. Among returning students, Winter GPA was approximately 0.10 points higher in the treatment group, although these estimates were conditional on reenrollment and should be interpreted cautiously. Enhanced probation communications delivered through institutional email may modestly improve short-term academic outcomes for students placed on academic probation. More broadly, such low-cost communication interventions may complement broader student support strategies.
Proactive referral, defined as a strategy to connect smokers with smoking cessation programs under the responsibility of healthcare professionals, is effective in increasing the uptake of such programs. A feasibility study in a health check-up setting of the Brief Tobacco Intervention with Proactive Referral (BTI-PR), our smoker-level implementation strategy for smoking cessation treatment (SCT), revealed that the BTI-PR could be delivered to 85.7% of smokers as intended by healthcare professionals following provider-level guidance on implementation, which included educational sessions and the provision of materials. The present study aimed to estimate smoker uptake of SCT following a multifaceted, provider-level implementation strategy in Japanese real-world health check-up settings. This single-arm, multi-center, uncontrolled hybrid type 3 effectiveness-implementation study is focused on providing stakeholders with the evidence necessary to support adoption of the BTI-PR together with its provider-level implementation strategy. The BTI-PR is a smoker-level implementation strategy for SCT which acts by motivating smokers to schedule an online SCT appointment by themselves. The provider-level implementation strategy consists of eight components: (a) conduct a training session, (b) provide a guide on the BTI-PR, (c) provide a checksheet for the BTI-PR, (d) provide a flyer on the online SCT, (e) conduct a kickoff meeting and request to discuss pre-specifiable matters, (f) schedule a pre-implementation phase, (g) request holding a review meeting and report, and (h) conduct a plenary meeting to share local knowledge. Primary outcome is the penetration of online SCT, namely the proportion of smokers eligible for the BTI-PR who attend the first session of the online SCT within 3 months after receiving the BTI-PR. Data collection was completed in February 2026. A total of 24 healthcare professionals who received the provider-level implementation strategy delivered the BTI-PR to smokers to explore the primary outcome. The final analyses were commenced in March 2026. This study is expected to support the adoption of proactive referral together with an implementation strategy in health check-up settings, although causal inference remains limited. The findings will contribute to the implementation of effective smoking cessation support into preventive health services. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000064502; UMIN-CTR, number UMIN000056447.
ICU-to-ward transfers are high-risk transitions marked by information loss and burdensome handoff preparation. We developed PAUSE-Agents, a clinician-in-the-loop multi-agent LLM pipeline that drafts source-attributed handoff briefs from structured ICU data and clinical notes using the clinician-developed ICU-PAUSE template. Mirroring ICU team structure, PAUSE-Agents routes each record through a scribe extractor, 6 role-specialized agents, explicit conflict surfacing, and deterministic safety checks before synthesis, producing an editable first draft rather than an autonomous note. In a single-center medical ICU cohort, 5 physicians completed 100 reviews of 84 agent-drafted briefs. Among adjudicable claims, 98.8% were verified and 1.2% were incorrect; 88% of briefs had no pertinent omission, and mean PDSQI-9 quality was 4.20/5. PAUSE-Agents surfaced 118 conflict warnings and 421 safety flags, making documentation inconsistencies visible before handoff. An o4-mini PDSQI-9 judge showed limited case-level discrimination but supported aggregate monitoring. We release PAUSE-Agents and its clinician evaluation application.
Longer life does not necessarily mean healthier ageing, and surveillance needs to distinguish survival gains from healthy-life gains. We used a longitudinal conversion framework to examine whether national life expectancy (LE) gains were matched by healthy life expectancy (HALE) gains. WHO LE and HALE series were linked with IHME burden and sociodemographic indicators, WHO expenditure data, and United Nations population data for 2000-2021. We decomposed survival gains into HALE gains and an unconverted remainder, reporting population-weighted trends, country-level conversion shares (ΔHALE/ΔLE), non-ratio checks, and a secondary age-60 module. WHO uncertainty bounds were propagated through 2000 Monte Carlo draws. Population-weighted global LE rose from 67.92 to 73.29 years in 2000-2019, while HALE rose from 59.17 to 63.69 years. The LE-HALE gap widened from 8.75 to 9.60 years, leaving 0.85 years of survival gain not matched by healthy-life gain (95% UI 0.50 to 1.21). HALE captured 84.2% of the LE gain (95% UI 77.9% to 90.5%). Among 185 countries, 181 (97.8%) had wider gaps; among 179 countries with positive LE gains, 177 (98.9%) had conversion shares below 1.0. In the age-60 module, LE60 rose by 1.92 years and HALE60 by 1.36 years. Added survival years were not fully converted into healthy years before 2020. Longer survival should not be treated as healthier survival unless HALE gains keep pace with LE gains.
The increasing prevalence of physical inactivity among adolescents has raised major health concerns worldwide. Schools, as key social institutions, play a crucial role in fostering lifelong active lifestyles. This study investigated whether a gamified physical education (PE) intervention within Health-Promoting Schools (HPS) could enhance students' sporting capital. In this quasi-experimental study with a pretest-posttest control group design, 244 Iranian students (aged 13-16) were randomly allocated into four groups; two control groups of boys/girls and two experimental groups of boys/girls. A six-week gamified intervention was implemented in experimental groups. Research tools included a 25-item Sporting Capital Questionnaire (SCQ), the Perceived Parental Sport Support Scale (PPSSC) and the Sense of Socialization Scale (SSS), administered at Week 0 (pre-test) and Week 7 (post-test). Statistical tests comprised assumption checks (Shapiro-Wilk, Levene), baseline comparisons (independent samples t-tests, χ²), within-group analyses (paired t-tests), between-group comparisons using ANCOVA with pre-test scores as covariates, interaction exploration via multiple regression, and reporting of effect sizes (Cohen's d, partial η²). Significant improvements were observed in the experimental groups as compared with the control groups across all three dimensions of sporting capital. For example, post-test scores for sporting capital increased from 63.1±5.4 to 74.8±6.2 in girls and from 61.5±5.6 to 72.9±6.4 in boys. Gender did not moderate the intervention effect (P=0.198), but perceived parental support positively influenced outcomes (P=0.004). Also, sense of socialization had a weak moderating effect (P=0.057). Gamified physical education (PE), embedded in Health-Promoting Schools (HPS) contexts and supported by families, can effectively build students' sporting capital beyond short-term motivation. Schools should adopt structured gamified modules, empower teachers with training, and engage parents to strengthen students' commitment to active lifestyles.
Inflammatory bowel disease (IBD) has variability in the pharmacokinetics of adalimumab, which may predispose patients to subtherapeutic concentrations, therapeutic failure, and/or drug immunogenicity. Population pharmacokinetic (popPK) models estimate individual pharmacokinetic parameters and allow to personalize therapeutic regimens through Model-Informed Precision Dosing (MIPD). This retrospective, longitudinal study evaluated the predictive performance of six popPK models of adalimumab in adult patients with IBD treated at a tertiary hospital. The adequacy and prediction of the models were externally validated using visual analysis of the goodness-of-fit (GOF) plots, prediction-corrected visual predicted checks (pcVPC), analysis of residuals, and statistical metrics such as the Akaike Information Criteria. Bias and prediction were also calculated using mean prediction error, mean absolute percentage error and root mean square error. Bootstrap resampling was applied for statistical comparisons. Pharmacokinetic parameters were estimated using Bayesian methods and compared to theoretical values. A total of 201 subjects were included, 88% with Crohn's disease, mean age 48.6 (± 16.2) years, 44.8% women. Overall, Berends and Vande Casteele models demonstrated the best predictive performance in the majority of comparative analyses: higher coverage in pcVPC and correlation between observed and predicted values, lower bias and precision values, the lowest AIC, and a homogeneous distribution of residuals. However, both models overestimated adalimumab population clearance. These findings support the application of the Berends and Vande Casteele models in clinical MIPD strategies. Therefore, pending broader evidence in different populations, driving MIPD adoption is critical to optimize adalimumab regimens and maximize sustained clinical outcomes.
To evaluate a multipurpose MZ CUBE-based workflow for selected CBCT QA endpoints, including translational IGRT-relevant geometric verification and core image quality (IQ) assessment, across three clinical Varian CBCT systems and multiple phantom units. CBCT was acquired on three Varian linacs under Head and Pelvis protocols. Unless otherwise specified, analyses used iterative CBCT (iCBCT). For HyperSight, datasets were additionally reconstructed using FDK, iCBCT, Acuros CTS, and Acuros CTS + MAR. Measurement accuracy was assessed using an imaging-guided couch-repositioning loop. IQ metrics included spatial linearity, spatial resolution, low-contrast detectability, HU constancy, HU uniformity, and noise. Cross-platform consistency was evaluated using a single phantom, while inter-phantom reproducibility was assessed using five independent units. Rotational verification was not included. Translational IGRT-relevant geometric verification demonstrated sub-millimeter residual couch translation with tight dispersion. Spatial linearity remained near unity, and spatial resolution and low-contrast detectability exceeded protocol thresholds (Head up to 7th group; Pelvis up to 6th group). HU constancy across four materials met acceptance limits (±50 HU), while HU uniformity and noise were within institutional CBCT QA tolerances aligned with AAPM TG-142 and TG-179. Results were consistent for both cross-platform constancy and inter-phantom reproducibility. On HyperSight, Acuros CTS produced the lowest HU uniformity differences among reconstruction methods. Comparison with a clinically established phantom demonstrated comparable HU constancy and uniformity. The MZ CUBE-based multipurpose phantom workflow yielded consistent performance for selected translational geometric and image quality QA endpoints across platforms and phantom units, supporting its use for constancy checks, benchmarking, and reconstruction-method QA.
Learning disabilities (LD) affect a substantial proportion of students worldwide, including in Iran. LD is regarded as persistent difficulties in reading, writing, and mathematics. The present study investigated the efficacy of cognitive behavioral play therapy (CBPT) in enhancing visual attention and mathematical concept acquisition among students with learning disabilities (LDs) in Dezful, Iran. This was a quasi-experimental study with pre-test, post-test, and one-month follow-up assessments, and a control group. The target population encompassed all male and female second- and third-grade primary school students diagnosed with LD who were enrolled in educational and rehabilitative services at Dezful Developmental and Educational Assessment Center, Dezful, Iran. A convenience sample of 30 students (15 per group) was selected based on DSM-5 criteria. The experimental group underwent 10 ninety-minute sessions of CBPT, delivered twice weekly. Data were collected using the Continuous Performance Test (CPT) to measure omission and commission errors of visual attention and Key Math Diagnostic Assessment (scored from 0 to 100). Repeated Measures ANOVA with standard assumptions, including sphericity checks, was employed for data analysis using SPSS version 26. According to our results, CBPT significantly improved visual attention and mathematical concept acquisition in the experimental group as compared with the control group in the post-test phase (P<0.001, partial η²=0.62 for visual attention, 0.78 for mathematical concepts). For visual attention, mean omission errors in the experimental group decreased from 4.69 (SD=0.94) to 2.63 (SD=1.14), and commission errors from 5.63 (SD=1.20) to 3.06 (SD=0.99), while the control group showed minimal change (omission errors: 4.94 [SD=0.89] to 4.24 [SD=1.42]; commission errors: 5.41 [SD=1.06] to 6.06 [SD=1.02]). For mathematical concept acquisition, the mean score in the experimental group increased from 42.81 (SD=5.02) to 70.81 (SD=3.92), while the mean score in the control group remained stable (45.24 (SD=3.83) to 45.12 (SD=4.56)). These effects persisted at follow-up (visual attention: partial η²=0.58; mathematical concepts: partial η²=0.74), with minimal decline in scores. The findings demonstrated that CBPT produced significant and sustained improvements in visual attention (reduced omission and commission errors) and mathematical concept acquisition among students with LDs compared with the control group.
Development and validation of an online adaptive proton therapy workflow for clinical use. A script-based online adaptive proton therapy workflow was developed in a graphics processing unit (GPU)-accelerated treatment planning system (TPS) to automate plan adaptation using traditional CT images acquired on an in-room CT-on-rails. Monte Carlo (MC) -based secondary dose calculation and log file analysis of machine parameters were integrated into the workflow to provide quality assurance (QA) pre- and post- plan delivery for the adapted treatment plan. In silico retrospective testing was performed with ten previously treated pelvic patients for validation of the workflow, a total of 50 fractions were included in this study. The fidelity of adapted dose distributions, time required for the in-silico workflow, and QA results were recorded and analyzed. The median (inter-quartile range, IQR) time required for this workflow was 61.9 (12.2) minutes, demonstrating technical feasibility for online adaptation. Of the 50 evaluated fractions, 15 (30%) showed clinically meaningful improvements in sparing of highest-priority organ-at-risk (OAR) using the adaptive plans (PA), and 8 (16%) showed improved target coverage relative to the scheduled plan. Both MC-based secondary dose checks and log file-based machine QA were within institutional tolerance criteria, confirming the dosimetric accuracy and delivery fidelity of the workflow. A fully integrated, QA-embedded online adaptive proton therapy workflow using in-room CT-on-rails imaging was developed and validated in silico on a clinical proton beamline. The workflow demonstrated clinically acceptable treatment times and reliable dosimetric accuracy and provided measurable benefits in OAR sparing and target coverage for a substantial subset of fractions. These results support the readiness of this workflow for clinical use.
This article presents a survey dataset on consumer responses to social media-endorsed advertising in Vietnam's fast-moving consumer goods (FMCG) sector. Data were collected through a cross-sectional online survey administered in Google Forms and distributed via relevant Facebook groups in Vietnam between August and December 2025, using a non-probability purposive sampling approach targeting adult social media users with recent exposure to influencer-endorsed FMCG advertising. Of the 1003 submitted responses, 563 were retained in the refined analytical dataset after informed consent screening, five eligibility screening questions, and post-screening quality checks. The instrument includes 36 Likert-type indicators measuring nine reflective constructs (credibility, expertise, congruence, authenticity, entertainment, informativeness, customer experience, brand association, and engagement), together with demographic and control variables. Measurement quality was assessed in SmartPLS 4, with results indicating satisfactory reliability, convergent validity, and discriminant validity for the reflective measurement scales. The repository package contains the raw dataset, the refined analytical dataset, the codebook, the informed consent form, and the questionnaire in English and Vietnamese. These data can be reused for scale assessment, replication, multigroup comparison, mediation analysis, and comparative research on influencer-led advertising and brand-related outcomes in emerging markets.
Response to neoadjuvant PD-1 inhibitor plus chemotherapy in locally advanced esophagogastric adenocarcinoma varies widely, and tumor biomarkers alone do not fully explain the variation. We developed an integrated Body Composition and Immunonutritional Signature (BCIS) from pretreatment CT body composition and routine blood markers, and tested whether it predicts pathological response, immune-related adverse events (irAEs), and survival. From four tertiary hospitals in Hebei Province, China, we enrolled 720 patients with histologically confirmed gastric or gastroesophageal junction (Siewert II/III) adenocarcinoma treated between 2019 and 2023 with neoadjuvant PD-1 inhibitor plus SOX or XELOX followed by D2 gastrectomy. BCIS was a 0-10 additive score from ten prespecified adverse host features. Analyses included logistic regression, restricted cubic spline (RCS) modeling, multivariable Cox regression, DeLong tests for nested AUC comparisons, decision-curve analysis, eleven sensitivity scenarios, and collinearity checks by Spearman correlation and variance inflation factors. BCIS classified 243 (33.8%) patients as favorable, 303 (42.1%) as intermediate, and 174 (24.2%) as unfavorable. Major pathological response (MPR) rates dropped sharply across strata (64.2%, 39.6%, 21.8%; P-trend<0.001). After adjusting for age, sex, cT/cN, PD-L1 CPS, MMR status, EGJ origin, and regimen, every BCIS point cut the odds of MPR by roughly 40% (adjusted OR = 0.61, 95% CI 0.55-0.68, P<0.001) and pCR by close to half (adjusted OR = 0.55, 95% CI 0.46-0.66, P<0.001). RCS modeling flagged CRP and CAR as nonlinear; BCIS itself was strictly linear. Adding BCIS to a clinical baseline lifted overall AUC for MPR from 0.597 to 0.710 (DeLong P<0.001) and external AUC from 0.588 to 0.704. At 42.5 months' median follow-up, each BCIS point raised the hazard of progression by 53% (adjusted HR = 1.53, 95% CI 1.44-1.63) and of death by 38% (adjusted HR = 1.38, 95% CI 1.29-1.47; both P<0.001). Direction of effect held across every prespecified subgroup (P-interaction>0.10 throughout) and all eleven sensitivity scenarios. BCIS is independently associated with pathological response and survival under neoadjuvant PD-1-based immunochemotherapy and adds discrimination beyond tumor-centered biomarkers and clinical staging. Because every component comes from routine pretreatment workup at no extra cost, BCIS could feasibly inform prehabilitation, toxicity surveillance, and shared decision-making.
Estonian households faced persistent financial hardship due to high out-of-pocket payments for outpatient prescription medicines. An "additional medicine benefit" was therefore introduced in 2003, which lowers co-payments once a person's spending for outpatient prescription medicine has reached a threshold. However uptake remained low due to administrative hurdles and lack of awareness. In response, Estonia reformed this benefit in 2018, including leveraging digital technologies to automate eligibility checks and benefit provision at the point of sale. This paper explores how Estonia developed, designed and implemented these digital technologies and analyses the reform's observed changes. This study employed a qualitative-dominant mixed-methods approach, including document reviews, key informant interviews, and analysis of administrative data from the Estonian Health Insurance Fund (EHIF). The WHO framework for assessing digital technologies in health financing guided data collection and thematic analysis. Built on Estonia's e-prescription system, the reform included lowering co-payment thresholds coupled with automating a member's benefit and enabling related real-time data exchange. The share of patients benefitting rose from 0.4% in 2017 to 15.6% in 2018, which is assumed to have contributed to decreasing the incidence of catastrophic health spending during the same time. Automation has significantly reduced the administrative burdens for EHIF, pharmacists and patients. Estonia's experience demonstrates how digital technologies support health financing reforms, contributing to increased efficiency, improved financial protection and utilization aligned with need. Yet, there is further potential to use existing data and digital technologies to better target benefits to those most in need.
Quetiapine is primarily metabolized by CYP3A4, and its coadministration with potent CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, carbamazepine) may substantially alter systemic and central nervous system exposure. Although clinical evidence supports these interactions, quantitative predictions of plasma and brain interstitial concentrations remain limited. This study aimed to develop an integrated physiologically based pharmacokinetic (PBPK) model to quantitatively predict drug-drug interactions (DDIs) among quetiapine, ketoconazole, and carbamazepine, and to propose model-based dose-adjustment strategies to mitigate exposure-related risks. Previously validated PBPK models for quetiapine, ketoconazole, and carbamazepine were incorporated. Clinical DDI data from previous reports were digitized for model calibration, and parameters related to CYP3A4 inhibition and induction were optimized. Model qualification included visual predictive checks, residual analysis, and fold-error evaluation. The final model simulated multiple DDI scenarios, including concurrent and sequential coadministration, and explored dose-adjustment strategies for all 3 drugs. The PBPK model accurately reproduced observed quetiapine-ketoconazole and quetiapine-carbamazepine interaction profiles in both plasma and brain. Ketoconazole coadministration markedly increased quetiapine exposure (approximately 6-fold to 8-fold), whereas carbamazepine reduced exposure by approximately 4-fold to 6-fold. Concurrent or sequential triple-drug combinations induced substantial quetiapine fluctuations, indicating potential clinical instability. Dose-adjustment simulations suggested that quetiapine reduction (eg, 200 mg daily) partially mitigates ketoconazole-mediated overexposure, whereas even high quetiapine doses could not fully compensate for carbamazepine-induced underexposure. This model provides a robust quantitative framework for predicting quetiapine exposure under clinically relevant DDI scenarios and highlights the substantial risks associated with coadministration of potent CYP3A4 modulators. SIGNIFICANCE STATEMENT: Physiologically based pharmacokinetic modeling was used to quantitatively predict CYP3A4-mediated drug-drug interactions of quetiapine with ketoconazole and carbamazepine, integrating both systemic and brain interstitial exposure. The model reveals how strong CYP3A4 inhibition or induction markedly alters quetiapine exposure and provides a mechanistic framework to evaluate clinically relevant drug-drug interaction scenarios and guide evidence-based dose-adjustment strategies in psychotropic polypharmacy.
Digital multidomain interventions hold promise for dementia risk reduction; however, populations at higher dementia risk, including those experiencing socioeconomic and educational disadvantage, remain underrepresented in trials, and engagement with digital interventions often declines over time. Coproduction and blended models that combine digital tools with human support may improve reach, acceptability, usability, and sustained engagement. Designing interventions that are usable and acceptable for individuals facing structural, educational, or digital barriers (underserved groups) is therefore likely to produce solutions that are both accessible and scalable for the wider midlife and older adult population. This study aims to describe the coproduction process used to develop ENHANCE (Tailored Intervention for Brain Health and Cognitive Enrichment)-a coach-supported digital intervention targeting 10 modifiable dementia risk factors in older adults from underserved groups-and report key outputs and lessons learned for equitable digital prevention design. We coproduced ENHANCE between July 2023 and February 2025 using a multistage development process guided by the Medical Research Council framework for complex interventions and the Double Diamond design model. The person-based approach informed user-centered guiding principles (key design objectives), while behavior change content was operationalized using behavioral change theories. Coproduction followed 4 phases. The Discovery phase explored barriers to engagement with existing digital materials and identified candidate components for each dementia risk-factor module. The Define phase translated these insights into guiding principles and blueprints of each risk-factor module integrated with behavioral change components. The Design phase involved iterative co-production and usability testing of prototypes. The Delivery phase evaluated a high-fidelity prototype through a 1-week usability study with coaching support. Contributors included 162 research participants recruited from underserved community settings, 33 patient and public involvement contributors, and 4 human-computer interaction experts. Throughout development, coproduction focused on reducing literacy, digital confidence, and cultural barriers to maximize usability across diverse adult populations. Coproduction produced (1) evidence-informed module strategies for targeted dementia risk factors; (2) a set of guiding principles to ensure low-literacy, culturally relevant, and accessible content, supporting both equity of access and wider population usability; (3) a meadow-themed app integrating tailored check-ins, educational videos, cognitive training games, and in-app messaging; and (4) a structured coaching model, including onboarding, brief follow-up, and accompanying coaching manuals. Iterative testing and refinement improved navigation, simplified language, reduced text burden, and ensured the use of familiar and accessible game formats, resulting in a feasibility-ready prototype. ENHANCE is a coproduced, coach-supported digital intervention designed to be accessible for underserved midlife and older adults at increased dementia risk, with design features to support accessibility, engagement, and scalability across the wider aging population. The development process illustrates how integrating coproduction with behavioral science and usability methods can support principled intervention design for equitable digital dementia prevention.
L-malic acid is one of the most important acids present in fruits. Its determination is important in the manufacture of beer, fruit and vegetable products. In the wine industry, its level is monitored during malolactic fermentation. It is also added to a variety of products as food preservative and flavor enhancer. To validate the performance of the Enzytec™ Liquid L-Malic acid test kit for the determination of L-Malic Acid in foods and beverages such as fruit juice (concentrates and products), vegetable juice, wine, beer, sauces, and carbonated soft drinks. The kit contains two ready-to-use components only which makes handling easy and suitable for automation. L-malic acid is oxidized to oxaloacetate by L-malate dehydrogenase and NAD+. The NADH produced is equivalent to the amount of L-malate converted and is measured at 340 nm. The Limit of Detection (LOD) was determined to be 8 mg/L for 100 µL test volume and the measurement range is 15 to 500 mg/L. Trueness was checked by analyzing a reference wine sample resulting in a recovery between 96 and 99%. Recovery was checked by spiking and resulted in mean values from 97 to 105% for red wine, beer, soft drink, carrot juice, apple juice, acerola juice concentrate, BBQ sauce, and quince jelly. Relative intermediate precision is between 1.5 and 3.6% for carrot juice, BBQ sauce, NIST SRM 3282, and a reference wine. D-tartaric acid and meso-tartaric acid interfere and cause a creep during the reaction. Sulfite interferes at concentrations higher than 0.025 g/L but can be masked by glyoxal. For automation, three applications with different test volumes were validated. Linearity is given from 3.5 to 2500 mg/L. The method was approved as AOAC Official Method of Analysis℠. Real time and in-use stability are at least 24 months.
Ultrasonography is the standard for diagnosing steatotic liver disease (SLD), but its use in population-based health screening is often limited by resource and workflow constraints. We evaluated alanine aminotransferase (ALT) and two non-imaging indices, the Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI), for screening attenuation imaging (ATT)-defined steatosis. We retrospectively analyzed 2,394 adults who underwent health checkups. Abdominal ultrasonography with ATT was optional and performed in participants who elected to undergo it. Steatosis grades were defined using ATT cutoffs (S0-S3), with SLD defined as S1-S3. Diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC), and screening-oriented thresholds were examined using prespecified rule-out (sensitivity ≥90%) and rule-in (specificity ≥90%) criteria. SLD prevalence was 35.5% (850/2,394). For detecting SLD, AUROCs were 0.653 for ALT, 0.692 for FLI, and 0.703 for HSI (both vs ALT, p < 0.001). Screening-oriented thresholds showed negative predictive values of 79.1%-82.3% and positive predictive values of 60.2%-67.4%, indicating modest but clinically useful rule-out and rule-in performance. In lean participants, HSI showed higher discrimination than ALT (AUROC 0.651 vs 0.561), and HSI also remained favorable in women. The advantage of FLI and HSI over ALT was more apparent at earlier steatosis stages than at severe stages. Using ATT as a quantitative reference, FLI and HSI discriminated ATT-defined SLD better than ALT, supporting their use as practical non-imaging tools for initial screening in routine health screening and primary care settings when ultrasonography is not readily available.
Thrombotic microangiopathy (TMA), an intractable disease, can present in a renal-limited mode. Data on infantile-onset renal-limited TMA (RL-TMA) is lacking. This study describes 5 cases of RL-TMA in infants. Case series. Five patients with infantile-onset RL-TMA who were admitted and/or followed up at Nanfang Hospital, Southern Medical University, from January 2024 to June 2025. Clinical data of 5 patients were collected. Amino acid conservation was analyzed by Clustal Omega, the secondary structure of the mutants was predicted by PolyPhen-2 and PHYRE2, and tertiary structure was predicted by AlphaFold3 and ChimeraX. All patients presented with acute nephritic syndrome with hematuria and proteinuria with onset in infancy, but without hemolytic anemia or thrombocytopenia. Corticosteroid treatment was attempted in 3 patients with no response. Renal pathology revealed microthrombi; segmental endothelial cells that swelled with widening of the subendothelial gap and/or mesangiolysis were observed. C3 heterozygous missense variant (c.2184 C>T, p.Cys728X), CD46 homozygous variant c.614A>G (p.Glu205Gly), and CFI heterozygous variant c.610A>G (p.Met204Val) were detected in 3 patients, respectively. Possible activation of alternative complement pathway (AP) was indicated in all 4 tested patients. Complete remission was achieved in 2 patients, and partial response was observed in another 2 patients who received eculizumab therapy. The patient who harbored the CFI variation and did not receive eculizumab therapy progressed to kidney failure at 11 months of age. Functional verification of genetic variants of C3, CD46 and CFI in this study were not implemented. AP activation-related factors were not checked in patient 5. RL-TMA can occur in infancy, which has not been reported previously. Activation of the AP may be the common cause of infantile-onset RL-TMA. Its diagnosis and therapy are challenging. Promising outcomes can be achieved with eculizumab therapy. In this study, 5 infants presented with acute nephritic syndrome with apparent and persistent hematuria, which is uncommon in congenital/idiopathic nephrotic syndrome. Renal pathology revealed thrombotic microangiopathy (TMA) changes, but hemolytic anemia or thrombocytopenia were absent in these patients. By exclusion of infectious diseases and immune-mediated renal diseases, and with the test results of alternative complement pathway components and genetic sequencing, a possible diagnosis of complement-mediated renal-limited TMA was considered. Rapid improvement was achieved in all 4 patients treated with eculizumab. Renal-limited TMA is rare in children and has not been reported in infants. Renal biopsy, genetic sequencing, and testing of alternative complement pathway-related factors may be highly valuable for precision diagnosis and therapy in patients with suspected TMA.