Nutrients

Obesity and related cardiometabolic diseases pose significant global health challenges. Konjac glucomannan, a soluble dietary fiber, has shown promise in managing these conditions. However, rigorous studies are necessary to establish its benefits on human health. We designed a parallel-arm, triple-blind, placebo-controlled RCT to test the effects of glucomannan (3 g/day, 12 weeks) on body weight and composition, lipid profile, glucose metabolism, inflammation, adipokines, intestinal permeability, gut microbiota, and fecal metabolites in 40 adults. Participants were randomly assigned to either the glucomannan or placebo group, with both groups adhering to personalized hypocaloric diets and moderate physical activity. Outcomes were analyzed as intention-to-treat using linear mixed-effect models. Irrespective of the treatment, our intervention reduced body weight (mean: -2.39 kg; 95% CI: -3.38, -1.40), BMI (-0.83 kg/m2; -1.15, -0.52), and waist (-2.70 cm; -3.87, -1.53). Glucomannan promoted additional benefits not obtained with the placebo, reducing body fat measured by DEXA (body fat%: -2.16%; -3.04, -1.28; VAT: -20.0 cm2; - 29.2, -10.8; FMI: -0.98 kg/m2; -1.34, -0.62), LDL (-14.1 mg/dL; -23.4, -4.9), and the atherogenic index (-0.50; -0.80, -0.21). It also diminished the Framingham score of 10-year risk of coronary heart disease (-0.370; -0.625, -0.115), C reactive protein (-1.01 mg/L; -2.18, 0.15), leptin (-2.06 ng/mL; -4.48, 0.365), and leptin/adiponectin (-0.282; -0.603, 0.040). The two treatments had similar intakes, physical activity, and adherence to the intervention. There were no adverse effects. This intervention fostered health benefits in a population at high risk of cardiometabolic diseases. Konjac glucomannan was an effective co-adjuvant for further reducing risk factors.

Although the co-occurrence of diarrhea and malnutrition is well documented, research has largely focused on the acute management of diarrheal illness. Despite its importance, longitudinal evidence characterizing post-diarrheal recovery trajectories is sparse. We sought to characterize post-diarrheal nutritional recovery trajectories among children aged 6-35 months who were malnourished at enrollment using data from the Enterics for Global Health (EFGH) Shigella Surveillance study (2022-2024). EFGH enrolled children aged 6-35 months presenting with medically-attended diarrhea and followed them at 4 weeks and 3 months post-enrollment. This analysis included children with baseline wasting, stunting, or underweight (z-score < -2) and complete anthropometric follow-up. Latent class mixed-effects models were used to identify distinct post-diarrheal growth trajectories based on changes in anthropometric z-scores over time. Multinomial modified Poisson regression models examined associations between baseline factors and trajectory membership. Among 9,480 enrolled children, 16.5% (n=1,561) were wasted, 22.7% (n=2,155) stunted, and 21.0% (n=1,994) underweight at baseline. Wasting showed greater recovery potential (80.8%) compared with stunting (38.5%) and underweight (40.3%). Recovery was shaped by factors across multiple levels. Clinical severity markers ( prolonged diarrhea, dehydration, and hypoxemia) increased the risk of nutritional failure. Age also influenced outcomes: infants were more likely to worsen, whereas older toddlers more often experienced stagnation. Interventions including exclusive breastfeeding, oral rehydration therapy, appropriate antibiotics, and zinc supplementation, improved outcomes, while unimproved sanitation undermined recovery. These findings highlight the need for integrated strategies combining infection control, nutritional rehabilitation, and water, sanitation, and hygiene interventions tailored to the childrens developmental stage. Key MessagesO_LIPost-diarrheal nutritional recovery is highly heterogeneous, with wasting showing the greatest potential for improvement, while stunting and underweight often result in persistent growth stagnation. C_LIO_LIBaseline anthropometric deficits alone are insufficient to predict recovery, highlighting the need for dynamic monitoring and individualized management. C_LIO_LIInfants are particularly vulnerable to acute nutritional deterioration, while older toddlers frequently experience growth stagnation. C_LIO_LIModifiable protective factors including exclusive breastfeeding, ORS, zinc, and appropriate antibiotics, improved outcomes, whereas poor sanitation undermined recovery. C_LIO_LIIntegrated strategies, tailored to a childs developmental stage, combining clinical care, nutrition, and environmental interventions are critical to support sustained child growth and development. C_LI

Child undernutrition remains a major public health challenge in Kenya. Suboptimal feeding practices contribute significantly to persistent underweight and stunting. This study evaluated the effect of a community-based Positive Deviance Hearth (PDH) intervention on feeding practices among children aged 6-59 months in Sub County within a County of study. The study adopted a two-group pretest-posttest randomized experimental study design conducted for six months period, among 84 caregiver-child pairs in intervention and control groups. A multi-stage sampling was employed to identify study settings and participants. Structured and pretested questionnaires, 24-hour food recall questionnaires and meal diversity questionnaires were used for data collection at pre-intervention and post-intervention periods. Data was analyzed using R software v.4.5.2. The differences between intervention and control groups at baseline and endline were assessed using difference-in-difference analysis, relevantly summarized using adjusted DID estimates, 95% confidence intervals and p-values, with p<0.05 considered significant. The PDH intervention significantly improved feeding practices among children 6-59 months. Meal frequency increased for 9-23 months (DiD = +1.4; 95% CI: 1.2-1.7; p = 0.034) and 24 months and above (DiD = +1.2; 95% CI: 1.1-1.5; p = 0.017), and dietary diversity rose (DiD = +1.3; 95% CI: 1.1-1.9; p < 0.001). Nutrient-dense food consumption improved, including legumes (DiD = +32.6%; p < 0.001) and animal-source foods (DiD = +35.4%; p < 0.001). Energy and protein intake increased across all age groups (p < 0.05), and micronutrients iron, vitamin A, vitamin C also rose significantly (p < 0.05). The PDH intervention substantially improved caregiver feeding practices, increased dietary diversity, and enhanced macro- and micronutrient intake, demonstrating its effectiveness as a scalable, community-driven strategy for sustainably improving child nutrition in high-burden settings.

BackgroundPaediatric liquid medicines (PLMs) routinely contain sucrose to improve palatability, yet their cariogenic potential is well established. Healthcare professionals awareness and prescribing practices regarding sugar-free PLMs have received limited study in India, particularly in Uttarakhand. MethodsA descriptive cross-sectional study was conducted among 500 healthcare professionals aged [&ge;]25 years, using a pilot-tested structured questionnaire (Cronbachs = 0.85), administered online and in person across Uttarakhand districts (January-March 2024). After excluding 69 incomplete responses, 431 participants were analysed (response rate: 86.2%), comprising general medicine practitioners (49%, n = 211), paediatricians (27%, n = 116), and dental practitioners (24%, n = 104). Descriptive statistics and chi-square tests were applied (p < 0.05). ResultsPrescription decisions were primarily driven by childs age and weight (58%), cost (40%), and pharmaceutical brand (37%). While 88% recognised PLM sweetness and 67% were aware of pH-dental harm links, only 20% associated PLMs with dental caries. Overall awareness of hidden sugars was 73%. Eighty-three percent knew of sugar-free alternatives (50% local availability), yet 80% found them less palatable and 85% costlier. Only 48% routinely provided oral health advice. A statistically significant association was found between specialty and sugar-free PLM awareness (p = 0.03), with dental practitioners recording the highest awareness (90%). ConclusionsHealthcare professionals demonstrated variable levels of knowledge, attitudes, and practices regarding PLMs, with critical gaps in caries recognition (20%) and oral health counselling (48%). Despite high sugar-free PLM awareness, uptake is constrained by perceived cost and palatability barriers. Targeted continuing medical education and policy measures, including sucrose-free labelling promotion, are needed to improve paediatric oral health outcomes in Uttarakhand. KEY MESSAGESO_LIOnly 20% of healthcare professionals in Uttarakhand associated pediatric liquid medicines (PLMs) with dental caries, representing a critical knowledge gap despite 88% recognising their sweetness. C_LIO_LIOverall awareness of hidden sugars in PLMs was 73%, yet only 48% routinely provided post-prescription oral health counsellingsubstantially below international benchmarks. C_LIO_LIEighty-three percent were aware of sugar-free PLM alternatives, but adoption was constrained by perceived inferior palatability (80%) and higher cost ([~]10% premium, cited by 85%). C_LIO_LIDental practitioners demonstrated significantly higher sugar-free PLM awareness than general practitioners and pediatricians (p = 0.03), supporting the case for interprofessional oral health education in medical training. C_LIO_LITargeted continuing medical education (CME) and policy measuresincluding sucrose-free labelling mandates and institutional formulary inclusionare needed to convert awareness into prescribing practice change. C_LI

Dropout from essential maternal health services across pregnancy, childbirth, and the postnatal period remains a major barrier to improving maternal and neonatal outcomes in Bangladesh. This study examined stage-specific dropout patterns along the maternal continuum of care and identified factors associated with discontinuation. We analysed nationally representative data from the Bangladesh Demographic and Health Survey 2022 for 5,162 women with a recent live birth. Dropout from antenatal care, skilled birth attendance, and postnatal care was examined using multivariable logistic regression to estimate adjusted odds ratios and 95% confidence intervals, with comparisons to BDHS 2017-18 and assessment of regional variation. Only 44% of women received four or more antenatal care visits. Of these, 33% delivered with a skilled birth attendant, and among those receiving both antenatal care and skilled delivery, only 15% received postnatal care within 48 hours. Overall, 57% dropped out before completing adequate antenatal care, with additional dropouts between antenatal care and delivery (10%) and between delivery and postnatal care (18%). Compared with 2017-18, overall dropout from the maternal continuum of care more than doubled in 2022 (5.0% to 11.7%), driven by increased antenatal care dropout, while skilled birth attendance dropout declined and postnatal care dropout increased slightly. Higher maternal education, household wealth, media exposure, and womens decision-making power were consistently associated with lower odds of dropout, whereas higher birth order increased dropout risk. Substantial regional variation was observed, with the highest overall dropout in Sylhet and the lowest in Khulna. High dropout from the maternal continuum of care in Bangladesh occurs predominantly at the antenatal care stage and is shaped by socioeconomic status, birth order, womens access to information, and regional disparities. Strengthening early antenatal engagement and womens decision-making autonomy is critical to improving continuity of maternal care and reducing preventable maternal and neonatal risks.

Gingival inflammation is associated with dysbiotic oral biofilms characterized by reduced nitrate-reducing capacity and diminished nitric oxide (NO) bioavailability. While dietary nitrate has been shown to influence oral microbial activity, the effects of sustained, localized nitrate delivery on oral biofilm ecology and gingival inflammation remain incompletely defined. In this randomized, double-blind, placebo-controlled trial, 30 adults with gingival bleeding were assigned to receive localized prebiotic nitrate (~0.989 mmol per dose) or placebo for 21 days. The primary outcome was mean bleeding on probing (mBOP). Secondary outcomes included modified Gingival Index (mGI), Quigley-Hein plaque index (QHPI), salivary nitrite (as a proxy for NO bioavailability), oral pH, and microbiome composition assessed by 16S rRNA gene sequencing. Prebiotic nitrate supplementation formulation delivered in a slow-release chewing gum significantly reduced mBOP (25.7% to 15.3%; p = 0.0002) compared to placebo chewing gum. Salivary nitrite levels and oral pH increased, indicating enhanced nitrate metabolism. Microbiome analysis demonstrated enrichment of nitrate-reducing taxa, including Rothia mucilaginosa and Neisseria spp., and a relative reduction in inflammation-associated genera such as Prevotella and Porphyromonas. Localized prebiotic nitrate formula delivered in a functional chewing gum was associated with reduced gingival inflammation and shifts in oral microbiome composition consistent with enhanced nitrate-reducing capacity critical in nitric oxide formation. These findings support a role for biofilm-directed nutritional modulation as a non-antimicrobial approach for managing gingival inflammation and improving nitric oxide bioavailability.

Gene-environment interactions (GEI) contribute to circulating polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) profiles. GEI may partly explain differences in trait variance across genotype groups. To identify GEI for circulating unsaturated fatty acids, we adopted a two-stage strategy. First, we detected quantitative trait loci associated with trait variance (vQTLs). Second, we tested these vQTLs for interaction with fish oil supplements (FOS). We performed genome-wide vQTL screens for 14 plasma PUFA and MUFA phenotypes in a UK Biobank subset of 200,478 participants. At the genome-wide significance threshold (p < 5.0 x 10-8), we identified 172 vQTL-trait pairs across all 14 traits, and 16 of these vQTLs had no marginal genetic effect on the corresponding trait. We found 46 non-overlapping loci across all phenotypes, with an average of 12 vQTLs per trait. Omega-6% and PUFA% had the most independent vQTLs (N = 24) while DHA% and Omega-3% had the least (N = 1 and 2, respectively). For each of the 172 vQTL-trait pairs, we tested the interaction effect of the vQTL with FOS on the corresponding trait. We found six significant interaction signals in DHA, DHA%, Omega-3, Omega-3%, LA, and Omega-6/Omega-3 ratio around the FADS1/2, ZPR1, and SUGP1/TM6SF2 genes. Our results provide a comprehensive resource of vQTLs and gene-FOS interactions shaping the circulating levels of unsaturated fatty acids.

Objective: To investigate in the National School Feeding Program (PNAE) the local level drivers and barriers to the implementation of four guidelines: the banning of sugary drinks; restrictions on the procurement of processed and ultra-processed foods; the mandatory increase in weekly servings of fruits and vegetables offered to students; and mandatory direct procurement from family farmers. Design: Qualitative study that used semi-structured interviews. Street level bureaucracy theory informed the theoretical framework and thematic analysis. Setting: Brazilian municipalities, across the country five geographic regions (North, Northeast, Southeast, South, and Midwest). Participants: Stakeholders (e.g. nutritionists, school cooks, and food procurement managers) involved in the local implementation of the PNAE program across the country. Results: Ninety stakeholders were interviewed. Stakeholders reported having autonomy to perform their activities, collaboration and support from other members within the local government and food providers, adequate infrastructure such as a well-equipped kitchens, the availability of trained personnel, and political commitment as drivers for optimum program implementation. Reported barriers included lack of support and resistance to change among cooks, teachers and parents; insufficient physical and human resources; and limited political commitment. When barriers outweighed drivers, interviewees reported adapting their practices, often in restrictive ways that could compromise the implementation of the program. Conclusions: Drivers and barriers to local PNAE implementation were generally similar across studied municipalities, although their magnitude varied. In contexts of greater economic vulnerability and fiscal constraint, additional support and targeted actions from the federal government may be required to strengthen local implementation

Diet is an important ecological modulator of the oral microbiome, yet population-level evidence on a broader spectrum of food components remains limited. This cross-sectional study investigated associations among dietary intake, oral rinse microbiome, and oral disease conditions in a nationally representative sample of United States adults from the National Health and Nutrition Examination Survey. A total of 3,254 participants with oral rinse microbiome sequencing data were included, with oral conditions classified as oral health, caries-only, periodontitis-only, or co-existing disease. Dietary intake was assessed using 24-hour dietary recalls and summarized as dietary indices and energy-adjusted food components. Associations between diet and the oral microbiome were evaluated using community-level analyses, regression models, mediation analyses, and unsupervised clustering, while accounting for oral conditions. This study found that dietary intake, as a combined variable set, explained 3.6% of the variance in oral rinse microbial community structure; this was comparable to oral disease status or smoking and larger than sociodemographic factors. Healthier dietary profiles, including higher health-associated dietary index scores and greater vegetable and fruit intake, were associated with taxa commonly linked to oral health (e.g., Neisseria, Cardiobacterium and Lautropia). In contrast, added sugars, alcoholic drinks, cured meat, potatoes, dairy products, and higher dietary inflammatory index scores showed opposite association patterns. Mediation analyses suggested that coordinated microbial groups may partly link dietary exposures with oral disease outcomes, particularly for vegetables and added sugars. Additionally, three population-level dietary patterns were identified, among which the plant-rich pattern was associated with more favorable oral health and microbial profiles enriched in nitrate-reducing commensals, including Neisseria and Haemophilus. Overall, dietary intake was associated with oral microbiota composition and oral health conditions, supporting ecological influences of dietary components beyond sugar on oral bacteria and dental diseases. Longitudinal studies are needed to clarify the direction and causality of these relationships.

IntroductionIncreasing global prevalence of overweight and obesity underscores the need for context-specific evidence to guide preventive policy implementation. Previous modelling showed that promoting healthy indigenous foods, implementing a 20% tax on sugar-sweetened beverages (SSBs), and introducing mandatory kilojoule menu labelling in formal-sector restaurants in Kenya were health-promoting, cost-saving, and cost-effective. Cost-effectiveness evidence is strengthened when considered alongside broader policy implementation considerations. We engaged stakeholders to assess additional implementation considerations relevant to decision-makers and to evaluate the stakeholder engagement process used in the modelling study. MethodsUsing the Assessing Cost-Effectiveness approach, we conducted a stakeholder-engaged study with national-level Kenya stakeholders recruited through purposive and snowball sampling. Through deliberative dialogue at a hybrid workshop, stakeholders assessed implementation considerations such as equity, feasibility and sustainability using a colour-coded scoring tool. We evaluated the engagement process using an anonymous survey covering seven stakeholder-engaged research domains. We analysed responses thematically. ResultsAcross the three interventions, most implementation considerations for feasibility, reach and impact, affordability, acceptability, and sustainability were assessed as medium or high. Industry acceptability of kilojoule labelling and SSB tax and affordability of kilojoule labelling to industry were rated low. Equity scores varied. Stakeholders proposed complementary measures that could raise low ratings to favorable scores. Clarity on stakeholder roles was identified as a key strength of the engagement process, while competing time commitments limited participation. ConclusionStakeholder insights contextualise prior cost-effectiveness evidence within policy-relevant implementation considerations and inform current fiscal and regulatory debates. Evaluation of the stakeholder engagement process underscores its contribution to strengthening public health research.

ABSTRACT Background Before obtaining professional medical care, many people in peri-urban and rural Pakistan contact herbalists, spiritual healers, and unlicensed caregivers. This study examined the social, economic, and cultural factors influencing the use of informal care by analysing the health-seeking behaviours of individuals in the Faisalabad District. Methods An exploratory mixed-methods study was conducted in Makkuana and the surrounding villages of Faisalabad District, Punjab. The quantitative component involved a cross-sectional survey of 69 adults using a structured questionnaire adapted from the I-CAM-Q. The qualitative component comprised twelve in-depth interviews and two focus group discussions. Descriptive statistics and chi-square analysis were used for quantitative data. Thematic analysis, guided by the Health Belief Model and Andersen's Behavioural Model, was applied to qualitative data. Results The mean age of participants was 40.4 years; 62.3% were female, and 79.7% had monthly household incomes below PKR 60,000. Of the 69 participants, 68 (98.6%) sought care from an informal provider first, most commonly an unqualified practitioner (50.7%), herbal practitioner (29.0%), or homeopath (17.4%). Trust was the leading reason for provider choice (43.5%), followed by proximity (24.6%) and low cost (15.9%). Complications were reported by 21.7% of participants, and 39.1% later required formal care for the same illness. Eight qualitative themes emerged: structural and economic barriers to formal care; proximity and convenience as determinants of informal care; trust, familiarity, and social networks; cultural and religious normalisation of traditional practices; poor doctor-patient communication in formal settings; perceived safety and naturalness of alternative remedies; awareness deficits about provider qualifications; and treatment-related harm and delayed escalation to formal care. Conclusion Informal health care seeking is nearly universal in this community, driven by intersecting economic, structural, cultural, and interpersonal factors. Enhancing primary care affordability, accessibility, and the quality of provider-patient communication together with culturally sensitive health literacy programs, is essential to redirect care seeking toward qualified providers.

OBJECTIVE: To evaluate the return on investment (ROI) of a community based Diabetes Self Management Program (DSMP) enhanced with health related social needs (HRSN) screening and referrals, implemented by the New York City (NYC) Department of Health and Mental Hygiene with three community based organizations in highly impacted, under resourced neighborhoods. RESEARCH DESIGN AND METHODS: A retrospective cost benefit analysis from a public sector payer perspective was conducted among 171 adults with type 2 diabetes who completed a six week, peer led DSMP delivered by community health workers (CHWs) in English, Spanish, and Korean during 2018 2019. A time driven, activity based costing model captured direct implementation costs, CHW workforce turnover, and administrative overhead. Monetized benefits included avoided diabetes related complications, reductions in self reported emergency department (ED) visits and hospitalizations, and quality adjusted life year (QALY) gains from improved medication adherence. Univariate sensitivity analyses tested robustness under conservative assumptions. RESULTS: Total program costs were $179,224; monetized benefits totaled $1,824,213, yielding a net benefit of $1,644,989 and an ROI of 918%, approximately $10 returned per $1 invested. Excluding QALY gains, ROI remained 551%. Self reported ED visits declined from 149 to 82 and hospitalizations from 93 to 24 in the six months following intervention. Over 80% of participants reported housing instability; 72% were Medicaid covered and 16% uninsured. Sensitivity analyses confirmed a positive ROI under all conservative scenarios. CONCLUSIONS: A CHW led, community based DSMP integrated with HRSN screening and referrals delivered substantial economic and public health value among adults facing housing instability and structural barriers to care. Findings support inclusion of DSMP as a covered benefit in Medicaid managed care, value based payment arrangements, and housing access initiatives to advance equitable diabetes outcomes.

Background: Elevated lipoprotein(a) [Lp(a)] is a known risk factor for several cardiovascular-related diseases established from multiple genetic and observational studies. However, the underlying mechanisms mediating the effects of Lp(a) levels on cardiovascular disease risk and major adverse cardiovascular events (MACE) are unclear. The aim of this study was to identify proteins downstream of Lp(a) using mendelian randomization (MR) - a genetic causal inference approach. Methods: A two-sample MR was performed by initially identifying Lp(a) genetic instruments based on data from genome wide association studies (GWAS) of Lp(a) blood concentrations. These instruments were then tested for association with proteins from proteomic pQTL data (Olink from UK Biobank, 2940 proteins and SomaScan from deCODE, 4907 proteins). Results: A total of 521 proteins associated with Lp(a) were identified. Using pathway enrichment analysis, the following MACE-relevant pathways were identified comprising a total of 91 Lp(a) downstream proteins: oxidized phospholipid-related, chemotaxis of immune cells and endothelial cell activation, pro-inflammatory monocyte activation, neutrophil activity, coagulation, and lipid metabolism. Conclusion: The results suggest that the influence of Lp(a) treatments is primarily through modifying inflammation rather than lipid-lowering, thus providing insight into the mechanistic framework which mediates the effects of elevated Lp(a) on atherosclerotic cardiovascular disease.

(1) Aims and hypothesisLoss-of-function mutations in SLC30A8, encoding the zinc ion (Zn2+) transporter ZnT8 in pancreatic beta cells, lower type 2 diabetes risk dose-dependently, but the underlying mechanisms remain unclear. Here, we combine proteomic, transcriptomic and functional approaches in human stem cell-derived islet-like clusters bearing common alleles or the inactivating variant R138X. We hypothesized that this variant protects against the deleterious effect of Zn2+ depletion on cell survival and function. (2) MethodsHuman embryonic stem cells INS(GFP/w) (MEL1), and CRISPR/Cas9-derived heterozygous or homozygous R138X lines were differentiated into stem cell-derived islet-like clusters. Intracellular Zn2+ levels were reduced using the chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-1,2-ethanediamine (TPEN). Apoptosis was assessed by TUNEL staining and protein expression by immunofluorescence. Glucose-stimulated calcium (Ca2+) dynamics were measured using the intracellular probe (Cal590) and insulin secretion by homogenous time-resolved fluorescence. Transcriptomic profiling was performed by bulk mRNA sequencing and proteomics by liquid chromatography-tandem mass spectrometry. (3) ResultsIntracellular Zn2+ depletion increased apoptosis in wild-type islet-like clusters, whereas R138X clusters were protected. R138X heterozygous clusters showed a mild increase in GCG+ cells and R138X homozygous clusters exhibited increased NKX6.1+ cells, without affecting polyhormonal populations. These changes were reversed under Zn2+ depletion. Transcriptomic and proteomic analyses, assessing genotype effects while accounting for Zn2+ depletion, showed that R138X clusters (versus wild-type) exhibited upregulation of genes and proteins involved in vesicle trafficking, secretion, Ca{superscript 2} signaling and mitochondrial metabolism, consistent with enhanced glucose-stimulated insulin secretion in homozygous clusters. Conversely, genes and proteins associated with extracellular matrix remodeling, metal-ion handling, apoptosis and cellular stress were downregulated. R138X clusters displayed altered Ca2+ signaling, with decreased area under the curve and oscillation amplitude, but increased frequency. These differences were reversed by TPEN, while Zn2+ depletion impaired Ca2+ response in wild-type clusters. Despite lowered overall activity, R138X homozygous clusters showed enhanced overall cell-cell connectivity, reversed by TPEN treatment. The opposite effects were observed in R138X heterozygous clusters, showing improved connectivity and activity under Zn2+ depletion. (4) Conclusion and interpretationIntracellular Zn2+ depletion compromises islet-like cluster identity and function, while the R138X variant confers protection against these effects. Under Zn2+-depleted conditions, ZnT8 deficiency promotes a more mature and metabolically active state of the R138X clusters, with enhanced Ca2+ signaling and insulin secretion, supported by a structural remodeling and the downregulation of apoptosis and cellular stress. These findings highlight the therapeutic potential of targeting ZnT8 in type 2 diabetes and support its relevance for further improving cell-based therapies. Research in ContextO_ST_ABSWhat is already know about this subject?C_ST_ABSO_LIRare inactivating mutations in the insulin granule-associated zinc transporter gene, SLC30A8/ZnT8, drive lowered type 2 diabetes risk. C_LIO_LIPrevious studies have indicated that apoptosis is lowered, and glucose-stimulated insulin secretion enhanced, after ZnT8 inactivation. C_LIO_LIThe molecular mechanisms underlying these changes are unclear. C_LI What is the key question?O_LIHow do inactivating mutations in SL30A8/ZnT8 lead to lowered apoptosis and enhanced insulin secretion from stem cell-derived islet-like clusters, and is altered susceptibility to intracellular zinc depletion involved? C_LI What are the new findings?O_LIThe rare inactivating R138X mutation in SLC30A8 leads to gene dose-dependent changes in the transcriptome and proteome of islet-like clusters. C_LIO_LIChanges include upregulation of maturity and downregulation of immaturity genes. C_LIO_LIDepletion of intracellular Zn2+ exaggerates the protective effects of the inactivating mutation on apoptosis and insulin secretion C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings suggest that careful monitoring of both dietary zinc intake and of circulating levels of zinc ions, whose effects are mitigated in SLC30A8 mutation carriers, may be helpful in some populations to lower diabetes risk. C_LI

Introduction: Accurate stratification of hard atherosclerotic cardiovascular disease (ASCVD) risk remains challenging despite advances in prevention. Liver function biomarkers (LFBs), particularly gamma - glutamyl transferase (GGT), have been linked to cardiovascular outcomes, yet their contribution to hard ASCVD risk prediction is not well defined. Methods: This study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2005 - 2018) to assess cross - sectional associations between LFBs and 10 - year hard ASCVD risk estimated by the ACC/AHA Pooled Cohort Equations. Multivariable regression, restricted cubic splines, and mediation analyses were applied to examine independent and dose - response relationships. External validation was performed in the China Health and Retirement Longitudinal Study (CHARLS) and NHANES using machine learning models (CoxBoost, Naive Bayes and Random Forest). Results: Among 5,731 NHANES participants, GGT showed an independent linear association with hard ASCVD risk (P - trend = 0.003), partly mediated by systolic blood pressure (44.8%), HbA1c (19.0%), and high density lipoprotein cholesterol (13.4%). Machine learning (ML) models incorporating GGT, alkaline phosphatase (ALP), and globulin alongside traditional risk factors improved predictive accuracy, with Naive Bayes achieving an AUC of 0.751 in NHANES validation. Conclusions: GGT is an independent and biologically plausible biomarker of hard ASCVD risk, acting through cardiometabolic pathways. Incorporating LFBs into risk prediction models, particularly with machine learning, enhances risk stratification and may facilitate early identification of high - risk individuals.

Ambulatory Care Sensitive Conditions (ACSCs) are conditions for which effective and timely primary health care (PHC) can prevent hospitalizations. They are widely used as a proxy indicator of access to and quality of PHC. Despite their relevance, evidence from Central America remains scarce. This study aimed to quantify the burden, describe the epidemiological profile, and assess temporal trends of ACSCs hospitalizations in Honduras from 2014 to 2024. We conducted a retrospective observational study using national administrative hospital discharge data from all Ministry of Health hospitals. ACSCs were defined using a standardized list of 20 diagnostic groups based on ICD-10 codes. We estimated percentages and sex-age-standardized hospitalization rates per 10,000 inhabitants. Clinical indicators included length of stay (LOS) and in-hospital fatality rates. Temporal trends were evaluated using joinpoint regression models to estimate annual percent changes (APC). Analyses included stratification by age, sex, and disease category. A total of 4,023,944 hospitalizations were analyzed, of which 547,486 (13.6%) were classified as ACSCs. The overall sex-age-standardized rate was 54.1 per 10,000 inhabitants. ACSCs' standardized rates increased between 2014 and 2018 (APC: 2.7%; 95% CI: -2.4; 15.2), declined sharply between 2018 and 2021 (APC: -17.8%; 95% CI: -30.6; -10.3), and increased again between 2021 and 2024 (APC: 15.9%; 95% CI: 4.6; 37.6). Despite this rebound, rates remained below pre-pandemic levels. ACSCs were concentrated among children under 5 years (27.7%) and adults aged 60 years and older (29.9%). Noncommunicable diseases accounted for 56.8% of cases, with diabetes mellitus as the leading cause. Compared with non-ACSCs hospitalizations, ACSCs were associated with longer LOS (4.9 vs. 3.9 days; p <0.001) and higher in-hospital fatality rates (2.4% vs. 1.7%; p <0.001). ACSCs hospitalizations constitute a substantial burden in Honduras and reflect persistent gaps in PHC performance. Strengthening PHC resilience and capacity, particularly for chronic disease management and vulnerable populations, is essential to reduce avoidable hospitalizations and improve health system efficiency and equity.

Introduction: Physical inactivity and sedentary behaviour are significant risk factors for noncommunicable diseases. Engaging in regular physical activity (PA) during childhood is crucial for preventing long-term health burdens. This study examined PA levels and associated factors among upper primary school children in Lusaka, Zambia. Methodology: A cross-sectional survey was conducted from August to October 2022 among 638 children aged 9-18 years from six public and six private schools. Data were collected using the Physical Activity Questionnaire for Children (PAQ-C), Youth Risk Behaviour Survey (YRBS), Model of Youth Physical Activity Questionnaire (MYPA), and 3-Day Physical Activity Recall Questionnaire (3DPAR). Analyses included descriptive statistics, Chi-square, Fishers exact tests and multivariable binary logistic regression at a 0.05 significance level and 95% confidence interval. Results: Most participants (82%) were insufficiently active, with only 18% achieving sufficient PA. Reported barriers included lack of playgrounds or parks near home (p=0.012), neighbourhood safety concerns (p=0.041), and limited parental supervision (p=0.006). Watching television reduced the odds of PA by 69% (aOR=0.31; 95% CI: 0.13-0.75). Conversely, peer support increased activity by 15% (aOR=1.15, 95% CI: 0.67-1.97), while not being concerned about showering or fixing hair after PA increased activity by 94% (aOR=1.94; 95% CI: 1.21-3.11). Conclusion: The majority of school children in this study did not meet recommended PA levels. Barriers to activity included personal, parental, and environmental factors. Interventions should prioritise safe play spaces, increased parental and peer support, and reduced screen time to curb future non-communicable disease risks.

Background: Sub-Saharan Africa (SSA) still experiences a high burden of micronutrient deficiencies. For monitoring of micronutrient status among young children in SSA, non-invasive alternatives to blood-based biomarkers are desirable. Handheld Raman spectrophotometry appears to offer this alternative to quantify intracellular stores of micronutrients. In rural Burkina Faso and Kenya, we validated the Cell-/SO-Check device (ZellCheck(R)) against conventional laboratory-based methods. Methods: For this validation study, we recruited children aged [&ge;]24 months attending routine clinics within the Health and Demographic Surveillance Systems (HDSS) in Siaya and Nouna. Anthropometric measurements and venous blood samples were taken. Plasma ferritin, soluble transferrin receptor (sTfR) and C-reactive protein (CRP) were measured by ELISA, and plasma zinc by atom absorption. The spectrometer was used to quantify zinc and iron. For continuous outcomes, we generated Bland Altman plots and calculated bias and limits of agreement (LoA). For binary outcomes, we produced Receiver Operator Characteristic (ROC) areas under the curve (AUC), and estimated sensitivity, specificity and predictive values. Results: We analysed data of 48 children from Burkina Faso and 54 children from Kenya (male: 53%; age range: 24-66 months). According to spectrophotometry, the proportions of iron deficiency and zinc deficiency were 16.7% and 25.5%, respectively. The median concentrations were for ferritin 24.0 {micro}g/L (range: 2.0-330.0), for sTfR 5.7 mg/L (2.8-51.0), and for zinc 9.9 {micro}mol/L (5.2-25.0). The corresponding bias for iron levels by spectrophotometry was 42.4 with LoA: -18.7, 103.6. The bias for zinc levels was 7.5 with LoA: -49.3, 64.2. For the classification of deficiency, the ROC-AUC, sensitivity, and specificity for spectrophotometry vs. biomarker-based diagnosis were for iron deficiency 0.62, 68% and 55%, respectively, and for zinc deficiency 0.55, 33% and 91%, respectively. Conclusions: The Cell-/SO-Check device may be used to rank children in population-based studies in SSA according to their zinc status, but not iron status. The method should not replace the standard laboratory measurements for clinical diagnoses of zinc and iron deficiencies.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Objectives: To identifiy risk factors for antimicrobial resistance (AMR) in seven pathogen-antimicrobial combinations in patients with cancer and cancer survivors. Methods: Using data from patients with recent or past cancer diagnostic codes in Oxfordshire, UK, we examined associations between 22 potential risk-factors and AMR in blood culture isolates, collected between 1-April-2015 and 31-March-2025. Results: Among 5,975 bacteraemias in 4,365 adults, we analysed 3,141 (52.6%) due to Enterobacterales and 620 (10.4%) due to Enterococcus faecalis/faecium in 2,752 patients. Fourteen risk-factors for antimicrobial-resistant bacteraemia were identified, varying across pathogen-antimicrobial combinations. Compared with no previous antimicrobial susceptibility test result, prior resistance to the same antibiotic in any culture in the last year was strongly associated with AMR across all pathogen-antimicrobial combinations (all p<=0.001). Prior antibiotic exposure and younger age were also positively associated with AMR in four and five combinations, respectively. Cancer type showed modest effects; lymphoid/haematopoietic malignancies were associated with higher odds (vs colorectal cancer) of trimethoprim-sulfamethoxazole-resistant Enterobacterales (aOR=2.07 95%CI 1.40-3.06) and vancomycin-resistant Enterococcus bacteraemia (aOR=6.68, 1.21-36.91). Conclusions: Previous resistance was the greatest risk factor for bacteraemia with AMR in cancer patients and survivors, with prior antibiotic exposure and age also contributing. Lymphoid/haematopoietic malignancies increased risk of resistance to specific antimicrobials. Keywords: antimicrobial resistance, bacteraemia, cancer, risk factors