BMC Nephrology

Introduction: Kidney volume is associated with renal function, but conventional whole-organ measurements may miss regional changes in kidney substructures. We used magnetic resonance imaging (MRI) to test whether kidney substructure volumes and three-dimensional (3D) thickness phenotypes are associated with disease, adiposity, and incident outcomes. Methods: Automated abdominal MRI segmentations from 70,270 UK Biobank participants were used to quantify left and right kidney cortex, medulla, and parenchyma volumes and mesh-based thickness maps. Mass univariate regression generated statistical parametric maps linking regional thickness to anthropometric traits and disease (CKD, type-2 diabetes [T2D], hypertension). Bidirectional causal mediation analyses were performed using kidney substructure volumetric, thickness PCs and kidney adiposity. Longitudinal changes were assessed in 2,610 participants with repeat imaging. Cox proportional hazards models tested the associations between kidney volumes and principal component (PC) scores of thickness and incident CKD, T2D, hypertension, cardiovascular disease (CVD), and mortality. Results: CKD was associated with thinning of the parenchyma and most pronounced in the medulla (87.7% left, 72.8% right), whereas associations in the cortex were mixed. In contrast, T2D and hypertension were predominantly associated with increased thickness, most extensively in the cortex (T2D: 84.39% left, 96.35% right; hypertension: 94.8% left, 99.9% right). Age-disease interactions were associated with reduced thickness across all conditions. Smaller medulla volume and lower cortical thickness mediated the association between CKD and renal sinus fat. Kidney substructure volume was inversely associated with incident CKD across all substructures and both kidney sides (p<0.05), but positively associated with incident hypertension and mortality (p<0.05). Thickness PC scores also predicted outcomes independently of volume, with PC3 in the left cortex (HR 0.91 [0.84-0.98]), reflecting inferior pole/hilar thickness, associated with incident CKD. Conclusions: MRI-derived kidney substructure volumes and 3D thickness maps provide complementary, spatially-resolved markers of kidney morphology, that are mechanistically linked to renal adiposity and future disease risk.

Background: Chronic kidney disease (CKD) imposes persistent metabolic stress, yet whether metabolic organization can be preserved under sustained renal stress remains unclear. Essential trace elements support redox defense, mitochondrial function, and intermediary metabolism, and their homeostasis is disturbed in CKD; however, single-element supplementation has yielded heterogeneous results. We examined whether a defined multi-element formulation preserves metabolic resilience in CKD. Methods: In a randomized, double-blind, placebo-controlled trial, 80 maintenance dialysis patients received standard care alone (n = 40) or plus a trace element cocktail (TEX, 20 mL/day; n = 40). Longitudinal trajectories were analyzed with linear mixed-effects models; endpoint plasma metabolomics and fecal metagenomics were profiled in subsets. A 5/6 nephrectomy mouse model was used to quantify plasma tryptophan-pathway branches and renal spatial metabolism by MALDI imaging mass spectrometry. Results: TEX was well tolerated, with no treatment-related safety signal, and was associated with modestly more favorable creatinine and eGFR trajectories. Supplementation constrained, rather than erased, CKD-associated metabolic displacement (median |Cohen's d|, 0.25 versus 2.09 for disease effects), selectively realigning circulating metabolism toward the healthy state. The host kynurenine branch responded most strongly, whereas microbial indole metabolism and gut community structure changed little. Renal metabolic remodeling was region-specific, with preservation of selected tubular and antioxidant features. Conclusions: Trace element supplementation preserved metabolic resilience in CKD, limiting metabolic displacement without complete restoration. Preservation of metabolic organization may represent a complementary dimension of therapeutic response in CKD. Trial registration: International Traditional Medicine Clinical Trial Registry, ITMCTR2026000263 (registered 3 February 2026).

Abstract Background Health-related quality of life (HRQoL) is an important outcome in patients with chronic kidney disease (CKD) receiving kidney replacement therapy (KRT), but the relationship between comprehensive metabolic control and the Symptoms/Problems domain of kidney diseasespecific HRQoL remains uncertain. Objective To evaluate the association between composite metabolic control and the Symptoms/Problems domain of the Kidney Disease Quality of Life-36 (KDQOL-36) in patients with stage 5 CKD receiving KRT, and to explore the relationship between individual metabolic parameters and the continuous Symptoms/Problems score. Materials and Methods We conducted an observational, cross-sectional, analytical study of 177 adults receiving hemodialysis or peritoneal dialysis at a nephrology unit in Chihuahua, Mexico. Metabolic control included blood pressure, glycated hemoglobin (HbA1c), total cholesterol, and triglycerides. Adequate control was defined as achievement of at least three of four studydefined operational thresholds. The KDQOL-36 Symptoms/Problems score was analyze as a continuous variable and categorized as low, moderate, or high according to the study protocol. Group comparisons, Spearman correlations, Pearson chi-square tests, and ordinal logistic regression were performed. Results Adequate metabolic control was present in 106 patients (59.9%). No, statistically significant association was observed between achievement of at least three of four study-defined operational thresholds and Symptoms/Problems score category (x2=3.983; p=0.137; Cramers V=0.150). None of the individual metabolic parameters differed significantly across Symptoms/Problems score categories or showed significant correlations with the continuous score. In ordinal logistic regression, adequate metabolic control yielded an odds ratio of 1.81 (95% CI: 0.98-3.35; p=0.057) after adjustment for age, sex, time receiving KRT, and KRT modality. Conclusions No, statistically significant association was identified between the operational definition of metabolic control used in this study and the KDQOL-36 Symptoms/Problems domain in patients with stage 5 CKD receiving KRT. The findings support evaluating HRQoL multidimensionally and warrant confirmation in larger longitudinal studies. Categories: Family/General Practice, Internal Medicine, Nephrology Keywords: chronic kidney disease (ckd), hemodialysis, kdqol-36, kidney replacement therapy, metabolic control, peritoneal dialysis (pd)

Background: Genomic reassessment may reveal clinically relevant diagnoses in patients with young-onset kidney failure despite established clinical diagnostic labels. We evaluated this approach after excluding clinically apparent polycystic kidney disease (PKD). Methods: Among 1,139 patients receiving maintenance dialysis at participating Japanese facilities, 355 had initiated dialysis at age [&le;]50 years. After excluding 17 patients with clinically apparent PKD, 108 of 338 eligible patients underwent whole-genome sequencing through voluntary, nonrandom enrollment. Analysis included 465 nuclear candidate genes, mitochondrial DNA, and copy-number/structural variants. Clinically concordant diagnoses were adjudicated using integrated clinical and genetic evidence, with a separate pathogenic/likely pathogenic (P/LP)-supported subset. Results: Diagnoses were identified in 10/108 participants (9.3%; 95% confidence interval, 5.1-16.2), comprising seven renal and three systemic/metabolic diagnoses. Nine diagnoses were P/LP-supported (8.3%; 95% confidence interval, 4.4-15.1). The remaining diagnosis was phenotype-based clinical Dent disease associated with a CLCN5 variant of uncertain significance. Diagnoses occurred across diabetic kidney disease, nephrosclerosis, chronic glomerulonephritis, unknown-cause, and other clinical categories. In a post hoc analysis excluding three participants with low target coverage, the integrated and P/LP-supported proportions were 9/105 (8.6%) and 8/105 (7.6%). Six exploratory findings were excluded from both diagnostic numerators. Gitelman syndrome was included as a clinically manifest renal disorder, although its contribution to kidney failure remained uncertain. Conclusions: Integrated genomic assessment can uncover renal and systemic/metabolic diagnoses across conventional labels in young-onset kidney failure after exclusion of clinically apparent PKD. Nonrandom enrollment and variable sequencing coverage limit generalizability and interpretation of negative results.

Background: Chronic kidney disease (CKD) may progress to stage 5 CKD (end-stage renal disease, ESRD), but stage-associated molecular alterations remain incompletely characterized. This study aimed to identify candidate biomarkers associated with CKD and ESRD. Methods: Two discovery datasets comparing CKD or ESRD with healthy controls were analyzed using differential expression analysis and weighted gene co-expression network analysis. Candidate genes were identified by intersecting differentially expressed genes with key co-expression modules, followed by protein-protein interaction network analysis using Degree, Closeness, and Maximal Clique Centrality algorithms. Candidate genes were evaluated in independent GEO validation datasets and further examined by quantitative real-time PCR and western blotting using clinical blood samples. Results: Ten hub genes were identified, among which EPB42, KLF1, and H3F3A were prioritized for further evaluation. EPB42 showed decreased expression in CKD but increased expression in ESRD, indicating an opposite-direction pattern between the two disease states. KLF1 showed no significant difference between healthy controls and CKD but was increased in ESRD, whereas H3F3A was increased in CKD and further increased in ESRD. Functional enrichment analysis highlighted processes related to oxygen transport, mitochondrial function, muscle-associated processes, and inflammation, suggesting possible involvement of hypoxia-associated oxidative injury and ferroptosis-related processes. Conclusions: Integrated transcriptomic and experimental analyses identified EPB42, KLF1, and H3F3A as candidate stage-associated biomarkers in CKD and ESRD. In particular, the opposite-direction expression pattern of EPB42 may provide additional molecular information for distinguishing CKD from ESRD.

Importance. Plasma phosphorylated tau 217 (p-tau217) is entering clinical use with fixed diagnostic threshold that do not account for kidney function. Chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2), raises plasma p-tau217 concentrations and can produce false positive results. It remains unclear whether milder reductions in kidney function, above the CKD threshold, have the same effect. Objective. To determine whether plasma p-tau217 is elevated with mildly reduced kidney function, above the chronic kidney disease threshold, in adults without neurological disease. Design. Cross-sectional analysis of a cohort enrolled between 2023 and 2025 and biomarker analysis blinded to clinical data. Setting. Two private psychiatric inpatient facilities in Australia. Participants. Adults admitted with psychiatric disorders and free of neurological disease. Exposures. eGFR calculated from serum creatinine using the CKD-EPI 2021 equation. Main Outcomes and Measures. Plasma p-tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured on the Simoa platform. Multivariable linear regression compared eGFR groups (< 60, 60 to 90, and [&ge;] 90 mL/min/1.73 m2), adjusted for age, BMI, and sex. Results. Among 180 participants (median age, 50.5 years [IQR, 38.0-61.5]; 94 [52%] female), eGFR was [&ge;] 90 mL/min/1.73 m2 in 106 (59%), 60 to 90 in 61 (34%), and < 60 in 13 (7.2%). Compared with an eGFR [&ge;] 90, plasma p-tau217 was 36% higher in both the 60 to < 90 group ({beta} = 0.42 [95% CI: 0.11, 0.74]; P = .008) and 116% higher in the < 60 group ({beta} = 1.05 [95% CI: 0.43, 1.72]; P = .002). Plasma NfL and GFAP were elevated in the < 60 group but differences in the 60 to < 90 group did not reach significance. Modelled continuously, plasma p-tau217 was 9.5% lower per 10 mL/min/1.73 m2 higher eGFR (95% CI: 3.3%, 15.4%). Conclusions and Relevance. Plasma p-tau217 was elevated in adults with mildly reduced kidney function, above the CKD threshold, in a cohort free of neurological disease. Kidney function across its full range should be incorporated into plasma p-tau217 reference ranges and clinical interpretation to reduce false positive and false negative results.

Background. Fluid collections are common after kidney transplantation, but their prevalence at scheduled imaging and their management are inconsistent from canter to canter. We describe the cross sectional prevalence and management of perigraft collections, including an exploratory deepdrain subgroup. Methods. In this retrospective single center cohort, 146 consecutive adult kidney transplant recipients (Cleveland Clinic Weston Hospital, July 2024 to June 2025) were imaged on postoperative day 0/1 and at approximately 1 and 3 months. Routine deep drainage was avoided (n=124), 22 clinically selected recipients with perioperative anticoagulation received a deep drain. The primary outcome was cross sectional prevalence of a perigraft collection at each visit. Secondary outcomes were management among patients with a collection. Drain group comparisons were exploratory. Results. Collections were present in 29 of 146 recipients at postoperative day 0/1 (19.9%; 95% CI, 14.2 to 27.1), 71 of 146 at 1 month (48.6%; 95% CI, 40.7 to 56.7), and 34 of 146 at 3 months (23.3%; 95% CI, 17.2 to 30.8). Prevalence in the no drain group was 21.0%, 50.0%, and 23.4%, respectively; corresponding prevalence in the deep drain group was 13.6%, 40.9%, and 22.7%. Between group prevalence comparisons were not statistically significant at any time point. BMI was higher in the deep-drain group than in the no-drain group (30.04 vs 27.1 kg/m2; P=0.01). Among patients with a 1-month collection, management did not differ significantly between groups (any invasive management, 11.1% vs 16.1%; P=1.00). Among patients with a 3month collection, invasive management was more common in the deep drain group than in the no drain group (80.0% vs 13.8%; P=0.007). This comparison included only five deep-drain recipients and was confounded by clinical selection, perioperative anticoagulation, and BMI imbalance. Conclusions. Perigraft collection prevalence was highest at 1 month and lower at 3 months in this predominantly no drain cohort. Most collections were managed conservatively, and invasive treatment was uncommon in the no-drain group. The deep drain subgroup provides clinically relevant information about high risk recipients selected for drainage but cannot support causal conclusions regarding drain benefit or harm. Patient level linkage is required to distinguish persistence, resolution, and new collection formation.

Objectives: To compare high-sensitivity C-reactive protein (hsCRP) profiles in Korean and US adults with low-density lipoprotein cholesterol (LDL-C) below 100 mg/dL and examine differences after adiposity adjustment. Study design: Cross-sectional analysis of national health examination surveys. Methods: We analysed the Korea National Health and Nutrition Examination Survey 2022-2024 (n=5,785) and US National Health and Nutrition Examination Survey August 2021-August 2023 (n=1,056). Eligible adults had Sampson-calculated LDL-C below 100 mg/dL and hsCRP of 10 mg/L or less; elevated hsCRP was defined as 2-10 mg/L. We estimated survey-weighted prevalence differences and adjusted prevalence ratios (PRs). Results: LDL-C distributions closely overlapped (weighted medians, 79.7 vs 80.1 mg/dL), whereas median hsCRP was 0.50 vs 1.34 mg/L. Elevated-hsCRP prevalence was 12.2% in Korea and 35.7% in the United States (difference, 23.5 percentage points; 95% CI, 19.4-27.7); the age-sex-standardised difference was 23.4 percentage points. Among 6,235 common complete cases, the age-sex-adjusted US-versus-Korea PR was 2.86 (95% CI, 2.48-3.30), decreasing to 1.66 (1.40-1.98) after waist circumference adjustment and 1.92 (1.62-2.26) after body mass index adjustment. Conclusions: Similar LDL-C distributions coexisted with markedly different hsCRP profiles. Waist adjustment attenuated the between-country contrast more than BMI adjustment, supporting joint consideration of inflammatory, lipid and anthropometric measures in population surveillance.

Introduction: Raised blood pressure is an important cardiovascular risk factor in Cambodia; however, national averages may obscure substantial local geographic heterogeneity. We assessed the spatial distribution of raised blood pressure and its demographic, metabolic, behavioural, built-environment, and environmental correlates using the 2023 Cambodia STEPwise approach to noncommunicable disease (NCD) risk factor surveillance (STEPS) survey. Methods: We analysed 289 georeferenced primary sampling units (PSUs) from the 2023 Cambodia STEPS Survey. PSU-level case counts and numbers of adults with valid blood pressure data were modelled using a frequentist binomial generalised additive model with a two-dimensional Gaussian-process smooth. An explanatory model included selected PSU-level and contextual covariates; a separate mapping model used spatially continuous predictors to generate predictions on a 5-km grid. Design-based national and residence-specific prevalence estimates were calculated separately using the survey design and Step-2 weights. Results: Among 4,225 adults with valid blood pressure data, unweighted prevalence of raised blood pressure was 28.6%, compared with 18.8% after Step-2 weighting; weighted prevalence was 17.5% in rural areas and 21.7% in urban/suburban areas. Mean observed unweighted PSU-level prevalence was 29.0%. In the adjusted spatial explanatory model, the proportion aged 60-69 years ({beta}=1.969, SE=0.327; p<0.001) and overweight/obesity prevalence ({beta}=0.996, SE=0.265; p<0.001) were positive ecological correlates. The spatial model had lower Akaike information criterion and residual deviance than its non-spatial counterpart, although Bayesian information criterion was higher. Prediction uncertainty was greater in some sparsely sampled areas. Conclusions: Raised blood pressure showed significant geographic heterogeneity across Cambodia. Older age composition and overweight/obesity prevalence were positive PSU-level correlates, not individual-level causal effects. Predicted prevalence should be interpreted alongside uncertainty and should complement, rather than replace, design-based STEPS prevalence estimates for geographically informed NCD planning.

Aims: To understand how users believe continuous glucose monitoring (CGM) changes their behaviour, which app features they credit, and whether endorsing more mechanisms of action (MoAs) is linked to reported diet and physical activity change. Methods: We surveyed 112 U.S. adults with type 1 or type 2 diabetes who had used a Dexcom or Abbott Libre CGM within 12 months. Participants rated 26 MoA statements mapped to the Capability, Opportunity, Motivation-Behaviour (COM-B) model, identified contributing app features, and reported CGM-attributed diet and physical activity change. Logistic regression examined MoA count and COM-B domains as predictors of behaviour change. Results: Participants (mean age 54.5 years; 60.7% female) reported dietary (82.1%) and physical activity (46.4%) change and endorsed a median of 18 MoAs, most often relating to knowledge, skills and behavioural consequences. Real-time glucose and graphs were attributed to many MoAs. Each additional MoA was associated with higher odds of dietary (OR 1.27, 95% CI 1.15-1.44) and physical activity change (OR 1.27, 95% CI 1.16-1.43). Motivation made the strongest distinct contribution among COM-B domains. Conclusions: Users perceive CGM as engaging many behavioural mechanisms; endorsing more was linked to behaviour change. Motivation may be a key target for CGM-based behavioural support.

Background: Conventional discrimination metrics, such as the area under the receiver operating characteristic curve (AUROC), do not characterize the composition of outcomes among patients flagged as high risk by clinical prediction models. This limitation is particularly relevant in critical care, where competing deaths and incomplete follow-up can complicate the interpretation of prediction alerts. We developed the Balanced Risk Integrity Index (BRII), a stratum-level metric defined as the proportion of target events among target events, competing deaths, and early-censored observations in a flagged high-risk stratum. BRII is algebraically related to positive predictive value (PPV) and is reported alongside its component decomposition to characterize the outcome composition of flagged patients. Methods: We evaluated BRII using seven acute kidney injury (AKI) prediction models developed in MIMIC-IV and externally validated in MIMIC-III and eICU-CRD (116,010 patients in total). Additional simulations examined the effects of competing deaths and early censoring on BRII and conventional model performance metrics. Results: For 48-hour AKI prediction in the top 10% risk stratum, BRII ranged from 0.90 to 0.96 in MIMIC-III, compared with less than 0.26 across all models in eICU-CRD, where 61.5% of evaluated patients were censored before the prediction horizon. In the eICU-CRD top 10% strata for the same target, 37.0% to 50.2% of patients were censored early, 12.2% to 15.5% had AKI, and 3.4% to 8.1% died before AKI. BRII and PPV ordered at least one model pair differently in 34 of 48 cohort-outcome-top-k groups. Under simulated random censoring for 48-hour AKI prediction, BRII declined by up to 0.80 while binary-label AUROC changed by less than 0.02. Conclusions: BRII provided complementary information on high-risk stratum composition, yielding different model rankings from PPV and revealing substantial differences across external validation cohorts. Interpreted alongside PPV and its component decomposition, BRII offers a standardized approach to evaluating clinical prediction alerts across models and observation environments.

Background: Noninvasive biomarkers capable of detecting kidney allograft injury and distinguishing rejection from infection remain an important clinical need. Torque teno virus (TTV) reflects host immune status, but its utility in urine has not been well established. We evaluated urinary TTV, total cell-free DNA (cfDNA), cfDNA fragmentation, and BK polyomavirus (BKV) as potential biomarkers of kidney transplant rejection and BK polyomavirus-associated nephropathy (BKPyVAN). Methods: Urine samples from 334 kidney transplant recipients were analyzed in association with kidney biopsies performed within 30 days of sample collection. TTV and cfDNA were measured by multiplex quantitative PCR (qPCR), with a subset analyzed by digital PCR (dPCR), and BKV was quantified by qPCR. Associations with biopsy results were evaluated using group comparisons and nominal logistic regression. Changes associated with outcomes of consecutive biopsies were assessed by matched pairs analysis. Results: Among 544 unique urine samples, the urinary TTV/cfDNA ratio was significantly lower in rejection than in non-rejection samples (P<0.0001). Logistic regression adjusted for demographic factors confirmed an inverse association between the qPCR-derived TTV/cfDNA metric and rejection (adjusted odds ratio per delta Cq, 0.91; 95% CI, 0.88-0.94; P<0.00001). Significant differences were observed for all types of rejection. Association was confirmed by dPCR: higher TTV was associated with lower rejection odds, whereas higher cfDNA was associated with greater rejection odds. A nominal logistic model incorporating dPCR measurements achieved an AUROC of 0.76 (95% CI, 0.69-0.82). Matched pairs analysis showed a significant decrease in TTV/cfDNA when rejection developed and an increase following recovery from rejection, with no significant changes when biopsy status remained unchanged. BKV levels were strongly associated with BKPyVAN. No correlation between TTV and BKV was observed. Nominal logistic regression integrating TTV, cfDNA, and BKV measurements yielded AUROCs of 0.75, 0.97, and 0.73 for rejection, BKPyVAN, and non-rejection, respectively. Conclusions: A reduced urinary TTV/cfDNA ratio is associated with biopsy-defined kidney transplant rejection, and changes in the ratio correlate with transitions in biopsy results. Combined TTV, cfDNA, and BKV measurements showed differential associations with rejection and BKPyVAN, supporting further evaluation as complementary urinary biomarkers.

Background: Iron deficiency (ID) and iron deficiency anaemia (IDA) have global and severe health implications, and disproportionately impact women of reproductive age. Current methods of supplementing diets with iron are challenged by poor adherence and palatability, reducing effectiveness of these treatment strategies. The aim of this study is to evaluate the efficacy of a novel home beverage fortification with a mineral-enriched powder, designed to enhance bioavailability and ease of use, for the treatment of ID in women of reproductive age. Methods: This single-centre, randomised, double-blinded placebo-controlled trial will enrol 150 eligible biologically female participants with ID. Participants will be randomly assigned to the active intervention (iron/zinc-enriched powder) or control group (placebo powder) over 6 months. Primary outcomes will include change in serum ferritin (SF) concentrations and proportion of participants who remain iron deficient at 6-months. Secondary outcomes will include change in SF and haemoglobin (Hb) concentrations across timepoints, and levels of metabolites and key circulating pro-inflammatory biomarkers, changes in dietary intakes, self-reported perceptions of health, barriers to use of the powder, adherence and palatability, safety outcomes, and cost-effectiveness. Exploratory outcomes will assess the gut microbial metagenome and metabolome. Discussion: Fortification, an effective approach for the prevention of ID/IDA, has advantages over some methods of supplementation because it uses low levels of iron, minimising unpleasant side effects, does not risk toxicity, and has high acceptability and compliance rates. This mineral-enriched powder uses electrolytic iron and zinc sulphate monohydrate of a small particle size, which is less irritating to the gut, and facilitates bioavailability. Findings from the study will be shared with those affected by and involved in treating these conditions, as a novel intervention that is both effective and acceptable among women of reproductive age would help to improve treatment compliance, and ultimately, reduce ID/IDA burden. Trial registration: This trial is registered at clinicaltrials.gov (NCT05990166): https://clinicaltrials.gov/study/NCT05990166, August 2023.

Background and Objective: Adding belzutifan to adjuvant pembrolizumab improved disease-free survival (DFS) in LITESPARK-022, but its durability beyond the 1-year treatment is unknown. Methods: Following a registered plan, we reconstructed individual patient data from published Kaplan-Meier curves of ten phase 3 adjuvant renal cell carcinoma trials. Within each trial, we estimated restricted mean survival time differences ({Delta}RMST), hazard ratios (HRs) before and after planned treatment ended, and DFS differences. Key Findings and Limitations: In LITESPARK-022 (central review), the 24-month {Delta}RMST was 1.34 months (95% confidence interval 0.73-1.95), and the belzutifan arm remained ahead after month 12 ({Delta}RMST increment 0.74 months/yr, 0.32-1.19). The HR was 0.55 (0.43-0.71) before month 12 and 1.16 (0.87-1.54) afterwards (post/pre ratio 2.10); investigator assessment showed similar attenuation. Similar ratios occurred in KEYNOTE-564 at its first interim analysis (2.02), whose benefit persisted, and in SORCE and PROTECT (2.09, 2.59), whose benefit faded. From months 12 to 30 (post hoc), the DFS difference changed by -3.7 percentage points (-8.1 to 0.8) with central review and 0.6 (-4.0 to 5.0) with investigator assessment. Data were reconstructed, and follow-up was short. Conclusions and Clinical Implications: Relative hazard reductions with belzutifan were greater before month 12; durability of the absolute DFS advantage is uncertain and assessment-dependent, so single-HR projections should be avoided.

Although physical activity is associated with better physical functioning, the effects of initiating regular physical activity among older adults with persistent inactivity remain unclear. We conducted a sequential target trial emulation using Health and Retirement Study (HRS) data to estimate the effect of physical activity initiation versus noninitiation on incident mobility difficulty. Participants were included in the analysis if they were aged [&ge;]65 years at the previous wave, reported no regular physical activity at the previous two waves, and had no mobility, activities of daily living (ADL), or instrumental activities of daily living (IADL) difficulties at baseline. Stabilized inverse probability of treatment weighting was applied to adjust for measured confounding. Weighted cumulative incidence was then estimated with death treated as a competing event, and risk differences were calculated at approximately 2, 4, and 6 years. At 2 years, the cumulative incidence of mobility difficulty was 32.75% among initiators and 39.73% among noninitiators, with a risk difference of -6.98 percentage points (95% CI, -13.11 to -0.88). At 4 and 6 years, risk differences were -2.90 percentage points (95% CI, -9.77 to 4.29) and -5.44 percentage points (95% CI, -12.27 to 1.99), respectively. Initiating regular moderate or vigorous physical activity was associated with a lower risk of incident mobility difficulty at approximately 2 years among older adults with persistent inactivity. This difference was less evident at later follow-up, and no clear differences were observed for incident ADL or IADL difficulty.

Objective: To estimate how often remission of type 2 diabetes is recorded in routine care, how long it lasts, and what ends it, separating a return of hyperglycemia from a restart of treatment. Research design and methods: We studied 136,781 adults aged 18 years or older with laboratory confirmed type 2 diabetes in the Protege linked electronic health record (EHR) and claims database. The 96,817 adults with glucose-lowering treatment recorded at or before cohort entry formed the primary (previously treated) cohort; 39,964 adults with no treatment recorded at entry were analyzed in parallel. Remission required two HbA1c values <6.5%, 90 to 365 days apart, the first at least 3 months after all glucose-lowering drugs were discontinued, with no therapy recorded between them. After remission we followed glycemic relapse (HbA1c over 6.5%) and treatment restart (a new outpatient prescription or dispensed fill) separately, with death as a competing event (Aalen Johansen). Results: Remission was documented in 4.33% of previously treated adults cohort and 15.57% in the cohort of untreated adults at entry. Five-year cumulative incidence (Aalen Johansen) was 3.82% (95% CI 3.69 ;3.93) and 13.27% (12.90;13.59) in each cohort, respectively. Remission was less common with greater baseline treatment burden: exploratory adjusted 5-year incidence was 4.65% in adults with 1 glucose-lowering class with a treatment episode recorded at or before entry, 3.62% with two, 2.69% with three, and 2.02% with four or more such drugs.. The Median Kaplan Meier duration of first remission was 226 days (IQR 93 to 855) in previously treated adults and 371 days (166 to 1,027) in adults untreated at entry; 37.9% (treated cohort) and 23.1% (untreated cohort) of episodes had ended by 152 days. Among remission episodes that had ended, median duration was 159 days (71 to 362) and 265 days (129 to 565) for the treated and untreated at entry cohort, respectively. Within 5 years of remission in previously treated adults, the first event ending remission was glycemic relapse in 31.94%, treatment restart in 47.83%, and death in 4.65%.Treatment restart was about 1.5 times as common as glycemic relapse as the first event ending remission. A second remission followed within 5 years in 19.53% of previously treated and 24.10% of untreated remitters. Conclusions: Recorded remission was uncommon and short-lived, and it ended more often with a treatment restart than with a rise in HbA1c. Studies of remission in real-world data should report relapse and restart separately and state how they confirm remission and establish that treatment stopped.

Background: Added sugars during early development may influence adiposity, but whether associations vary by developmental timing and child sex is unclear. Objectives: To determine whether child sex modifies associations of added sugars and fructose exposure from pregnancy through 24 months with body composition at 24 months. Methods: This secondary longitudinal analysis included 130 mother-child dyads. Maternal diet was assessed during mid-pregnancy and child diet at 2wk and 6mo (infancy), and 12mo and 24mo (toddlerhood). Multivariable regression tested sex-by-exposure interactions for anthropometric outcomes; 42 children had usable dual-energy X-ray absorptiometry (DXA) data. Results: Prenatal added sugars were more positively associated with percentage body fat and total and regional fat mass in girls than in boys. Prenatal fructose was more positively associated with waist circumference in boys. During infancy, added sugars were more positively associated with percentage body fat and total and regional fat mass in boys, whereas fructose was more positively associated with fat-free mass in girls. Conclusions: Associations of early-life sugars exposure with body composition varied by developmental timing and child sex. Findings from the smaller DXA subset are exploratory and require replication but suggest that susceptibility to early dietary sugars may differ across developmental windows.

Abstract Background: Respiratory failure (RF) and atrial fibrillation/flutter (AF/AFL) often occur together in older adults, but long-term national mortality trends for the two conditions combined have not been described. We examined trends and disparities in deaths with co-listed RF and AF/AFL among U.S. adults aged 65 years and older from 1999 to 2024, and projected rates through 2035. Methodology: We used the CDC WONDER Multiple Cause of Death database to identify deaths with ICD 10 codes J96 (RF) and I48 (AF/AFL) listed together. Age-adjusted mortality rates (AAMRs) per 100,000 were standardized to the 2000 U.S. population and stratified by sex, race/ethnicity, census region, urbanization, state, and place of death. Joinpoint regression was used to estimate annual percent changes (APCs) and average annual percent changes (AAPCs). Forecasts for 2025 to 2035 were generated with an exponential smoothing (ETS) model. Results: A total of 433,598 deaths were recorded. The overall AAMR rose from 12.8 in 1999 to 66.7 in 2024 (AAPC 8.11%; 95% CI, 7.35 to 8.87; P < 0.0001). Three segments were identified: an increase from 1999 to 2018 (APC 7.73%), a sharp rise from 2018 to 2021 (APC 18.10%), and a decline from 2021 to 2024 (APC -5.25%). Males had a higher AAMR and a steeper increase than females (AAPC 8.44% vs 7.81%). Non-Hispanic White adults had the highest mean AAMR, Hispanic adults had the largest relative increase (AAPC 8.72%), and Non-Hispanic Asian/Pacific Islander adults had the smallest (AAPC 6.23%). The Midwest had the fastest regional growth (AAPC 9.35%). From 1999 to 2020, non-metropolitan areas increased faster than metropolitan areas (AAPC 10.09% vs 8.21%). State AAMRs ranged from 24.7 in Ohio to 85.1 in Louisiana. Most deaths occurred in hospital inpatient settings (64.1%), followed by nursing homes (14.1%) and the home (11.9%). The model projects an AAMR of 122.96 per 100,000 by 2035 (95% prediction interval, 85.42 to 160.50). Conclusions: Mortality involving RF with AF/AFL among older U.S. adults increased more than fivefold over 25 years, with a marked surge during the COVID 19 period and only a partial decline afterward. Differences by sex, race/ethnicity, region, and urbanization point to groups that may benefit from earlier detection and coordinated cardiopulmonary care.

Background: Although point-of-care testing is the standard method for inpatient glucose monitoring; it is associated with patient discomfort and late detection of dysglycaemic events. Continuous glucose monitoring (CGM) may improve glycaemic management; however, limited staff education and experience among may hinder its implementation. Aim: To investigate experience, perceptions and training needs on CGM use among inpatient nursing staff across diverse hospital wards. Methods: This is a single-centre, 38-item online survey recruited inpatient nurses in a hospital in the UK. Participants were invited via the e-newsletter and posters; the survey remained open for five months. Results: Nineteen nurses reported positive perceptions of inpatient CGM. Most considered CGM reliable (77.8%) and preferred CGM combined with POCT (66.7%). Views on its impact on workload and patient-room entries were mixed (30% agreed, 30% disagreed). Training needs included sensor placement (92.9%) and alarm management (78.6%). Conclusion: Nurses viewed CGM favourably but highlighted important training needs for inpatient use.

Introduction: Primary care electronic health records (EHRs) are an important resource for health research, but death recording in primary care EHRs may be incomplete or differ from Office for National Statistics (ONS) death registrations. We used OpenSAFELY-TPP to assess the completeness and concordance of death recording and provide recommendations for using date-of-death information. Methods: Using linked primary care EHRs and ONS death registrations, we assessed whether ONS-registered deaths from 2020-2025 had a primary care date of death and, where present, calculated the difference between dates. Where a primary care date was absent, we assessed death-related SNOMED CT codes. Analyses were conducted overall and by year, population subgroup, and general practice. We also examined GP registration end dates and primary-care-recorded deaths without a corresponding ONS record, including monthly patterns near the data extraction date. Results: Among 1,409,275 ONS-registered deaths, 88% had the same date recorded in primary care and 8% had no corresponding primary care date. Among 1,324,995 deaths recorded in primary care, <2% had no corresponding ONS record. Deaths recorded in only one source were more frequent among people aged <45 years and those from Mixed, Asian or Asian British, Black or Black British, and Chinese or Other ethnic groups. ONS-only dates were also more frequent in London and the West Midlands. Primary-care-only deaths increased close to date of data extraction, reaching 7% in February 2026. Same-day GP deregistration increased from 9% in 2020 to 85% in 2025. Conclusions: Death recording in primary care EHRs showed high completeness and concordance with ONS registrations, but discrepancies remained for recent deaths and some population groups. Data recency and population-specific completeness should therefore be considered when using linked mortality data for research.