Kidney International

Abstract Background Alport Syndrome (AS), caused by pathogenic variants in type IV collagen genes COL4A3/4/5, is a leading monogenic cause of Kidney Failure (KF). Clinical course varies widely, and disease specific predictors of progression relevant to clinical care and trial design remain incompletely defined. Methods In this retrospective cohort study of individuals with AS in the UK National Registry of Rare Kidney Diseases, patients were classified as having AS or heterozygous genotypes and followed to assess proteinuria progression, eGFR slope and kidney survival. Proteinuria and eGFR trajectories were analysed using mixed effects regression models; kidney survival using Kaplan Meier analysis. Results Among 1032 participants (median follow up 11.6 years; 47% female), 475 (46%) had AS genotypes (Male XLAS or autosomal recessive AS). eGFR decline accelerated with advancing CKD stage across all genotypes (p<0.001). Proteinuria increased as eGFR declined and occurred earlier in AS genotypes. After reaching proteinuria thresholds of more than 1.0 and 3.0g/g, kidney survival over the subsequent 5 years did not differ significantly between genotypes (logrank p=0.14, p=0.17, respectively), although modest differences emerged over longer follow-up. Across eGFR thresholds (90, 60, and 45mL/min/1.73m2), higher proteinuria was associated with shorter time to KF; for example, at eGFR 45mL/min/1.73m2, median time to KF was 3.0 years (IQR, 1.6-5.4) for above-median vs 6.5 years (5.1-not estimable) for below-median proteinuria (p<0.0001). Almost all patients who reached KF had developed proteinuria of more than 0.3g/g. Conclusion In this national cohort, eGFR decline accelerated with CKD stage and proteinuria was strongly associated with progression to KF across genotypes. The non linearity of eGFR decline may inform its interpretation in clinical practice and use as a trial endpoint. Once comparable proteinuria levels were reached, differences in outcomes by genotype were attenuated, supporting proteinuria as a key prognostic marker and strengthening rationale for its use as a surrogate endpoint in AS clinical trials

Importance: Recently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD). Methods: Real world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg/g (PCR~0.9 g/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes. Results: In the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL/min/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg/g, mean eGFR slope was -4.67[-6.00, -3.33] mL/min/1.73m2/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL/min/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001). Conclusions and relevance: Changes in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.

Background. Chronic kidney disease (CKD) affects 10-13% of adults worldwide but remains largely undiagnosed until advanced stages. Hospitalization provides an opportunity for early detection through opportunistic urine albumin-to-creatinine ratio (UACR) measurement. Methods. We conducted a prospective three-arm study of opportunistic CKD screening in general internal medicine wards at Hadassah Mt. Scopus (MS), Hadassah Ein Kerem (EK), and Shaare Zedek Medical Center (SZMC) in Jerusalem (Protocol HMO-23-0300). Adult inpatients without known CKD or recent UACR were enrolled. Pathological UACR was defined as [&ge;]30 mg/g. Confirmed CKD required two pathological measurements [&ge;]90 days apart (KDIGO-compatible). eGFR was computed using the 2021 CKD-EPI race-free equation. Pooled proportions were estimated by fixed-effects logit meta-analysis; odds ratios by DerSimonian-Laird random-effects models. Results. A total of 158 patients were enrolled (MS n=50, EK n=57, SZMC n=51). Pathological first UACR was identified in 43/158 patients (27.2%; 95% CI 21.3-34.1%; I2=0% across centers). Of 24 patients with a second UACR available, 14 (58%) confirmed CKD, yielding a pooled confirmed-CKD rate of 8.9% of all screened patients. In-hospital mortality was significantly higher among patients with pathological UACR (9.3% vs ~2%; Fisher's exact p=0.012). In per-center multivariate logistic regression, three predictors reached pooled significance: BUN (OR 1.10 per mg/dL, 95% CI 1.04-1.17, p=0.002, I2=0%), heart failure (OR 3.21, 95% CI 1.34-7.70, p=0.009, I2=0%), and diabetes mellitus (OR 2.54, 95% CI 1.11-5.82, p=0.028, I2=17%). Cardiac/vascular admissions had the highest pathological UACR rate (~42%); GI/hepatic admissions had 0%. Conclusions. Opportunistic inpatient UACR screening identifies previously unrecognized CKD in approximately 9% of general internal medicine patients, with consistent results across three independent centers. BUN elevation, heart failure, and diabetes are the strongest independent predictors. Pathological UACR carries significant short-term mortality risk, supporting integration of routine screening into inpatient care pathways.

Background: Cardiac surgery using cardiopulmonary bypass uses controlled hypoperfusion which leads to relative organ damage. Acute kidney injury is the most frequent and most important organ failure, in particular in patients with chronic kidney disease. To date, there are no approved drug treatments that could effectively prevent acute kidney injury. SP16, an agonist of the low-density lipoprotein receptor-related protein 1, has been shown to exert both reno- and cardioprotective effects in preclinical trials. Early clinical use of SP16 in phase I trials was safe. Administration of SP16 had beneficial trends on inflammatory response and infarct size in patients with ST-segment elevation myocardial infarction. The primary objective of this phase IIa trial is to demonstrate that injection of SP16 is safe and superior to placebo in preventing cardiac surgery-associated acute kidney injury within 7 days after surgery. Methods: This randomised, double-blinded, placebo-controlled, single centre study evaluates the efficacy and safety of SP16 in 120 high-risk chronic kidney disease patients with disease stadium G2-G3b undergoing cardiac surgery who are randomised into one of two treatment groups in a 1:1 ratio: SP16 (12 mg) or placebo. The study medication is administered via two subcutaneous injections, with the first dose given before surgery, followed by an additional dose after 9 h. Primary endpoints are the incidence of acute kidney injury during 7 days post-surgery and the frequency of adverse events within 72 h after index surgery. Important secondary endpoints include the incidence of major adverse kidney events at day 90 and impact on cardiac function. Safety assessments encompass adverse events, vital signs, electrocardiograms and routine safety laboratory tests. Additional evaluations include pharmacokinetics and immunological biomarkers. Discussion: This single-centre phase IIa trial will assess the incidence of cardiac surgery-associated acute kidney injury, describing the renoprotective potential of SP16 and its safety profile in patients undergoing cardiac surgery.

Background: Chronic low-grade inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related driver of systemic inflammation, is linked to several cardiometabolic disorders. However, whether CHIP modifies CKM progression and contributes to heterogeneity in cardiovascular disease (CVD) risk within the CKM framework remains uninvestigated. Methods: This cohort study included 307,025 UK Biobank participants at CKM stages 0-3 free of baseline CVD. CHIP status was identified via whole-exome sequencing (WES). The association between CHIP and baseline CKM severity was examined, along with the independent and joint effects of CHIP and CKM stages on incident CVD risk. The joint effects of CHIP and polygenic risk scores (PRS) were further assessed, and the incremental predictive value of incorporating CHIP into the AHA PREVENT equations was evaluated. Results: CHIP carriers were more likely to present with advanced CKM stages [OR 1.14 (1.09-1.20), P < 0.001] and exhibited higher incident CVD risk during follow-up [HR 1.13 (1.08-1.18), P < 0.001]. Significant joint effects between CHIP and CKM stages were observed, with the highest risk among CHIP carriers at CKM stage 3 [HR 1.63 (1.50-1.78), P < 0.001]. Large or multiple CHIP mutations conferred greater hazards, with distinct gene-specific effects observed. Moreover, CHIP and high genetic risk also jointly amplified CVD susceptibility. Most importantly, incorporating CHIP into AHA PREVENT significantly improved risk discrimination. Conclusions: CHIP is a significant risk factor associated with more advanced CKM stages and amplifies incident CVD risk. Integrating CHIP into existing prevention strategies may refine CVD risk stratification.

Chronic kidney disease is characterized by decreased glomerular filtration rate (eGFR, estimated from serum creatinine or cystatin C) or increased urinary albumin-to-creatinine-ratio (UACR). Genome-wide association studies provided the genetic make-up of these traits, but their overlap remained largely unknown. Our multi-trait GWAS (N=1M) identified 812 signals and multi-trait fine-mapping sharpened the identification of likely causal variants. Of 333 signals classified for filtration function or albuminuria, only 11 overlapped. Their effects on eGFR and UACR were directionally concordant, dominated by eGFR and independent of HbA1c or mean arterial pressure. Mapped genes pinpointed mechanisms related to glomerular filtration area (SHROOM3, EPB41L5) and sodium-mediated intraglomerular pressure (NRBP1, DPEP1/CHMP1A). Genetics of fluid intake resulted in shadow effects on UACR without albumin leakage into urine. Our multi-trait approach sharpened the identification of likely causal genes for kidney traits, demonstrated largely distinct genetics for filtration function versus albuminuria, and provided new biological insights into the overlap.

Introduction: To investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum. Methods: Data on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden. Results: In 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China. Conclusions: The CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a leading driver of cardiovascular morbidity and mortality. Whole-body molecular imaging is well-positioned to phenotype such syndromes, yet no imaging biomarker quantifies cumulative CKM burden. Bone scintigraphy with 99mTc-labeled bisphosphonates is widely performed and expanding with transthyretin amyloidosis assessment, under which Perugini grade 0 (absent cardiac uptake) is considered clinically benign. Objective: We hypothesized that the soft tissue-to-bone ratio (STBR) on these scans captures CKM burden and is an independent prognostic biomarker. Methods: We retrospectively analyzed 8,769 consecutive patients without cardiac uptake on 99mTc-DPD whole-body planar scintigraphy. The primary endpoint was all-cause mortality. Secondary endpoints were major adverse cardiovascular events (MACE) and heart failure hospitalization. Cox models were adjusted for ten established cardiovascular risk factors. Imaging-phenotype association (IPA) analysis mapped STBR to 1,210 clinical traits. STBR distribution across CKM stages was assessed in four prespecified analyses, including a non-cancer subgroup. Results: During a median follow-up of 5.1 years (IQR 2.5-8.2), 2,418 deaths occurred. Patients with prespecified STBR >0.5 (n=772, 8.8%) had significantly higher mortality (adjHR 1.73, 95% CI 1.54-1.94, p<0.0001) with an adjHR of up to 3.42 at higher thresholds (95% CI 2.05-5.42, p<0.0001). Hazard increased monotonically with STBR. STBR >0.5 was independently associated with MACE (adjHR 1.51, 95% CI 1.11-2.05, p=0.008) and heart failure hospitalization (adjHR 1.31, 95% CI 1.02-1.67, p=0.03). The association was robust across all prespecified subgroups and sensitivity analyses, including continuous STBR and patients without renal insufficiency. IPA analysis identified significant associations with type 2 diabetes, chronic kidney disease, chronic ischaemic heart disease, heart failure, atrial fibrillation, liver disease, amyloidosis, and hypertension among binary traits, as well as with CRP, NT-proBNP, BUN, cholesterol (inverse), and hemoglobin (inverse) among continuous parameters. STBR increased monotonically across CKM stages in all sensitivity analyses (all p<0.0001). Conclusions: STBR derived from routine 99mTc-DPD bone scintigraphy in patients without cardiac uptake is an independent prognostic imaging biomarker associated with cumulative cardiovascular-kidney-metabolic burden. As an opportunistic measure from scans already acquired at scale, STBR could refine CKM risk stratification at no additional cost, radiation, or acquisition time.

PURPOSE: As the armamentarium of BPH therapies continues to expand, it remains imperative to maximize patient satisfaction and minimize decisional regret. We sought to determine the impact of time from BPH diagnosis to index treatment on symptom improvement and subsequent procedural events. MATERIALS AND METHODS: We queried the American Urological Association Quality Registry for men [&ge;] 40 years old with BPH, available IPSS data, and no receipt of prior BPH treatment. Index treatment included medication, surgery, or minimally invasive surgical therapy (MIST). Outcomes included IPSS over 3 years of follow-up, change in percentage of mild lower urinary tract symptoms (LUTS) by 3 months, and time to procedural event. Patients were stratified by time from index diagnosis to treatment by <12 months, 1-3 years, and >3 years. Outcomes were compared across time-to-treatment cohorts with appropriate statistical tests with p < 0.05 as significant. RESULTS: 43,919 patients met criteria with 19,642 pursuing treatments. Patients pursued treatment at comparably lower baseline IPSS compared to prior prospective series. Patients undergoing surgery and MIST had significantly higher baseline IPSS, while medical comorbidities were significantly more common among men initiating pharmacotherapy. Early surgery and MIST were associated with significant improvement in IPSS within 6-12 months and an increase in mild LUTS by 3 months. All forms of early treatment were associated with delayed time to procedural events, including catheterization and fulguration. CONCLUSIONS: Early procedural intervention for BPH is associated with early symptom improvement and delayed time to procedural events among real-world, contemporary practice.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex and incompletely understood molecular mechanisms. Understanding circulating proteins associated with RA may improve understanding of disease biology and clarify its pathological links with cardiometabolic comorbidities. Methods A proteome-wide two-sample Mendelian randomisation (MR) drug target analysis was conducted using plasma proteins measured in 54,219 participants from the UK Biobank Pharma Proteomics Project as exposures and RA and cardiometabolic diseases as the outcomes. Summary statistics for RA included 53,663 cases and 1,070,200 controls. Colocalisation analysis was performed to confirm shared single causal variants and prioritise RA proteins supported by both MR and colocalisation. The prioritised proteins were then evaluated in the Accelerating Medicines Partnership RA Phase II synovial single-cell dataset for cell-type expression patterns. Druggability was then assessed followed by analysis of genetic overlap between RA-associated proteins and cardiometabolic diseases. Results 37 plasma proteins had a causal effect on RA risk, supported by combined evidence from MR and conditional colocalisation. In synovial tissue, TPPP3, RARRES2, AKAP12, and GGT5 were predominantly expressed in stromal and endothelial cell clusters. Druggability assessment identified IFNGR2, IL6R, CD40, and FCGR2B as Tier 1 targets. However, several biologically relevant proteins, including RARRES2, AKAP12, TPPP3, and SNX2, had limited available druggability data. Genetic overlap analysis demonstrated shared protein signals between RA and cardiovascular diseases, including overlap of RARRES2 and TPPP3 with coronary artery disease (CAD) and FCGR2B with atrial fibrillation (AF). To approximate the therapeutic effect of target inhibition, the direction of effect estimates for proteins showing overlap between RA-CAD and RA-AF was reversed. Conclusion This study identified circulating proteins involved in RA pathogenesis and reveals shared mechanisms between RA and cardiovascular diseases. While some proteins showed clear translational potential targets, several prioritised proteins had limited available druggability information and could not be confidently classified. Addressing these gaps may help identify new targets relevant to RA management. Future work should also use phenome-wide MR studies to evaluate potential on-target adverse effects of protein inhibition across RA-CAD and RA-AF.

Diabetic peripheral neuropathy (DPN) is a common and disabling condition for which no disease-modifying therapies are available. Glycemic and metabolic drivers do not fully explain why only a subset of individuals with diabetes develop DPN, and genetic contributors remain poorly defined. We aimed to perform a multi-population genome-wide association study (GWAS) of DPN to highlight potential new etiological pathways and therapeutic targets. Methods We performed a multi-population GWAS of neuropathy in people with and without diabetes using the VA Million Veteran Program and UK Biobank, followed by replication in the All of Us Research Program (AoU), and gene-based and gene-set analyses to identify implicated pathways. Causal relationships between circulating serine levels and DPN were further tested using two sample Mendelian randomization. To further evaluate pathogenic potential, we analyzed rare, high impact variants in GWAS implicated genes among individuals with unresolved inherited neuropathies using the GENESIS platform. Findings Among individuals with type 2 diabetes, we identified seven genome wide significant loci (p<5x10-): PHGDH and PSPH (key serine synthesis genes), TEAD1, CYP4F11, LARGE1, FTO, and COBLL1. No loci were significant in individuals without diabetes or with type 1 diabetes. Four loci (PHGDH, TEAD1, FTO and CYP4F11) replicated in AoU (p <0.05). Mendelian randomization demonstrated that higher genetically predicted serine levels were associated with lower DPN risk, consistent with a causal role of serine metabolism in disease pathogenesis. Rare-variant burden analyses revealed associations of predicted deleterious variants with inherited neuropathy case status in PHGDH (odds ratio [OR] 12.7 [95% CI 7.9, 20.4]), PSPH (OR 8.5 [7.2, 10.2]), PHKG1 (OR 4.8 [3.7, 6.3]), and LARGE1 (OR 0.007 [0.0004, 0.1]). Interpretation Convergent genetic evidence across common and rare variation implicates serine synthesis as a key pathway in DPN. These findings link diabetic and inherited neuropathies through a shared metabolic mechanism, identifying serine metabolism as a potential therapeutic target.

Vaccines to prevent infant group B streptococcus (GBS) disease are advancing, with licensure likely based on safety and immunologic endpoints rather than clinical efficacy data. This approach requires robust, generalisable serological thresholds of risk reduction (SToRRs). We combined data from six case-control studies in Europe and Africa to define SToRRs for early-onset (EOD) and late-onset (LOD) GBS disease. Across diverse epidemiological and healthcare settings, anti-capsular polysaccharide IgG concentrations were consistently higher in infants who remained disease free than in those who developed disease. Higher antibody concentrations were required to reduce the risk of EOD than LOD, and higher concentrations were required for serotype Ia than for serotype III. This study provides a quantitative framework to support correlates-based evaluation and potential licensure of maternal GBS vaccines.

Background and Aims: MASLD has become the most prevalent chronic liver disease globally. Although MVPA and plasma fatty acids have been individually studied in relation to metabolic health, their independent and combined associations with MASLD incidence remain unclear. We aimed to investigate these associations. Methods: This study included 51,717 UK Biobank participants free of liver disease at baseline, with MVPA measured using wrist-worn accelerometers and plasma fatty acids quantified via NMR. Multivariable-adjusted Cox models and restricted cubic splines were used. Results: Over a median follow-up of 7.8 years, 472 incident cases were identified. In fully adjusted models, meeting recommended MVPA levels together with higher n-6 PUFA concentrations was associated with a 71% lower risk (HR 0.29, 95% CI 0.18-0.45). The MVPA-MASLD association was nonlinear, with risk reduction plateauing at approximately 189 minutes per week. Higher n-6 PUFA was associated with reduced risk, whereas n-3 PUFA showed no significant association. Conclusions: These findings suggest that behavioral and metabolic factors may jointly influence MASLD risk. Further studies in diverse populations are needed to confirm these associations.

Background: Pathologic aldosteronism induces oxidative stress, tissue injury, and increases in hemoglobin. Conversely, aldosterone antagonist therapy decreases hemoglobin. Whether these effects are attributable to aldosterone-mediated changes in iron and oxygen metabolism is unknown. Methods: The plasma proteome of participants with overt primary aldosteronism (PA) (n=50) was compared with participants without overt PA (n=61). To isolate aldosterone-dependent effects, participants without overt PA underwent oral sodium suppression testing to quantify the magnitude of renin-independent aldosterone production, enabling monotonic dose-response analyses across the continuum of renin-independent aldosteronism (subclinical to overt PA). Differential abundance testing was performed using empirical Bayes linear modeling, followed by Reactome pathway enrichment analysis and covariate-adjusted sensitivity analyses. To validate clinical relevance, aldosterone dose-response trends with blood count parameters were examined in this cohort, and an independent population-based cohort of 5,713 people with hypertension. Results: 903 proteins in the peripheral circulation were differentially abundant in overt PA versus participants without PA. The most significantly increased protein in overt PA was CYBRD1, involved in iron reduction and absorption. Pathway enrichment identified 16 iron- and heme-related pathways, including erythropoietin signaling, heme biosynthesis and mitochondrial iron-sulfur cluster biogenesis, with increases in heme and erythroid proteins and decreases in mitochondrial iron-sulfur proteins. Linear aldosterone dose-dependent trend analyses across the PA continuum further supported this signature, identifying progressive increases in hemoglobin subunits (HBA1/HBB), heme-related proteins (HMBS, UROS, AMBP, HPX, GLO1) and erythrocyte oxygen handling enzymes (CA1/CA3), alongside progressive reductions in mitochondrial electron transport chain subunits (CYCS, ETFA). These proteomic changes corresponded with aldosterone dose-dependent increases in red blood cell count, hemoglobin, and hematocrit, in this cohort and another population-based cohort. Conclusion: The continuum of PA is characterized by a progressive shift away from mitochondrial oxidative phosphorylation and toward increased intestinal iron absorption, preferential iron transport over storage, and enhanced heme synthesis and recycling, possibly reflecting cellular pseudohypoxia and systemic adaptations to increase oxygen delivery. These findings provide a novel mechanistic basis for aldosterone-mediated tissue injury and the benefits of aldosterone-directed therapy.

Background: Alpha-1 antitrypsin deficiency (AATD) caused by the PI*ZZ mutation (Glu342Lys) results in hepatic accumulation of misfolded AAT-Z protein and reduced circulating AAT levels, leading to progressive liver disease and emphysema. Gene correction therapy represents a potentially curative approach by directly correcting the underlying genetic defect. We report the first case of successful hepatic gene correction with early histological and functional assessment. Methods/Case presentation: We report the case of a 66-year-old male patient with PI*ZZ AATD who underwent gene correction therapy within the YOLT-202 phase I/Ia clinical trial (clinical trial.gov ID NCT07193615). Ten weeks post treatment a liver biopsy was performed to re-evaluate pre-existing F2 liver fibrosis as measured by elastography before entering the study. Serum samples allowed functional assessment of the AAT-mediated elastase inhibition. Results: Liver biopsy did not show signs of hepatic inflammation and demonstrated 54% (Sanger) and 57% (Illumina) gene correction rate of the PI*ZZ variant on the DNA level with no bystander edits or off-target effects. Following a transient elevation of transaminases during the early post-treatment period, liver enzymes normalized. Monthly serum AAT measurements demonstrated biologically active and stable therapeutic levels throughout follow-up. Conclusions: This case demonstrates efficient and precise hepatic gene correction without concerning histological alterations and with substantial improvement of functional parameters, supporting the feasibility and safety of gene editing approaches for AATD.

Background Iron deficiency (ID) is a readily treatable condition once identified. Ferritin is the primary diagnostic marker, but cut-offs vary and inflammation complicates interpretation in patients with long-term conditions (LTCs). Aim To describe ferritin distribution and the prevalence of threshold-defined low ferritin in adults with and without LTCs in primary care. Design and setting Cross-sectional observational study using routinely collected electronic health records from a national primary care database in England (1st January 2015 to 31st December 2021). Method Adults with >1 ferritin test in Clinical Practice Research Datalink (CPRD) Aurum were included. LTCs were identified using validated primary-care code lists. Outcomes included ferritin distribution and threshold-defined ID prevalence using World Health Organization (WHO) (<15 ug/L; <70 ug/L if inflammation) and National Institute for Health and Care Excellence (NICE) (<30 ug/L) cut-offs, stratified by sex and, in women, by age <50 versus >=50 as a proxy for menopausal status. Results 4,489,594 individuals were included; 55% (n=2,469,882) had >1 LTC. Ferritin was lowest in women <50 and in LTCs characterised by impaired absorption or blood loss (coeliac disease, inflammatory bowel disease). Among women <50 with an LTC, 80% had ferritin <70 ug/L versus 47% <30 ug/L, leaving 33% in the 30 to 70 ug/L range potentially missed by standard cut-offs; equivalent figures were 28% in women >=50 and 17% in men. Conclusion Threshold-defined low ferritin is very common across LTCs and disproportionately affects women, particularly those under 50. Condition-specific, inflammation-adjusted ferritin thresholds may improve detection, management, and equity in primary care.

Background. Nascent findings suggest that people with attention-deficit/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).

Background Myocardial remodeling precedes symptomatic heart failure, which is important to detect early. We assessed feasibility and clinical correlates of a novel integrated assessment of myocardial remodeling in a large rural cohort in the Southeastern United States. Methods Echoes were obtained with AI assistance (Caption guidance) in 3100 adults in the NHLBI-funded RURAL cohort study. Of those, 1895 had quantifiable global longitudinal strain (GLS), left ventricular mass (LVM), and left atrial volume (LAV). LV-LA Health was based on a simple count of sex-specific abnormalities (0-3), indexed to body surface area (BSA) or height (Table 1). Relationships with demographics and risk factors were compared with Spearman correlation and Mantel-Haenszel tests, with moderate and severe results combined. Results Median (IQR) age was 49 (40-58). Impaired LV-LA Health is common even in a low PREVENT cardiovascular (CV) risk population (median 10-year risk 3.3%; 25th, 75th 1.2,7.2) with preserved ejection fraction (EF; 60%; 57,62). The prevalence of abnormalities differed greatly by indexing method: 18.2% with BSA (15.1% mild; 3.1% mod/severe) vs 51% with height (38.3% mild; 12.7% mod/severe) (Figure 1). LV-LA impairment increased with age, PREVENT CV risk score and cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity); all p<0.001. Impairment was more common in Black vs White people (p<0.001) and differed by sex only with height indexation. Conclusions A novel LV-LA health composite of routinely acquired echocardiographic measures identifies substantial subclinical cardiac remodeling in a middle-aged rural community cohort, not detected by PREVENT score or ejection fraction. This is the first application of this framework in a large, unselected community sample. Indexation method affects prevalence, with BSA likely underestimating risk in adiposity-enriched populations. Findings suggest a high rural burden and longitudinal evaluation with future CV events is ongoing.

Skin cancer requires early detection for improved survival rates. Most existing methods rely on deep learning based image classification, which is affected by visual similarity among lesions. Fewer studies use Gene Expression (GE) analysis, which captures molecular characteristics but lacks structural and visual details. To overcome limitations of individual modalities, this paper proposes a multimodal framework integrating dermoscopic images and GE profiles for skin cancer classification. EfficientNet and logistic regression are used for image based analysis and genomic skin lesion profiling, respectively, followed by fuzzy rule based decision systems to reduce uncertainty within individual modalities. Finally, fuzzy fusion combines predictions from both modalities using uncertainty based weighting of classifier outputs. The experimental findings show that both the image based and GE based classification models individually achieved accuracies of nearly 92%. However, the integration of prediction results through the proposed fuzzy fusion strategy further enhanced the classification performance, achieving an overall accuracy of 94.25%. The results obtained outperform contemporary methods, highlighting the effectiveness of combining complementary multimodal information compared with single modality approaches.

Background: Two-thirds of Dutch cardiovascular risk management (CVRM) for patients at risk of cardiovascular disease is delivered in primary care practices. While individual risk scores are increasingly used during consultation, a population-level structure for risk-based patient outreach is not currently available. We therefore developed the PROSPERA programme, a multilevel intervention comprising population-level risk stratification and individual-level support tools. Aim: To assess anticipated and experienced barriers and facilitators among healthcare professionals (HCPs) to inform implementation in primary care. Methods: We conducted four focus groups and six interviews with nine primary care HCPs to explore anticipated and experienced barriers and facilitators. Inductive codes were thematically analysed and assigned to corresponding domains of the Theoretical Domains Framework (TDF) and the related Capability, Opportunity, Motivation model of Behaviour. Results: Barriers and facilitators were identified in 11 TDF domains. Population-level barriers included altered professional roles and limitations in technological infrastructure. Individual-level barriers were limited skills in interpreting risk calculations and difficulty integrating tools into clinical routine. Facilitators were related to beliefs on the importance of providing proactive care (population level), the use of U-Prevent for risk communication (individual level) and positive patient responses to the Lifestylecheck questionnaire (individual level). Conclusion: Addressing barriers and facilitators identified at both the population and individual levels can support implementation of the PROSPERA programme. Opportunities exist in education and training of HCPs in risk communication, as well as support in restructuring the physical and digital environment.