Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] < 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p<5×10-8; MAF>0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p<2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB390.

Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10-11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.

Highly heritable, polygenic, and easily measured, adult height has long been the model trait in human genetics 1,2 . While the landscape of height-associated common genetic variation has been studied extensively 2 , rare variation remains relatively unexplored 1 . Using rare protein-altering variants in a discovery set of 826,066 exomes, we identify 207 height-associated genes - 98% of which replicate in an additional 624,567 individuals. The rarest and most deleterious class of variation, singleton (frequency <0.0001%) putative loss-of-function (pLoF) variants implicated 17 genes with large effects on height ranging from -17 cm ( ACAN ) to +11 cm ( FBN1 ) per allele, 52× larger than the average effect of common height-associated variants and comparable to the 1% tails of a common variant polygenic score. Several genes (e.g., TET1 , DTL , IGF2BP2 ) have effect sizes at least as large as established Mendelian height genes but lack documented stature or skeletal growth syndromes. This is particularly true for genes in which rare variants associate with increased height. We performed the largest rare-variant study of height to date, directly implicate 207 genes that broadly overlap with both GWAS associations and Mendelian height syndromes, assess the impact of rare variants on heritability and prediction, provide evidence that height is an underappreciated clinical feature of Mendelian disorders, and demonstrate the utility of large population-scale sequencing studies for classifying individual variants and dissecting complex trait architecture.

Context:Even within the physiological range, serum calcium (sCa++) may influence vascular tone and blood pressure (BP); however, the potential modulatory role of dietary calcium intake remains unclear. Objective:To investigate the association between sCa2+ and BP (including central BP) and to assess whether calcium intake affects this relationship. Methods:sCa2+ was measured in patients referred for suspected secondary hypertension (VerHyperReg; n = 81) and in 2 population-based cohorts: the Malmö Preventive Project (MPP; n = 18 240) and the UK Biobank (UKB; n≈330 000). Calcium intake was assessed in the Malmö Diet and Cancer Study (MDC; n = 28 098) and in a subsample of MPP participants (MPP×MDC; n = 4095). Multivariable regression models were used to analyze the associations. Results:In MPP and UKB, sCa2+ was positively associated with systolic and diastolic BP (even within the normal range). In VerHyperReg, sCa2+ was associated with central systolic BP. In the MDC, higher calcium intake was inversely associated with BP. In MPP×MDC, sCa2+ was positively associated with systolic BP in the lower 3 quartiles of intake, whereas this association was reversed in the highest quartile. Conclusion:Serum calcium levels within the normal range are positively associated with BP. Increased dietary calcium intake may attenuate this relationship, thus suggesting a modulatory role in BP regulation. Further investigations are warranted.

Abstract Emerging evidence suggests that bidirectional lung–kidney crosstalk may influence outcomes, but this has not been systematically evaluated in unselected emergency department populations. We therefore examined the association between peripheral oxygen saturation (SpO₂), estimated glomerular filtration rate (eGFR), and 30‑day mortality, and tested whether the prognostic association of oxygenation with mortality differs across levels of kidney function (and vice versa), using an SpO₂×eGFR interaction term to model effect modification We analyzed 12,651 adults with complete data on SpO₂, creatinine-derived eGFR, lactate, C-reactive protein (CRP), RETTS triage, and prespecified covariates from the Skåne Emergency Medicine (Skåne 17/18) cohort (2017–2018). We fitted multivariable logistic regression models including SpO₂ and eGFR (Model 1) and then added an SpO₂×eGFR interaction term (Model 2). Nested models were compared using a likelihood-ratio test, and discrimination was compared using AUROC (DeLong test) based on model-predicted probabilities. In a predefined subgroup with arterial blood gases (n = 3,068), we evaluated eGFR in relation to PaO₂/FiO₂ (P/F). In the full cohort, SpO₂ and eGFR were significantly correlated. Adding the SpO₂×eGFR interaction term improved model fit versus the main-effects model (LRT ΔDeviance = 15.77, p = 7.17 × 10⁻⁵), but discrimination was essentially unchanged (AUROC 0.744 vs. 0.745; ΔAUROC 0.0009; 95% CI − 0.00227 to 0.00046; DeLong p = 0.193). In the interaction model, higher SpO₂ and eGFR were associated with lower 30-day mortality (OR 0.81, 95% CI 0.77–0.85; OR 0.85, 95% CI 0.80–0.91), and the interaction term indicated stronger protection when both were higher (OR 0.90, 95% CI 0.86–0.95). Exploratory subgroup analyses suggested the interaction effect was most pronounced among patients presenting with chest pain. SpO₂ and eGFR showed evidence of interaction in relation to 30-day mortality. Although adding the interaction term improved model fit, it did not meaningfully improve discrimination compared to main model (without interaction). This suggests that, in unselected ED populations, measuring and interpreting SpO₂ and eGFR remains clinically useful, whereas explicitly modeling their interaction is unlikely to add substantial predictive benefit.

While prostate cancer (PrCa) is highly heritable, the genes associated with PrCa survival after diagnosis remain poorly understood. We aimed to identify genes associated with PrCa-specific survival through transcriptome-wide association studies (TWAS) using genetic predictors of gene expression in the prostate. We used the Transcriptome-Integrated Genetic Association Resource (TIGAR) to train expression prediction models separately using normal prostate, primary tumor, and metastatic tumor tissues. We performed TWAS using these models in data from the Malmö Diet and Cancer (MDC) study (discovery) and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (validation). We identified and validated seven genes associated with PrCa-specific survival at a common locus on chromosome 1. We found two genes using prediction models from normal prostate tissues and five with models from metastatic tumor tissues. Elevated RCC1 expression is linked to a shorter time to biochemical recurrence, while higher PHACTR4 expression was observed in tumors with a higher Gleason grade. The study is limited to European ancestry and can only show associations. Further research across other populations and experiments to establish causality will be needed. Our multi-tissue study identified novel genes associated with PrCa survival, particularly RCC1 and PHACTR4, providing new insights for potential genomic markers for PrCa survival.

Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health. Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%. Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.

Background Diabetes is a heterogeneous disease and stratification into severe autoimmune (SAID), severe insulin-deficient (SIDD), severe insulin-resistant (SIRD), moderate obesity-related (MOD), and moderate age-related (MARD) diabetes reveals differing clinical courses. Identifying early predictors for these disease trajectories could enable more precise prevention. We studied the relationship between adolescent fitness and BMI, adult physical activity, genetic predisposition, and future subgroup-specific risk. Methods We analysed 4,417 men with diabetes (cases) from the ANDIS study with military conscription fitness and BMI data, compared with 235,953 controls. Adult physical activity was assessed using questionnaire data (2,616 cases and 2,753 controls). Finally, we performed polygenic score analyses (6,986 cases; 2,744 controls) and two-sample Mendelian randomisation (MR) analysis using published GWAS summary statistics. Findings Higher BMI at age 18 was associated with increased risk of MOD (OR 1·69 [95% CI 1·64–1·74]), SIRD (OR 1·31 [1·23–1·40]), and SIDD (OR 1·26 [1·19–1·33]), but not MARD (OR 0·85 [0·79–0·90]). In BMI-adjusted models, higher aerobic capacity at age 18 was most strongly associated with a lower SIRD risk (OR 0·69 [0·61–0·77]), but was also associated with SIDD and MOD risk. BMI-adjusted physical activity at age 30 was associated with lower SIRD, MOD, and SIDD risk. MR indicated a causal relationship, mediated by BMI, between sedentary lifestyle and SIRD. No evidence supported a causal link between BMI and MARD. Interpretation Adolescent fitness and BMI are divergent risk factors for diabetes subgroups. Low physical capacity is a specific risk factor for individuals following a SIRD-like trajectory, whereas the MOD phenotype is characterised by early obesity. In contrast, MARD exhibits preserved fitness and no causal link with BMI. These findings provide a pathophysiological rationale for stratified strategies, from prevention to clinical management, prioritising those with high cardio-renal-hepatic burden, such as individuals with a SIRD-like disease course.

Background: Copeptin, a surrogate marker for vasopressin activity, is associated with cardiovascular disease, insulin resistance and glucose metabolism dysregulation. The cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may involve vasopressin modulation through fluid redistribution, but whether this effect persists long-term in high-cardiovascular-risk patients with newly detected dysglycaemia remains unknown. Methods: In this post-hoc analysis of the SOCOGAMI double-blind, placebo-controlled trial, 42 patients (mean age 67.5 years, 19% female) with impaired glucose tolerance or newly diagnosed type 2 diabetes following an ACS and no heart failure were randomized to empagliflozin 25 mg/day (n=20) or placebo (n=22) for 7 months. Copeptin was serially measured during oral glucose tolerance tests (OGTT) at baseline, after 7 months on-treatment, and 3 months after treatment withdrawal. Treatment effects were assessed by repeated-measures ANOVA with treatment×time interaction and linear mixed-effects models. Results: Baseline copeptin did not differ between groups and correlated positively with arterial pulse wave velocity (r s =0.40, p=0.03), linking vasopressin activity to subclinical vascular stiffness. During treatment, a non-significant trend toward higher copeptin at 7 months in the empagliflozin group reversed to baseline after treatment discontinuation (treatment×time interaction p=0.64), with haematocrit showing a parallel non-significant pattern. Copeptin was not associated with the glucose-lowering effect of empagliflozin. No differential copeptin response during the OGTT across groups or visits was observed. Conclusions : Chronic empagliflozin treatment does not induce sustained vasopressin system activation in post-ACS patients with newly detected dysglycaemia and preserved cardiac function, suggesting physiological adaptation limits this response over time. These findings refine the mechanistic understanding of SGLT2i and provide a foundation for studies examining whether vasopressin modulation contributes to their cardiorenal benefits in specific high-risk subgroups. Trial registration number : EudraCT number 2015-004571-73.

BACKGROUND:It remains unclear why cool temperatures cause more persistent adverse health effects compared with hot weather. Fluid homeostasis may constitute a causal link between past temperatures and adverse health effects. In this study, we investigated the association between past outdoor temperatures and current fluid homeostasis. METHODS:We studied participants from five cohorts during three decades in Sweden (total n = 29,755, age 18-86 years, 50.4% women). We quantified fluid homeostasis through indicators of hormonal regulation (vasopressin biomarker plasma copeptin), urine concentration (urine osmolality), and replenishment of fluid loss (total water intake) and related these parameters to past outdoor temperatures (21 days) using distributed nonlinear lag models. RESULTS:Past temperatures were nonlinearly associated with current copeptin and urine osmolality. Cool temperatures during days and weeks prior contributed to distinct patterns of high copeptin with concomitant influence on urine osmolality. Overall, a scenario of temperatures of 0 °C for 21 days showed 14.9% (95% confidence interval = 11.5%, 18.3%) higher copeptin levels compared with reference temperatures of 14.3 °C for 21 days. Associations between copeptin and warm temperatures were less complex and of shorter duration, linking elevated temperatures within 24 hours with higher copeptin compared with the reference temperature. CONCLUSIONS:Alterations in human fluid homeostasis may partly explain the observed link between moderately cool outdoor temperatures and adverse health effects weeks later. If so, avoiding altered water balance through moderately increased water intake might mitigate the adverse health effects of cool weather.

Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. Here, to investigate the genetic basis of energy metabolism, we perform an exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)-an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P < 1.04 × 10-7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

Heart failure (HF) is a common complication of diabetes, associated with a high mortality rate and a substantial healthcare burden. Residual HF risk persists despite achieving current treatment targets, suggesting a role for additional mechanisms beyond conventional risk factors. We sought to prospectively assess HF incidence and independent risk factors in individuals with new-onset diabetes. We used a prospective inception cohort (ANDIS, n=19,892) that included all individuals with newly diagnosed diabetes from southern Sweden between 2008 and 2021. Baseline clinical, biochemical and questionnaire data were linked to the Region Scania Care Database to obtain data on cardiovascular events and to the National Diabetes Registry to gather further data on cardiovascular risk factors that were not collected in the ANDIS study protocol. All-cause HF included all cases of HF regardless of underlying aetiology, whereas non-ischaemic HF was defined as HF occurring in individuals without prior acute myocardial infarction at baseline or during follow-up before the HF diagnosis. Cardiovascular disease incidence was estimated using the Kaplan–Meier method, and the associations with risk factors and incident HF were assessed using Cox proportional hazards regression. The median age of the overall population was 62.5 years (IQR 52.6–70.3), while the median age among individuals who developed incident all-cause HF was 69.8 years (IQR 62.7–76.7). A total of 819 individuals (4.1

Copeptin, a surrogate marker for vasopressin secretion, is associated with cardiovascular disease, insulin resistance and dysglycaemia. The cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may involve vasopressin modulation through fluid redistribution, but whether this effect persists long-term in high-cardiovascular-risk patients with newly detected dysglycaemia remains unknown. In this post-hoc analysis of the SOCOGAMI double-blind, placebo-controlled trial, 42 patients (mean age 67.5 years, 19

BACKGROUND:Pro-neurotensin (pro-NT) is the stable circulating precursor of neurotensin (NT), a neuropeptide expressed mainly in the central nervous system and small intestine that regulates key physiological processes like fatty acid absorption in the gut and suppresses appetite via central mechanisms. Studies in NT-deficient mice and humans implicate NT in obesity and insulin resistance, highlighting its role in metabolic regulation. METHODS:To explore the genetic determinants of circulating pro-NT and its causal relationships with obesity and brain phenotypes, we conducted a genome-wide meta-analysis of serum pro-NT levels in 10,096 individuals of European ancestry across four independent cohorts. We further examined causal effects of pro-NT on brain structures and function using Mendelian Randomisation (MR) and analysed brain magnetic resonance imaging (MRI) data from a subset (N = 1090) of the LIFE-Adult cohort. FINDINGS:Three genome-wide significant loci associated with serum pro-NT were identified on chromosomes 4 (rs6822751), 11 (rs41392245), and 12 (rs2723889). MR analyses revealed causal links between elevated pro-NT and structural variation in selected subcortical brain regions, notably the pallidum and brainstem. MRI analyses in the LIFE-Adult subset showed reduced reward network coherence in alleles linked to higher pro-NT levels, suggesting a potential neural mechanism contributing to obesity. INTERPRETATION:These findings suggest a potential causal relationship between serum pro-NT levels and variance in structural brain phenotypes that could be implicated in obesity. FUNDING:See Acknowledgements. Key funding bodies: Deutsches Zentrum für Diabetesforschung (DZD, Grant: 82DZD06D03) to MSt; European Union, by the European Regional Development Fund (ERDF) to RB; Swedish Foundation for Strategic Research (IRC LUDC), Swedish Research Council (SFO-EXODIAB), Swedish Research Council (AIR Lund- Artificially Intelligent use of Registers at Lund University, VR; Grant No. 2019-61406) to OM.

Introduction and Objective: Increasing evidence suggests that prediabetes may be associated with an increased cancer risk. We determined whether distinct prediabetes subphenotypes differ in their tumor profiles. Methods: A total of 2,260 participants without diabetes from the Malmö Diet and Cancer cohort study, aged 61-85 years, were assigned to the six established Tübingen prediabetes clusters and followed up for a median duration of 10.6 years. Overall survival and diabetes incidence were analyzed using Cox proportional hazards models, overall and site-specific tumor prevalence and incidence using log-binomial regression models. Cluster 2 served as the reference and adjustments were made for age and sex. Results: Cluster assignment was associated with differential risks for tumor outcomes, mortality, and diabetes incidence. Cluster 4 (overweight, metabolically healthy) showed an increased risk of uterine tumors including cervix and endometrium (RR 5.17, [95% CI 1.32-20.29], p-value 0.02). Cluster 5 (obese, insulin-resistant with fatty liver) was associated with elevated pancreatic cancer risk (RR 16.23, [2.8-94.12], 0.002, median time-to-event 6.1 years, range 2.2-8.7 years), increased mortality (HR 1.47, [1.09-1.98], 0.01), and higher incidence of diabetes (HR 13.48 [7.29-24.9], < 0.001). Cluster 6 (obese, insulin-resistant with kidney disease) showed higher overall tumor prevalence (RR 1.45, [1.07-1.91], 0.01), particularly for uterine (RR 2.59, [1.58-4.02], < 0.001) and kidney tumors (RR 6.25, [1.17-33.46], 0.03) and diabetes incidence (HR 5.84, [2.78-12.28], < 0.001). Conclusion: Distinct prediabetes subphenotypes show different risk profiles for diabetes, tumors and mortality. Specifically, clusters 4, 5, and 6 show an increased risk for uterine, pancreatic, and renal tumors. The clustering of individuals with prediabetes may allow targeted tumor screening and earlier intervention, potentially improving long-term outcomes. Disclosure J. Seigner: None. S. Hülskämper: None. C. Hoffmann: Other - External Research Fellow in a Graduate Program; Ended; Boehringer Ingelheim International GmbH. R. Wagner: Advisory Panel; Current; Sanofi. Speaker's Bureau; Ended; Daiichi Sankyo, Novo Nordisk. K. Prystupa: None. O. Melander: None. A. Fritsche: None. A.L. Birkenfeld: None.

This narrative review provides a historical perspective on how observational research on type 2 diabetes has been developed and consolidated over the last 50 years and how well-designed cohort studies will provide us with knowledge for research and practice in the future and aid guideline development. We have included data from a large number of cohorts from every continent that have been used to study the development and/or progression of type 2 diabetes, including cohorts that are general population-based, disease-based, intervention-based and registry-based. We have structured the results from the past 50 years based on the following themes: diagnosis and screening, complications, risk factors and pathophysiology. We also discuss the strengths and weaknesses of observational research when compared with other research designs. Finally, we discuss the emerging and future directions for type 2 diabetes research using cohorts, which include novel developments, such as artificial intelligence, precision health and the exposome. We conclude that cohort research has significantly advanced our understanding of type 2 diabetes and aided guideline development, and complements experimental work, such as human randomised controlled trials and animal studies. Both approaches are essential and complementary in our pursuit to provide a more comprehensive understanding of the development and progression of type 2 diabetes, and to change dogma, practice and policies for better outcomes.

Acute dyspnoea is one of the most common presenting symptoms in the emergency department (ED) and has a variety of underlying causes. Calprotectin is a neutrophil activation marker associated with adverse outcomes in acute cardiovascular and infectious diseases. However, the usefulness of calprotectin in the risk stratification of patients with acute dyspnoea is unknown. The objectives were to, in unselected patients presenting to the ED with acute dyspnoea, investigate the association between (1) calprotectin and 90-day mortality, (2) calprotectin and 90-mortality in subgroups of patients with cardiovascular disease or pneumonia, and (3) calprotectin and illness severity. Single-centre observational cohort study from a university hospital in southern Sweden. A total of 1186 patients from the original Acute Dyspnoea Study, were included. Patients were followed for discharge diagnosis and mortality. Calprotectin concentration was measured in plasma samples collected at the ED. Mean age was 72 years and 56% were women. During follow-up, 143 patients died. In multivariate Cox regression for 90-day mortality, calprotectin in the highest quartile (> 0.96 mg/L) compared to the lowest quartile (< 0.27 mg/L) was associated with a hazard ratio of 2.71 (95% confidence interval 1.39–5.26, p < 0.01). The association with mortality remained significant in the subgroup of patients with acute cardiovascular disease ( N = 205, p < 0.01). There was no statistically significant difference in median calprotectin values between survivors and non-survivors with pneumonia (1.62 vs. 1.31, p = 0.155). Multivariate linear regression showed a strong positive correlation between calprotectin and illness severity (respiratory rate ≥ 29 or oxygen saturation ≤ 90%, p < 0.001). In conclusion, calprotectin was associated with 90-day mortality and correlated strongly with illness severity. This indicates that measurement of calprotectin at admission could improve clinical risk stratification of the acute dyspnoeic ED patient. Clinical trial number : Not applicable.