Patient-oriented measures for phase 3 studies of tralokinumab for the treatment of atopic dermatitis (ECZTRA 1, 2, and 3).

BACKGROUND: Tralokinumab, as monotherapy or in combination with topical corticosteroids (TCS), has exhibited marked efficacy through 52 weeks in phase 3 trials of adults with moderate-to-severe atopic dermatitis and additional efficacy in a long-term extension trial. Early changes in patient-reported symptoms have not been communicated. OBJECTIVE: To evaluate early changes in patient-reported outcomes (PROs) across the ECZTRA 1, 2, and 3 tralokinumab trials. METHODS: Monotherapy data (ECZTRA 1 + 2) was pooled; ECZTRA 3 evaluated tralokinumab plus optional TCS. The PROs were assessed through the trials. RESULTS: A total of 1596 and 380 patients were randomized in ECZTRA 1 and 2 and ECZTRA 3, respectively. Baseline demographics and clinical characteristics were similar between groups. Early separation from placebo was observed in percentage improvement in worst average daily pruritus numerical rating score (NRS) (week 1, ECZTRA 1 + 2; week 2, ECZTRA 3) and from day 2 in ECZTRA 1 and 2 daily data. More tralokinumab-treated patients achieved clinically meaningful improvements (≥ 4 points) in NRS by week 2 (ECZTRA 1 + 2) or week 3 (ECZTRA 3) vs placebo. Improvements in eczema-related sleep NRS were seen within 2 weeks (week 1, ECZTRA 1 + 2; week 2, ECZTRA 3), supported by similar improvements in other sleep measures. Meaningful changes in Dermatology Life Quality Index were observed from week 2 (ECZTRA 1 + 2). Results were supported by numerical differences from placebo in Patient-Oriented Eczema Measure total score (week 2, both data sets). CONCLUSION: Tralokinumab with or without TCS exhibited early and clinically meaningful improvements vs placebo in several PROs, which may be beneficial to patients because atopic dermatitis symptom relief is a key treatment concern for patients.

Correction to: The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

Unfortunately, 'Present address' was omitted from one of the addresses provided for Mark I. McCarthy (#26).

Health-related quality of life with tralokinumab in moderate-to-severe atopic dermatitis: A phase 2b randomized study.

BACKGROUND: Atopic dermatitis (AD) is associated with a substantial burden on quality of life (QoL). OBJECTIVE: To evaluate the effects of tralokinumab on health-related QoL in patients with moderate-to-severe AD using patient-reported outcomes. METHODS: This was a phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study in adults with moderate-to-severe AD. The patients received subcutaneous tralokinumab or placebo (1:1:1:1) every 2 weeks for 12 weeks and class 3 topical corticosteroid cream or ointment at least once daily from the run-in to end of follow-up. Patient-reported outcome end points were change from baseline to week 12 in the Dermatology Life Quality Index (dermatology life quality index (DLQI); prespecified secondary objective), the Short Form 36 Health Survey (SF-36) version 2, and sleep interference numeric rating scale score (prespecified exploratory objectives). RESULTS: A total of 204 patients were randomized to placebo (n = 51) or tralokinumab (45 mg, n = 50; 150 mg, n = 51; 300 mg, n = 52). Tralokinumab 300 mg every 2 weeks improved total Dermatology Life Quality Index vs placebo at week 12 (placebo-adjusted mean change, -3.51 [95% confidence interval, -6.00 to -1.02]). At week 12, both the mental component summary (4.23 [0.98-7.47]) and the physical component summary (4.26 [1.83-6.69]) and all 8 domains of the Short Form 36 Health Survey were improved in patients treated with tralokinumab 300 mg vs placebo. Sleep interference was improved at week 12 with all tralokinumab doses vs placebo. CONCLUSION: Tralokinumab improved health-related QoL in patients with moderate-to-severe atopic dermatitis, providing further evidence of the value of targeting interleukin-13 in such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02347176; https://clinicaltrials.gov/ct2/show/NCT02347176.

The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

AIMS/HYPOTHESIS: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.

Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. CONCLUSIONS: In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814915.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden: the GLACIER Study.

BACKGROUND: Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential. METHODS: Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used. RESULTS: Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (Pint = 0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (Pint = 0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (Pint = 0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (Pint < 0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score. CONCLUSIONS: The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant.

The heritable basis of gene-environment interactions in cardiometabolic traits.

AIMS/HYPOTHESIS: Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions. METHODS: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. RESULTS: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h 2) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction. CONCLUSIONS/INTERPRETATION: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.

Changes in dietary intake following a culturally adapted lifestyle intervention among Iraqi immigrants to Sweden at high risk of type 2 diabetes: a randomised trial.

OBJECTIVE: To investigate the effectiveness of a culturally adapted lifestyle intervention for changing dietary intake, particularly energy, fat and fibre intakes, in the intervention group (IG) compared with the control group (CG). DESIGN: Randomised controlled trial. SETTING: IG (n 50) and CG (n 46). The IG was offered seven group sessions, including one cooking class, over a period of 4 months. The participants filled out 4 d food diaries at the start, mid and end of the study. SUBJECTS: Iraqi-born residents of Malmö, Sweden, at increased risk for developing diabetes. RESULTS: At baseline, participants' fat intake was high (40 % of total energy intake (E%)). The predefined study goals of obtaining <30 E% from fat and ≥15 g fibre/4184 kJ (1000 kcal) were met by very few individuals. In the IG v. the CG, the proportion of individuals obtaining <40 E% from fat (48·4 v. 34·6 %, P=0·65), <10 E% from saturated fat (32·3 v. 11·5 %, P=0·14) and ≥10 g fibre/4184 kJ (45·2 v. 26·9 %, P=0·46) appeared to be higher at the last visit, although the differences were statistically non-significant. A trend towards decreased mean daily intakes of total energy (P=0·03), carbohydrate (P=0·06), sucrose (P=0·02) and fat (P=0·02) was observed within the IG. Differences in changes over time between the groups did not reach statistical significance. CONCLUSIONS: Although no significant differences were observed in the two groups, our data indicate that this culturally adapted programme has the potential to modify dietary intake in Middle Eastern immigrants. The high fat intake in this group should be addressed.

Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction  = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction  = 0.014 vs. n = 71,611, Pinteraction  = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction  = 0.003) and the SEC16B rs10913469 (Pinteraction  = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial.

Importance: Safe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited. Objective: To evaluate the efficacy and safety of interleukin-13-targeted treatment with tralokinumab monotherapy in adolescents with AD. Design, Setting, and Participants: The 52-week, randomized, double-blinded, placebo-controlled, phase 3 ECZTRA 6 trial was conducted from July 17, 2018, through March 16, 2021, at 72 centers across 10 countries in North America, Europe, Asia, and Australia. Enrolled patients were 12 to 17 years old with moderate to severe AD (Investigator's Global Assessment [IGA] score ≥3; Eczema Area and Severity Index [EASI] ≥16). Interventions: Patients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients with an IGA score of 0 (clear) or 1 (almost clear) and/or 75% or higher improvement in EASI (EASI 75) at week 16 without rescue medication received maintenance treatment; other patients switched to open-label tralokinumab, 300 mg, every 2 weeks. Main Outcomes and Measures: Primary end points at week 16 were an IGA score of 0 or 1 and/or achieving EASI 75. Key secondary end points were a reduction of Adolescent Worst Pruritus Numeric Rating Scale of 4 or more, change in SCORing AD, and change in Children's Dermatology Life Quality Index from baseline to week 16. Safety end points were the number of adverse events and serious adverse events. Results: Of 301 patients randomized, 289 comprised the full analysis set (median [IQR] age, 15.0 [13.0-16.0] years; 149 [51.6%] male). More patients receiving tralokinumab, 150 mg, (n = 98), and tralokinumab, 300 mg (n = 97), achieved an IGA score of 0 or 1 without rescue medication at week 16 (21 [21.4%] and 17 [17.5%], respectively) vs placebo (n = 94; 4 [4.3%]) (adjusted difference, 17.5% [95% CI, 8.4%-26.6%]; P < .001 and 13.8% [95% CI, 5.3%-22.3%]; P = .002, respectively). More patients receiving tralokinumab, 150 mg (28 [28.6%]), and tralokinumab, 300 mg, (27 [27.8%]) vs placebo (6 [6.4%]) achieved EASI 75 without rescue at week 16 (adjusted difference, 22.5% [95% CI, 12.4%-32.6%]; P < .001 and 22.0% [95% CI, 12.0%-32.0%]; P < .001, respectively). Proportions of patients with Adolescent Worst Pruritus Numeric Rating Scale reduction of 4 or more from baseline were greater with tralokinumab, 150 mg (23.2%), and tralokinumab, 300 (25.0%), vs placebo (3.3%), and adjusted mean changes were greater in SCORing AD with tralokinumab, 150 mg (-27.5), and tralokinumab, 300 mg (-29.1), vs placebo (-9.5) and in Children's Dermatology Life Quality Index with tralokinumab, 150 mg (-6.1), and tralokinumab, 300 mg (-6.7), vs placebo (-4.1) at week 16. At week 52, tralokinumab efficacy was maintained without rescue in more than 50% of patients meeting primary end point(s) at week 16. In the open-label phase, IGA score of 0 or 1 and EASI 75 were achieved in 33.3% and 57.8%, respectively, at week 52. Tralokinumab was well tolerated, without frequency of conjunctivitis increasing through week 52. Conclusions and Relevance: In this randomized clinical trial, tralokinumab was efficacious and well tolerated, supporting its value for treating adolescents with moderate to severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03526861.

Tralokinumab Efficacy and Safety, with or without Topical Corticosteroids, in North American Adults with Moderate-to-Severe Atopic Dermatitis: A Subanalysis of Phase 3 Trials ECZTRA 1, 2, and 3.

INTRODUCTION: In pivotal phase 3 tralokinumab monotherapy (ECZTRA 1/2) and topical corticosteroid (TCS) combination (ECZTRA 3) trials in adults with moderate-to-severe atopic dermatitis (AD), tralokinumab significantly improved signs and symptoms of AD. Geographic region may impact treatment response due to potential differences in race and ethnicity, and based on findings in other therapy areas. Here, we evaluated the efficacy and safety of tralokinumab in the ECZTRA 1/2/3 North American population at week 16, as well as maintenance of responses over time, and compared these data side-by-side with those of the ECZTRA 1/2/3 non-North American population. METHODS: Primary endpoints were Investigator's Global Assessment score of 0 or 1 (IGA 0/1; clear or almost clear) or at least 75% improvement in Eczema Area and Severity Index (EASI-75) at week 16. At week 16, tralokinumab-treated IGA 0/1 or EASI-75 responders were re-randomized 2:2:1 to tralokinumab 300 mg q2w, or q4w, or placebo (ECZTRA 1/2) and 1:1 to tralokinumab 300 mg q2w or q4w (ECZTRA 3). RESULTS: Overall, 559/1596 (35%) and 160/380 (42.1%) patients randomized in ECZTRA 1/2 and ECZTRA 3 were from North America, respectively. At week 16, IGA 0/1 and EASI-75 response rates were greater with tralokinumab versus placebo in ECZTRA 1/2 (IGA 0/1: 25.3% vs 15.1%; 95% confidence interval [CI] 3.0, 17.3; p = 0.012; EASI-75, 40.1% vs 19.4%; 95% CI 12.6, 28.7; p < 0.001) and ECZTRA 3 (IGA 0/1, 40.0% vs 25.9%; 95% CI - 0.5, 28.3; p = 0.074; EASI-75: 58.1% vs 37.0%; 95% CI 4.9, 37.0; p = 0.012) and tralokinumab was well tolerated in the North American population. Patients with IGA 0/1 or EASI-75 response at week 16 demonstrated sustained responses at week 52 and week 32 in ECZTRA 1/2 and ECZTRA 3, respectively. Similar findings were observed in the non-North American trial populations. CONCLUSIONS: Tralokinumab, with or without TCS, displayed similar efficacy and safety in patients with moderate-to-severe AD across the North American population, and was comparable to the non-North American population. CLINICAL TRIAL REGISTRATION: NCT03131648 (registered 27-Apr-2017); NCT03160885 (registered 19-May-2017); NCT03363854 (registered 6-Dec-2017).

Exposome-wide ranking of modifiable risk factors for cardiometabolic disease traits.

The present study assessed the temporal associations of ~ 300 lifestyle exposures with nine cardiometabolic traits  to identify exposures/exposure groups that might inform lifestyle interventions for the reduction of cardiometabolic disease risk. The analyses were undertaken in a longitudinal sample comprising > 31,000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test associations with 10-year change in the cardiometabolic traits. 'Physical activity' and 'General Health' were the exposure categories containing the highest number of 'tentative signals' in analyses assessing the average association of lifestyle variables, while 'Tobacco use' was the top category for the 10-year change association analyses. Eleven modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to the domains: (i) Smoking, (ii) Beverage (filtered coffee), (iii) physical activity, (iv) alcohol intake, and (v) specific variables related to Nordic lifestyle (hunting/fishing during leisure time and boiled coffee consumption). We used an agnostic, data-driven approach to assess a wide range of established and novel risk factors for cardiometabolic disease. Our findings highlight key variables, along with their respective effect estimates, that might be prioritised for subsequent prediction models and lifestyle interventions.

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study.

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired ß cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.

Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study.

OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), ß-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R 2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and ß-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, ß-cell function, and insulin clearance may be relevant to prevent progression.

Escherichia coli isolates from broiler chicken meat, broiler chickens, pork, and pigs share phylogroups and antimicrobial resistance with community-dwelling humans and patients with urinary tract infection.

Escherichia coli is the most common cause of urinary tract infection (UTI). Phylogroup B2 and D isolates are associated with UTI. It has been proposed that E. coli causing UTI could have an animal origin. The objective of this study was to investigate the phylogroups and antimicrobial resistance, and their possible associations in E. coli isolates from patients with UTI, community-dwelling humans, broiler chicken meat, broiler chickens, pork, and pigs in Denmark. A total of 964 geographically and temporally matched E. coli isolates from UTI patients (n = 102), community-dwelling humans (n = 109), Danish (n = 197) and imported broiler chicken meat (n = 86), Danish broiler chickens (n = 138), Danish (n = 177) and imported pork (n = 10), and Danish pigs (n = 145) were tested for phylogroups (A, B1, B2, D, and nontypeable [NT] isolates) and antimicrobial susceptibility. Phylogroup A, B1, B2, D, and NT isolates were detected among all groups of isolates except for imported pork isolates. Antimicrobial resistance to three (for B2 isolates) or five antimicrobial agents (for A, B1, D, and NT isolates) was shared among isolates regardless of origin. Using cluster analysis to investigate antimicrobial resistance data, we found that UTI isolates always grouped with isolates from meat and/or animals. We detected B2 and D isolates, that are associated to UTI, among isolates from broiler chicken meat, broiler chickens, pork, and pigs. Although B2 isolates were found in low prevalences in animals and meat, these sources could still pose a risk for acquiring uropathogenic E. coli. Further, E. coli from animals and meat were very similar to UTI isolates with respect to their antimicrobial resistance phenotype. Thus, our study provides support for the hypothesis that a food animal and meat reservoir might exist for UTI-causing E. coli.

Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes: An IMI-DIRECT study.

AIM: Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. METHODS: The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. RESULTS: At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. CONCLUSIONS: Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

A general method for linkage disequilibrium correction for multipoint linkage and association.

Lately, many different methods of linkage, association or joint analysis for family data have been invented and refined. Common to most of those is that they require a map of markers that are in linkage equilibrium. However, at the present day, high-density single nucleotide polymorphisms (SNPs) maps are both more inexpensive to create and they have lower genotyping error. When marker data is incomplete, the crucial and computationally most demanding moment in the analysis is to calculate the inheritance distribution at a certain position on the chromosome. Recently, different ways of adjusting traditional methods of linkage analysis to denser maps of SNPs in linkage disequilibrium (LD) have been proposed. We describe a hidden Markov model which generalizes the Lander-Green algorithm. It combines Markov chain for inheritance vectors with a Markov chain modelling founder haplotypes and in this way takes account for LD between SNPs. It can be applied to association, linkage or combined association and linkage analysis, general phenotypes and arbitrary score functions. We also define a joint likelihood for linkage and association that extends an idea of Kong and Cox (1997 Am. J. Hum. Genet. 61: 1179-1188) for pure linkage analysis.

Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension: A Population-Based Cohort and Sibling Study.

BACKGROUND: Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown. METHODS: We studied 13,893 first-born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Västerbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population-based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable poisson and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N = 135). RESULTS: Offspring participants of women with HDP (N = 383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2-hour 75 g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses. CONCLUSION: Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period.

Physical Activity in a Randomized Culturally Adapted Lifestyle Intervention.

INTRODUCTION: Middle Eastern immigrants exhibit high levels of physical inactivity and are at an increased risk for Type 2 diabetes. The primary aim of this study was to examine the changes in objectively assessed physical activity levels following a culturally adapted lifestyle intervention program. The secondary aim was to examine the association between objectively assessed physical activity and insulin sensitivity. STUDY DESIGN: RCT conducted over 4 months in 2015. PARTICIPANTS: Iraqi immigrants residing in Malmö, Sweden, exhibiting one or more risk factors for Type 2 diabetes. INTERVENTION: The intervention group (n=50) was offered a culturally adapted lifestyle intervention comprising seven group sessions including a cooking class. The control group (n=46) received usual care. MAIN OUTCOME MEASURES: Raw accelerometry data were processed by validated procedures and daily mean physical activity intensity, vector magnitude high-pass filtered (VM-HPF), was inferred. Further inferences into the number of hours/day spent in sedentary (VM-HPF <48 milli-Gs [mGs] where G=9.8 m/sec2) and light- (48- <163 mGs); moderate- (163- <420 mGs); and vigorous-intensity (≥420 mGs) activities were also calculated (year of analysis was 2016-2017). RESULTS: No difference was observed between the two groups in terms of change over time in VM-HPF. There was a significant increase in the number of hours/day spent in light intensity physical activity in the intervention group compared with the control group (ß=0.023, 95% CI=0.001, 0.045, p=0.037). The intervention group also increased the time spent in sedentary activities, with the highest VM-HPF (36- <48 mGs) within the sedentary behavior (B=0.022, 95% CI=0.002, 0.042, p=0.03). Higher VM-HPF was significantly associated with a higher insulin sensitivity index (ß=0.014, 95% CI=0.0004, 0.025, p=0.007). CONCLUSIONS: The findings favor the culturally adapted intervention approach for addressing low physical activity levels among Middle Eastern immigrants. Replacing sedentary time with light-intensity activities could be an achievable goal and will have potential beneficial effects for diabetes prevention among this sedentary group of immigrants. TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov NCT01420198.