Longitudinal Change in Serum Neurofilament Light Chain in Type 2 Diabetes and Early Diabetic Polyneuropathy: ADDITION-Denmark.

OBJECTIVE: To investigate the longitudinal development of neurofilament light chain (NfL) levels in type 2 diabetes with and without diabetic polyneuropathy (+/-DPN) and to explore the predictive potential of NfL as a biomarker for DPN. RESEARCH DESIGN AND METHODS: We performed retrospective longitudinal case-control analysis of data from 178 participants of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care-Denmark (ADDITION-Denmark) cohort of people with screen-detected type 2 diabetes. Biobank samples acquired at the ADDITION-Denmark 5- and 10-year follow-ups were analyzed for serum NfL (s-NfL) using single-molecule array, and the results were compared with established reference material to obtain NfL z-scores. DPN was diagnosed according to Toronto criteria for confirmed DPN at the 10-year follow-up. RESULTS: s-NfL increased over time in +DPN (N = 39) and -DPN participants (N = 139) at levels above normal age-induced s-NfL increase. Longitudinal s-NfL change was greater in +DPN than in -DPN participants (17.4% [95% CI 4.3; 32.2] or 0.31 SD [95% CI 0.03; 0.60] higher s-NfL or NfL z-score increase in +DPN compared with -DPN). s-NfL at the 5-year follow-up was positively associated with nerve conduction studies at the 10-year follow-up (P = 0.02 to <0.001), but not with DPN risk. Areas under the curve (AUCs) for s-NfL were not inferior to AUCs for the Michigan Neuropathy Screening Instrument questionnaire score or vibration detection thresholds. Higher yearly s-NfL increase was associated with higher DPN risk (odds ratio 1.36 [95% CI 1.08; 1.71] per 1 ng/L/year). CONCLUSIONS: Our findings suggest that preceding s-NfL trajectories differ slightly between those with and without DPN and imply a possible biomarker value of s-NfL trajectories in DPN.

Use of medication in pregnancy on the rise: Study on 1.4 million Danish pregnancies from 1998 to 2018.

INTRODUCTION: Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy (concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics. MATERIAL AND METHODS: A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy. RESULTS: Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short-time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period. CONCLUSIONS: Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age-based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks.

Large Language Models for Epidemiological Research via Automated Machine Learning: Case Study Using Data From the British National Child Development Study.

Background: Large language models have had a huge impact on natural language processing (NLP) in recent years. However, their application in epidemiological research is still limited to the analysis of electronic health records and social media data. objectives: To demonstrate the potential of NLP beyond these domains, we aimed to develop prediction models based on texts collected from an epidemiological cohort and compare their performance to classical regression methods. Methods: We used data from the British National Child Development Study, where 10,567 children aged 11 years wrote essays about how they imagined themselves as 25-year-olds. Overall, 15% of the data set was set aside as a test set for performance evaluation. Pretrained language models were fine-tuned using AutoTrain (Hugging Face) to predict current reading comprehension score (range: 0-35) and future BMI and physical activity (active vs inactive) at the age of 33 years. We then compared their predictive performance (accuracy or discrimination) with linear and logistic regression models, including demographic and lifestyle factors of the parents and children from birth to the age of 11 years as predictors. Results: NLP clearly outperformed linear regression when predicting reading comprehension scores (root mean square error: 3.89, 95% CI 3.74-4.05 for NLP vs 4.14, 95% CI 3.98-4.30 and 5.41, 95% CI 5.23-5.58 for regression models with and without general ability score as a predictor, respectively). Predictive performance for physical activity was similarly poor for the 2 methods (area under the receiver operating characteristic curve: 0.55, 95% CI 0.52-0.60 for both) but was slightly better than random assignment, whereas linear regression clearly outperformed the NLP approach when predicting BMI (root mean square error: 4.38, 95% CI 4.02-4.74 for NLP vs 3.85, 95% CI 3.54-4.16 for regression). The NLP approach did not perform better than simply assigning the mean BMI from the training set as a predictor. Conclusions: Our study demonstrated the potential of using large language models on text collected from epidemiological studies. The performance of the approach appeared to depend on how directly the topic of the text was related to the outcome. Open-ended questions specifically designed to capture certain health concepts and lived experiences in combination with NLP methods should receive more attention in future epidemiological studies.

HbA1c-defined prediabetes and progression to type 2 diabetes in Denmark: A population-based study based on routine clinical care laboratory data.

AIMS: To estimate the prevalence, incidence, mortality, and risk of progression to type 2 diabetes for individuals with HbA1c-defined prediabetes based on Danish nationwide population-based laboratory databases. METHODS: We included all HbA1c measurements from general practice and hospitals during 2012 to 2018. We estimated the cumulative incidence of having at least one HbA1c measurement. The prevalence and incidence rates of prediabetes (HbA1c 42-47 mmol/mol) were examined in the adult Danish population. The 5-year cumulative incidence of progression to type 2 diabetes was estimated with death as competing event. RESULTS: Among 4,979,590 adult Danes, 70.8% (95% CI 70.8-70.9) had at least one HbA1c measurement during 2012 to 2018. The prevalence of prediabetes was 7.1% (95% CI 7.1-7.1) in 2018. The incidence rate was 14.2 (95% CI 14.1-14.3) per 1,000 person-years, with median age 66.9 years (IQR 56.7-75.7) and median HbA1c 43 mmol/mol (IQR 42-44) at prediabetes diagnosis. Within five years, 17.5% (95% CI 17.3-17.7) died and the 5-year cumulative incidence of type 2 diabetes was 21.3% (95% CI 21.1-21.5). CONCLUSIONS: Out of 100 Danish adults, 1.4 develop prediabetes each year and they can be identified at an early stage in laboratory databases. Within five years, one in five individuals with prediabetes progresses to diabetes and one in six dies.

The association between sleep duration and detailed measures of obesity: A cross sectional analysis in the ADDITION-PRO study.

Background: Sleep duration is associated with BMI and waist circumference. However, less is known about whether sleep duration affects different measurements of obesity differently. Objective: To investigate the association between sleep duration and different measures of obesity. Methods: In this cross-sectional analysis 1309, Danish, older adults (55% men) completed at least 3 days of wearing a combined accelerometer and heart rate-monitor for assessing sleep duration (hours/night) within self-reported usual bedtime. Participants underwent anthropometry and ultrasonography to assess BMI, waist circumference, visceral fat, subcutaneous fat, and fat percentage. Linear regression analyses examined the associations between sleep duration and obesity-related outcomes. Results: Sleep duration was inversely associated with all obesity-related outcomes, except visceral-/subcutaneous-fat-ratio. After multivariate adjustment the magnitude of associations became stronger and statistically significant for all outcomes except visceral-/subcutaneous-fat-ratio, and subcutaneous fat in women. The associations with BMI and waist circumference demonstrated the strongest associations, when comparing standardized regression coefficients. Conclusions: Shorter sleep duration were associated with higher obesity across all outcomes except visceral-/subcutaneous-fat-ratio. No specifically salient associations with local or central obesity were observed. Results suggest that poor sleep duration and obesity correlate, however, further research is needed to conclude on beneficial effects of sleep duration regarding health and weight loss.

Autonomic dysfunction is associated with the development of arterial stiffness: the Whitehall II cohort.

This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people.

The STC2-PAPP-A-IGFBP4-IGF1 axis and its associations to mortality and CVD in T2D.

Objective: Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2-PAPP-A-IGFBP4-IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). Design: We followed 1284 participants with T2D from the ADDITION trial for 5 years. Methods: Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model. Results: During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09-3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98-3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11-1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91-4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16-2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34-0.76); P = 0.001. Conclusions: This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A-IGF1 axis. Significance statement: PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2-PAPP-A-IGFBP4-IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2-PAPP-A-IGFBP4-IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

Serum neurofilament light chain - A potential biomarker for polyneuropathy in type 2 diabetes?

AIMS: To investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN). METHODS: We performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage. RESULTS: 39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI's 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73). CONCLUSIONS: S-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated tothe severity of the nerve damage underlying DPN.

Association of general health and lifestyle factors with the salivary microbiota - Lessons learned from the ADDITION-PRO cohort.

Introduction: Previous research indicates that the salivary microbiota may be a biomarker of oral as well as systemic disease. However, clarifying the potential bias from general health status and lifestyle-associated factors is a prerequisite of using the salivary microbiota for screening. Materials & Methods: ADDDITION-PRO is a nationwide Danish cohort, nested within the Danish arm of the Anglo-Danish-Dutch Study of Intensive treatment in People with Screen-Detected Diabetes in Primary Care. Saliva samples from n=746 individuals from the ADDITION-PRO cohort were characterized using 16s rRNA sequencing. Alpha- and beta diversity as well as relative abundance of genera was examined in relation to general health and lifestyle-associated variables. Permutational multivariate analysis of variance (PERMANOVA) was performed on individual variables and all variables together. Classification models were created using sparse partial-least squares discriminant analysis (sPLSDA) for variables that showed statistically significant differences based on PERMANOVA analysis (p < 0.05). Results: Glycemic status, hemoglobin-A1c (HbA1c) level, sex, smoking and weekly alcohol intake were found to be significantly associated with salivary microbial composition (individual variables PERMANOVA, p < 0.05). Collectively, these variables were associated with approximately 5.8% of the observed differences in the composition of the salivary microbiota. Smoking status was associated with 3.3% of observed difference, and smoking could be detected with good accuracy based on salivary microbial composition (AUC 0.95, correct classification rate 79.6%). Conclusions: Glycemic status, HbA1c level, sex, smoking and weekly alcohol intake were significantly associated with the composition of the salivary microbiota. Despite smoking only being associated with 3.3% of the difference in overall salivary microbial composition, it was possible to create a model for detection of smoking status with a high correct classification rate. However, the lack of information on the oral health status of participants serves as a limitation in the present study. Further studies in other cohorts are needed to validate the external validity of these findings.

Kidney function and risk of dementia: Observational study, meta-analysis, and two-sample mendelian randomization study.

Whether impaired kidney function is associated with increased risk of developing dementia is unclear. We investigated the association between estimated glomerular filtration rate (eGFR) and dementia. Using a triangulation approach, we performed (1) a prospective study in 90,369 Danes from the Copenhagen General Population Study (CGPS), (2) a meta-analysis in 468,699 Scandinavians (including CGPS) and (3) a two-sample Mendelian randomization study in 218,792-1,004,040 Europeans using summary data from largest publicly available genome wide association studies (GWASs). During up to 15 years of follow-up (CGPS), 2,468 individuals developed dementia. Age and sex standardized percentile of eGFR below versus above the median conferred a multifactorially adjusted hazard ratio of 1.09 (95% confidence interval: 1.01-1.18). In meta-analysis, random-effects risk of dementia was 1.14 (1.06-1.22) for mildly decreased eGFR (60-90 mL/min/1.73 m2), 1.31 (0.92-1.87) for moderately decreased eGFR (30-59 mL/min/1.73 m2) and 1.91 (1.21-3.01) for severely decreased eGFR (< 30 mL/min/1.73 m2), compared to reference eGFR (> 90 mL/min/1.73 m2). Using directly comparable eGFR measures (log[eGFR] scaled to one standard deviation, as well as eGFR below versus above 60 mL/min/1.73 m2), we found no association with risk of dementia in observational CGPS or in Mendelian randomization analyses. In conclusion, impaired kidney function was associated with modestly increased risk of developing dementia. This was not supported by causal, genetic analyses using a Mendelian randomization approach. However, future stronger genetic instruments for kidney function and larger GWASs with more dementia cases, particularly for the vascular dementia subtype, warrant a re-evaluation of the causal hypothesis.

Long-term effects of intensive multifactorial treatment on aortic stiffness and central hemodynamics after 13 years with screen-detected type 2 diabetes: the ADDITION-Denmark trial.

BACKGROUND: Peripheral and central hemodynamic indices are modifiable by lifestyle and medical intervention. We aimed to determine the long-term effect of intensive multifactorial treatment on peripheral and central hemodynamic indices among people with screen-detected diabetes. METHODS: Between 2001 and 2006, people with screen-detected type 2 diabetes were included in the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) trial (NCT00237549, ClinicalTrials.gov). In the Danish arm, participants were invited to a clinical examination in 2015-2016, 13 years after inclusion and 8 years after trial-end. Out of 586 eligible participants who attended the clinical examination, 411 had a valid examination of central and peripheral hemodynamic indices (242 received intensive treatment and 169 received routine care). Carotid-femoral pulse wave velocity (cfPWV), central blood pressure and augmentation index were assessed by applanation tonometry. We used mixed-effect models to examine the intervention effect adjusting for cluster randomization and heart rate. RESULTS: Randomization to intensive treatment during the trial-period was associated with a 0.58 m/s lower cfPWV (95% CI - 1.09 to - 0.06) at follow-up. Adjustment for blood pressure attenuated the association. Differences between intervention groups for central augmentation index were - 1.25% (95% CI: - 3.28 to 0.78), central pulse pressure - 1.74 mmHg (95% CI - 4.79 to 1.31), central systolic blood pressure - 3.06 mmHg (- 7.08 to 0.96), and central diastolic blood pressure - 1.70 mmHg (- 3.74 to 0.34). CONCLUSIONS: Intensive multifactorial treatment of screen-detected type 2 diabetes has a sustained positive effect on aortic stiffness measured by cfPWV. Although all estimates pointed in favor of intensive treatment, we observed no clear beneficial effect on other hemodynamic indices.

The Arg82Cys Polymorphism of the Protein Nepmucin Implies a Role in HDL Metabolism.

Context: Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive. Objective: Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism. Methods: We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status. Results: A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels. Conclusion: Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Health-related quality of life for normal glycaemia, prediabetes and type 2 diabetes mellitus: Cross-sectional analysis of the ADDITION-PRO study.

AIMS: We estimated and compared health-related quality of life for individuals with normal glucose tolerance, prediabetes and diabetes. METHODS: Participants in the ADDITION-PRO study, Denmark, who attended a health assessment between 2009 and 2011, and who completed the 3-level EuroQoL 5-dimensions (EQ-5D-3L) questionnaire were included. For the present study, they were classified as normal glucose tolerance, prediabetes and diabetes (screen-detected and known) using the 2019 American Diabetes Association criteria. Prediabetes was defined as impaired fasting glucose, impaired glucose tolerance or HbA1c between 5.7-6.4% (39-47 mmol/mol). EQ-5D-3L data were converted into utility scores using Danish and UK values, where '1' equals full health and '0' equals death. Regression models estimated the association between utility and the different glucose health states. RESULTS: The mean EQ-5D-3L score in the sample population was 0.86 ± 0.17 (median 0.85, interquartile range 0.76 to 1) using UK values. Almost half of the sample (48%) reported full health with an EQ-5D score of '1'. Individuals with known diabetes reported the lowest EQ-5D-3L utility scores (0.81 ± 0.20), followed by individuals with screen-detected diabetes (0.85 ± 0.19), prediabetes (0.86 ± 0.17) and normal glucose tolerance (0.90 ± 0.15). The differences were statistically significant for normal glucose and known diabetes relative to prediabetes, after adjusting for sex, age, smoking, BMI and physical activity. These findings also held using Danish values albeit the differences were of smaller magnitude. CONCLUSIONS: Having prediabetes and diabetes was significantly associated with lower health-related quality of life relative to normal glucose tolerance. Our estimates will be useful to inform the value of interventions to prevent diabetes or prediabetes.

Changes in type 2 diabetes incidence and mortality associated with introduction of HbA1c as diagnostic option: A Danish 24-year population-based study.

BACKGROUND: In 2011, the World Health Organization began recommending glycated haemoglobin (HbA1c) as a measure for diagnosing type 2 diabetes (T2D). This initiative may have changed basic T2D epidemiology. Consequently, we examined time changes in T2D incidence and mortality during 1995-2018. METHODS: In this population-based cohort study, we included 415,553 individuals with incident T2D. We calculated annual age-standardized incidence rates of T2D. We examined HbA1c testing and used Poisson-regression to investigate all-cause mortality among the T2D patients and a matched comparison cohort from the general population over successive 3-year periods. FINDINGS: From 1995 to the 2012 introduction of HbA1c testing as a diagnostic option in Denmark, the annual standardized incidence rate (SIR) of T2D doubled, from 193 to 396 per 100,000 persons (4.1% increase annually). From 2012 onwards, the T2D incidence declined by 36%, reaching 253 per 100,000 persons in 2018 (5.7% decrease annually). This was driven by fewer patients starting treatment with an HbA1c measurement of <6·5% or without prior HbA1c testing. Mortality per 1,000 person-years following a T2D diagnosis decreased by 44% between 1995-1997 and 2010-2012, from 69 deaths to 38 deaths (adjusted mortality rate ratio: 0·55 (95% CI: 0·54-0·56)). After the low level during 2010-2012, mortality increased again by 27% to 48 per 1,000 person-years (95% CI: 46-50) by 2016-2018. INTERPRETATION: Our findings suggest that introducing HbA1c as a diagnostic option may have changed basic T2D epidemiology by leaving patients undiagnosed, that previously would have been diagnosed and treated. FUNDING: Aarhus University funded the study and had no further involvement.

Effectiveness of the population-based 'check your health preventive programme' conducted in a primary care setting: a pragmatic randomised controlled trial.

BACKGROUND: Health checks have been suggested as an early detection approach aiming at lowering the risk of chronic disease development. This study aimed to evaluate the effectiveness of a health check programme offered to the general population, aged 30-49 years. METHODS: The entire population aged 30-49 years (N=26 216) living in the municipality of Randers, Denmark, was invited to a health check during 5 years. A pragmatic household cluster-randomised controlled trial was conducted in 10 505 citizens. The intervention group (IG, N=5250) included citizens randomised to the second year and reinvited in the 5th year. The comparison group (CG, N=5255) included citizens randomised to the 5th year. Outcomes were modelled cardiovascular disease (CVD) risk; self-reported physical activity (PA) and objectively measured cardio respiratory fitness (CRF); self-rated health (short-form 12 (SF-12)), self-rated mental health (SF-12_Mental Component Score (MCS)) and, registry information on sick-leave and employment. Due to low participation, we compared groups matched on propensity scores for participation when reinvited. RESULTS: Participation in the first health check was 51% (N=2698) in the IG and 40% (N=2120) in the CG. In the IG 26% (N=1340) participated in both the first and second health checks. No intervention effects were found comparing IG and CG. Mean differences were (95% CI): modelled CVD risk: -0.052 (95% CI -0.107 to 0.003)%, PA: -0.156 (-0.331 to 0.019) days/week with 30 min moderate PA, CRF: 0.133 (-0.560 to 0.826) mL O2/min/kg, SF-12: -0.003 (-0.032 to 0.026), SF-12_MCS: 0.355 (-0.423 to 1.132), sick leave periods ≥3 weeks: -0.004 (-0.025 to 0.017), employment: -0.004 (-0.032 to 0.024). CONCLUSIONS: Preventive health checks offered to the general population, aged 30-49 years, had no effects on a wide range of indicators of chronic disease risk. TRIAL REGISTRATION NUMBER: NCT02028195.

Polypharmacy in polymorbid pregnancies and the risk of congenital malformations-A systematic review.

With an increased prevalence of concurrent morbidities during pregnancy, polypharmacy has become increasingly common in pregnant women. The risks associated with polypharmacy may exceed those of individual medication because of drug-drug interactions. This systematic review aims to evaluate the risk of congenital malformations in polymorbid pregnancies exposed to first-trimester polypharmacy. PubMed, Embase and Scopus were searched to identify original human studies with first- trimester polypharmacy due to polymorbidity as the exposure and congenital malformations as the outcome. After screening of 4034 identified records, seven studies fulfilled the inclusion criteria. Four of the seven studies reported an increased risk of congenital malformations compared with unexposed or monotherapy, odds ratios ranging from 1.1 to >10.0. Particularly, short-term anti-infective treatment combined with other drugs and P-glycoprotein substrates were associated with increased malformation risks. In conclusion, knowledge is limited on risks associated with first-trimester polypharmacy due to polymorbidity with the underlying evidence of low quantity and quality. Therefore, an increased focus on pharmacovigilance to enable safe drug use in early pregnancy is needed. Large-scale register-based studies and better knowledge of placental biology are needed to support the clinical management of polymorbid pregnancies that require polypharmacy.

Obesity and Kidney Function: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). METHODS: Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. RESULTS: One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [ß=-0.032 (95% confidence intervals: -0.036, -0.027) log[eGFR], P = 1 × 10-43], increased blood urea nitrogen (BUN) [ß = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10-6], increased urinary albumin-to-creatinine ratio [ß = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04-1.28], P = 0.009] and CKD [1.13 (1.07-1.19), P = 3 × 10-6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. CONCLUSIONS: Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

Potentially inappropriate medications (PIMs): frequency and extent of GP-related variation in PIMs: a register-based cohort study.

OBJECTIVES: Potentially inappropriate medications (PIMs) pose an increasing challenge in the ageing population. We aimed to assess the extent of PIMs and the prescriber-related variation in PIM prevalence. DESIGN: Nationwide register-based cohort study. SETTING: General practice. PARTICIPANTS: The 4.2 million adults listed with general practitioner (GP) clinics in Denmark (n=1906) in 2016. MAIN OUTCOME MEASURES: We estimated the patients' time with PIMs by using 29 register-operationalised STOPP criteria linking GP clinics and redeemed prescriptions. For each criterion and each GP clinic, we calculated ratios between the observed PIM time and that predicted by multivariate Poisson regressions on the patients. The observed variation was measured as the 90th/10th percentile ratios of these ratios. The extent of expectable random variation was assessed as the 90th/10th percentile ratios in randomly sampled GP populations (ie, the sampled variation). The GP-related excess variation was calculated as the ratio between the observed variation and sampled variation. The linear correlation between the observed/expected ratio for each of the criteria and the observed/expected ratio of total PIM time (for each clinic) was measured by Pearson's rho. RESULTS: Overall, 294 542 individuals were exposed to 1 44 117 years of PIMs. The two most prevalent PIMs were long-term use (>3 months) of non-steroidal anti-inflammatory drugs (51 074 years of PIMs) or benzodiazepines (48 723 years of PIMs). These two criteria showed considerable excess variation of 2.33 and 3.05, respectively; for total PIMs, this figure was 1.65. For more than half of the criteria, we observed a positive correlation between the specific PIM and the sum of remaining PIMs. CONCLUSIONS: This study documents considerable variations in the prescribing practice of GPs for certain PIMs. These findings highlight a need for exploring the causal explanations for such variations, which could be markers of suboptimal GP-prescribing strategies.

Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes.

OBJECTIVE: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown. METHODS: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants. RESULTS: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids. INTERPRETATION: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.

Diabetic Polyneuropathy Early in Type 2 Diabetes Is Associated With Higher Incidence Rate of Cardiovascular Disease: Results From Two Danish Cohort Studies.

OBJECTIVE: Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death. RESEARCH DESIGN AND METHODS: We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors. RESULTS: In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48). CONCLUSIONS: The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.