Search

Background: The development of diseases with a possible autoimmune pathogenesis is common in adults with inflammatory bowel disease (IBD). In early onset IBD, it may differ but the evidence is sparse. We aimed to investigate the risk and time span from IBD diagnosis to outcomes with different associated disorders with possible autoimmune pathogenesis., Methods: A register-based study included all Danish patients with early onset of IBD (≤18 years) between 1980 and 2021 and 50 matched references without IBD for each case. We examined the risk of type 1 and type 2 diabetes, celiac disease, thyroid disease, rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis in Cox regression models., Results: In total, 6822 patients with IBD were identified, and 337 728 matched references. The median age at the time of IBD diagnosis or index date for the matched references was 16 years (25-75 percentile: 13-18 years), and the median age at the time of an outcome or at the end of follow-up was 28.1 years (25-75 percentile: 21.5-37.0 years). According to the cumulative incidence plots psoriatic arthritis, and spondyloarthritis was diagnosed approximately 10 years after the IBD onset, and the remaining outcomes later. The adjusted hazard ratio after full follow-up was 4.72 (95% CI, 3.85-5.80) for psoriatic arthritis, 5.21 (95% CI, 4.17-6.50) for spondyloarthritis, 2.77 (95% CI, 1.92-4.00) for celiac disease, 2.15 (95% CI, 1.54-3.01) for rheumatoid arthritis, 1.69 (95% CI, 1.23-2.32) and 1.64 (95% CI, 1.21-2.21) for type 1 and type 2 diabetes, respectively. For thyroid disease, it was 1.16 (95% CI, 0.97-1.40)., Conclusions: The risk estimates were significantly increased for all outcomes at the end of follow-up, except for thyroid disease, but according to the cumulative incidence plots, only psoriatic arthritis and spondyloarthritis occurred earlier in the IBD cohort than in the matched references., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: Today about 12.5% of all children are conceived using assisted reproductive technology. Intracytoplasmic sperm injection (ICSI) was introduced without knowledge of the possible long-term adverse consequences on the offspring health. We aimed to examine risk of neurodevelopmental disorders, asthma, epilepsy, inflammatory bowel disease, rheumatoid arthritis, thyroid disease, and diabetes in the offspring conceived with ICSI, compared with offspring conceived with in vitro fertilization (IVF) and natural conception., Patients and Methods: All offspring conceived using ICSI, IVF, and natural conception in Denmark from July 9th, 1994 until December 31st, 2019 were included in this nationwide cohort study using Danish national health registries., Results: Median follow-up time was 10 years (6-16 years, interquartile range (IQR)) for offspring conceived with ICSI (n = 22,906), 13 years (7-20 years, IQR) for offspring conceived with IVF (n = 32,458), and 13 years (8-20, IQR) for offspring born after natural conception (n = 1,397,791). Several of the outcomes occurred rarely. The most frequent outcome in offspring conceived with ICSI was neurodevelopmental disorder which did not show an increased risk when comparing offspring conceived with ICSI with offspring conceived with IVF (hazard ratio 1.02 (95 % CI: 0.92;1.12)) and natural conception (hazard ratio 0.96 (95 % CI: 0.88;1.40))., Conclusion: Reassuringly, there were no statistically significantly increased risks of the examined outcomes in offspring conceived with ICSI. Before any firm conclusions are made, this study should be replicated in large populations with longer follow-up time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High-impact chronic pain (HICP), defined as chronic pain with a significant impact on daily function, affects approximately 8% of the Western population. In Denmark, HICP still remains to be described at the population level. Some patients with HICP are referred to the Danish pain centres, where they are registered with a procedural code. We conducted a nationwide registry-based study of all Danish patients registered with a visit to a pain centre from January 2005 to March 2022, to explore time trends in the prescription of analgesics and sedatives in this HICP subpopulation. Furthermore, data on socioeconomics and hospital diagnoses are reported., Methods: We used data from the Central Person Registry, the Danish National Patient Registry, the Danish National Prescription Registry, combined with data on socioeconomic information from Statistics Denmark. Data was collected on prescriptions 3 months before the first visit to a pain centre. Prescriptions were stratified into five calendar periods: before 2011, 2011-2013, 2014-2016, 2017-2019, and 2020-2022., Results: We identified 66,577 patients referred to a pain centre. Over 15 years, prescriptions before referral declined for opioids (from 53.2% to 31.7%), NSAIDs (from 28.3% to 23.5%), antidepressants (from 20.5% to 16.8%), anxiolytics (from 12.3% to 3.2%), and sleep medication (from 15.8% to 7.6%). In contrast, prescriptions increased for paracetamol (from 31.1% to 48.9%) and gabapentinoids (from 19.2% to 27.7%)., Conclusions: In patients with HICP visiting Danish pain centres, prescriptions before referral decreased for opioids over 15 years, with a simultaneously increased prescription of gabapentinoids (gabapentin and pregabalin)., Significance Statement: This nationwide study of 66,577 Danish patients with high-impact chronic pain reveals a significant decrease in filled opioid prescriptions over the past 15 years, with a simultaneous rise in gabapentinoid use before referral to pain centres. These findings suggest a shift in clinical practice towards alternative pain management strategies. The study underscores the need for continued research into the long-term effects of these changes and their impact on patient outcomes., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: There is a global increase in the prevalence of obesity, including among individuals with inflammatory bowel disease (IBD). Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are potential anti-obesity medications due to their weight-lowering effects. However, concerns exist regarding ileus and intestinal obstruction as a severe side effect., Methods: This nationwide Danish cohort study evaluates the risk of ileus and intestinal obstruction in patients with IBD receiving GLP-1RAs. Patients with IBD and their exposure to GLP-1RAs were identified using Danish health registries. Cox regression analysis was used to estimate hazard ratios for the risk of ileus and intestinal obstruction adjusted for age at diagnosis of IBD, sex, type of IBD, prior ileus or intestinal obstruction, diabetes status, steroid use, and small bowel or colon surgery., Results: This study found that GLP-1RA exposure was not associated with an increased risk of ileus or intestinal obstruction in patients with IBD., Conclusion: This study suggests that GLP-1RAs do not increase the risk of ileus or intestinal obstruction in patients with IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: About 15% of all pregnancies end in pregnancy loss. As most studies have focused on maternal factors little is known regarding the influence of paternal factors on the chance of successful pregnancy., Objectives: This cohort study aims to assess the chance of biochemical pregnancy, clinical pregnancy, and live-born children in couples where the male partner has diabetes mellitus (DM)., Materials and Methods: We performed a nationwide cohort study. Couples undergoing assisted reproductive technology treatment from 2006 to 2019 were included. The exposed cohorts comprised embryo transfers in couples with paternal type 1 DM (T1DM), type 2 DM (T2DM), or mixed type DM (TMDM). The unexposed cohort included embryo transfers in couples without paternal DM., Results: A total of 101,875 embryo transfers were included. Of these, 503 males had T1DM, 225 males had T2DM, 263 males had TMDM, and 100,884 did not have DM. For paternal T1DM, the adjusted OR for achieving a biochemical pregnancy, clinical pregnancy, and live-born child were 0.97 (95% CI 0.77-1.23), 1.08 (95% CI 0.65-1.79), and 0.75 (95% CI 0.49-1.14), respectively. For paternal T2DM, the adjusted OR for achieving a biochemical pregnancy, clinical pregnancy, and live-born child were 0.80 (95% CI 0.56;1.16), 0.67 (95% CI 0.32-1.41), and 1.03 (95% CI 0.48-2.20), respectively. For the paternal TMDM, the adjusted OR for achieving a biochemical pregnancy, clinical pregnancy and livebirth were 0.95 (95% CI 0.67-1.33), 1.31 (95% CI 0.56-2.92), and 1.19 (95% CI 0.59-2.38), respectively., Conclusion: Paternal DM was not associated with a statistically significant decreased chance of biochemical pregnancy, clinical pregnancy, or live birth., (© 2024 The Author(s). Andrology published by John Wiley & Sons Ltd on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Only about 30% of conceptions end in live births, yet there are little data on paternal causes of pregnancy loss. Men with inflammatory bowel disease may have multiple disease-related issues that may affect fertility. We aimed to examine pregnancy outcomes in women undergoing assisted reproduction whose male partners had Crohn's disease or ulcerative colitis., Methods: This nationwide study included all embryo transfers registered in the Danish Assisted Reproduction Registry from January 2, 2006, to September 3, 2019. The exposed cohort included embryo transfers from couples in which the male partners had Crohn's disease or ulcerative colitis. The unexposed cohort included embryo transfers in which male partners did not have inflammatory bowel disease., Results: For fathers with ulcerative colitis, the adjusted odds ratio for a positive biochemical pregnancy (positive human chorionic gonadotropin) was 1.14 (95% confidence interval [CI], 0.92-1.42), for a clinical pregnancy (positive vaginal ultrasonography at 7-8 weeks) was 0.91 (95% CI, 0.59-1.40), and for a live birth was 0.99 (95% CI, 0.71-1.60). For fathers with Crohn's disease, the adjusted odds ratio for a biochemical pregnancy was 0.83 (95% CI, 0.63-1.09), for a clinical pregnancy was 0.58 (95% CI, 0.34-0.97), and for a live birth was 0.88 (95% CI, 0.51-1.55)., Conclusions: These findings may indicate that partners of men with Crohn's disease may have an increased risk of early pregnancy loss. Future studies should confirm these results and examine the impact of paternal medications, paternal disease activity, and other factors associated with chronic inflammatory bowel disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Patients with back pain are often in contact with 2-4 hospital departments when receiving a back pain diagnosis and treatment. This complicates the entire clinical course description. There is, currently, no model that describes the course across departments for patients with back pain. This study aims to construct an interdisciplinary clinical course using the central register's information., Methods: All patients with back pain referred for diagnosis and treatment at the Spine Center of Southern Denmark from 1 January 2011 until 31 December 2017 were included. By means of information available in central registers, we described the interdisciplinary clinical course for the individual patient, including information on all contacts at different departments, and proposed three different models to define the index and final date. The index date was defined as the first visit without a previous contact to the Spine Center for 6 months for model I, 1 year for model II, and 2 years for model III. The final date was defined as the last visit without following contacts for 6 months, 1 year, and 2 years, respectively, for models I, II, and III., Results: A total of 69,564 patients (male: n = 30,976) with back pain diagnosis were identified. The three models all leave the information on the entire course at the hospital. In model I (64,757 clinical back pain courses), the time span to a possible previous clinical course is too short to secure the start of a new course (14% had two or more). With at least 1 year between a possible previous contact, model II (60,914 courses) fits the everyday clinical practice (9% had two or more clinical back pain courses). In model III (60,173 courses) it seems that two independent courses might be connected in the same course as only 5% had two or more clinical back pain courses., Conclusions: Despite contact with different departments, the clinical course for back pain patients can be described by information from the central registers. A one-year time interval fits best the clinicians' everyday observations., (© 2022. The Author(s).)

Objective: To examine whether medications used to treat rheumatoid arthritis (RA)/chronic inflammatory bowel disease (IBD), or factors related to the assisted reproductive technology (ART) procedures, impact the success of ART. In women with RA/IBD, initial studies have shown a reduced chance of a live-born child after ART., Design: Cohort study., Setting: Nationwide Danish health registries., Patients: All Danish women with a fresh embryo transfer from January 1, 2006, through 2018. The cohorts comprised 1,824 embryo transfers in women with RA/IBD and 97,191 embryo transfers in women without RA/IBD., Interventions: Observational, noninterventional study., Main Outcome Measure: Live birth per fresh embryo transfer., Results: The chance of a live birth in women with RA/IBD receiving ART, compared with other women receiving ART, had an adjusted odds ratio (OR) of 0.79 (95% confidence interval [CI], 0.68-0.91). Prescribed corticosteroids before embryo transfer were positively associated with a live-born child (adjusted OR, 1.21; 95% CI, 1.12-1.31), while the use of antiinflammatory/immunosuppressive agents did not have significant importance. Intracytoplasmic sperm injection was associated with a reduced chance (adjusted OR, 0.94; 95% CI, 0.90-0.97). Type of hormone treatment protocol did not have significant importance, and transfer at the blastocyst stage was positively associated with a live-born child (adjusted OR, 1.54; 95% CI, 1.46-1.62)., Conclusions: In women with RA and/or IBD, prescribed corticosteroid before embryo transfer and embryo transfer at the blastocyst stage were associated with successful ART. Intracytoplasmic sperm injection was associated with a slightly reduced chance. Antiinflammatory/immunosuppressive agents and type of hormone protocols did not have significant importance., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Despite the relevance of semantic fluency measures to risk for dementia and psychiatric disorders, little is known about their genetic and environmental architecture in mid-to-late life. Participants represent 21,684 middle-aged and older adult twins (M = 60.84 years, SD = 11.21; Range 40-89) from six studies from three countries participating in the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium. All completed the same measure of semantic fluency (naming animals in 60 seconds). Results revealed small-to-moderate phenotypic associations with age and education, with education more strongly and positively associated with fluency performance in females than males. Heritability and environmental influences did not vary by age. Environmental variance was smaller with higher levels of education, but this effect was observed only in males. This is the largest study to examine the genetic and environmental architecture of semantic fluency, and the first to demonstrate that environmental influences vary based on levels of education.

Background: Transient cognitive impairment is common in adult patients of all ages following anaesthesia and surgery. Apolipoprotein E (APOE) ε4 carriers may have a larger deterioration in short-term cognitive function after major surgery compared with APOE ε4 noncarriers., Objectives: The aim was to examine the effect of APOE ε4 on the association between exposure to surgery and anaesthesia, and subsequent cognitive functioning. A more pronounced deterioration in cognitive function in APOE ε4 carriers was hypothesised., Design: An observational cross-sectional and a 6 to 10 years longitudinal twin cohort design., Setting: Survey and register study of 2936 Danish twins aged 45 to 92 years., Main Outcome Measures: Cognitive function was assessed using five age-sensitive cognitive tests. In the cross-sectional study, we compared twins exposed to surgery with a reference group (unexposed). Linear regression models were used adjusting for sex and age and stratified by APOE ε4 carrier status. In the longitudinal cognitive follow-up study 1671 twins participated. Intrapair analyses were also performed using 70 same-sexed twin pairs concordant for APOE ε4 carrier status, but discordant for major surgery., Results: APOE ε4 carriers had lower cognitive scores compared with noncarriers, and this was statistically significant in elderly twins 70+ years of age (mean difference, -0.67; 95% CI, -1.14 to -0.17). There was no significant impact on cognitive function after surgery according to APOE ε4 carrier status in the cross-sectional study. Similarly, there was no APOE ε4 modification in the longitudinal study. Also, in the intrapair analyses no evidence was found of lower cognitive score after major surgery compared with the nonexposed cotwins among APOE ε4 carriers., Conclusion: No evidence was found of more pronounced long-term deterioration in cognitive function after surgery among APOE ε4 carriers, but elderly APOE ε4 carriers in general performed worse on the cognitive tests than noncarriers.

Background: β-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) and many β-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. β-adrenoceptor antagonists are used by billions of patients with neurological disorders, primarily for the treatment of migraine and action tremor (mainly essential tremor), worldwide., Recent Developments: An observational study reported a link between the chronic use of the β-adrenoceptor antagonist propranolol and an increased risk of Parkinson's disease, while the chronic use of the β-adrenoceptor agonists was associated with a decreased risk. Further support of this association was provided by a dose-dependent decrease in the risk of Parkinson's disease with chronic β-adrenoceptor agonist (eg, salbutamol) use, and by functional data indicating a possible underlying molecular mechanism. Five additional epidemiological studies have examined the modulation of the risk of Parkinson's disease as a result of the use of β-adrenoceptor-acting drugs in different populations. Overall, similar estimates but different interpretations of the associations were provided. Several findings suggest that the increase in risk of Parkinson's disease associated with β-adrenoceptor antagonists use can be explained by reverse causation because prodromal Parkinson's disease is often associated with non-specific action tremor, which is usually treated with propranolol. The lower risk of Parkinson's disease seen in patients receiving β-adrenoceptor agonists is likely to be indirectly mediated by smoking because smoking has a strong inverse association with Parkinson's disease (people that smoke have a reduced risk of developing Parkinson's disease). Smoking also causes chronic obstructive pulmonary disease, which is treated with β-adrenoceptor-agonist medications. Even if causal, the effect of β-adrenoceptor antagonists on the risk of Parkinson's disease would be small compared with other Parkinson's disease risk factors and would be similar to the risk evoked by pesticide exposure. The estimated risk of Parkinson's disease because of β-adrenoceptor antagonists use corresponds to one case in 10 000 patients after 5 years of propranolol use, and would be considered a very rare adverse effect. Thus, not using β-adrenoceptor antagonists would severely harm patients with recommended indications, such as heart disease or migraine. Similarly, 50 000 people would have to be treated for 5 years with salbutamol to prevent Parkinson's disease in one patient, suggesting that primary preventive therapy studies on disease modification are not warranted. WHERE NEXT?: Epidemiological evidence for a causal relationship between use of β2-adrenoceptor antagonists and the increased risk of Parkinson's disease is weak, with other explanations for the association being more probable. Future observational studies are warranted to clarify this association. However, given the very low risk associated with propranolol, most clinicians are unlikely to change their treatment approach., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The number of very old individuals in the population is rapidly increasing. Previous studies have indicated that many factors known to be strongly associated with survival among middle-aged and elderly show no association among the oldest old. Resting heart rate (RHR) is associated with increased risk of death in the general population as well as in patients with various types of heart disease. The association between RHR and mortality in the very old is the subject of this report. The study population was identified in The Nationwide Danish 1905 Cohort Study ( n  = 1086) and comprised 854 subjects with a median age of 95.2 years (range 94.7-95.9), in whom RHR was measured by radial pulse palpation. Participants were followed until death through the civil registration system, and remaining lifespan after RHR measure was used as outcome. Participants were divided into six groups according to RHR (≤50, 51-60, 61-70, 71-80, 81-90 and ≥91) with the largest group used as the reference group (61-70 beats per minute (bpm)). Survival analyses using Cox' proportional hazards models were performed to study the association between RHR and mortality. Median RHR was 68 bpm in males (IQR 62-76) and 70 bpm (IQR 64-78) in females. After stratifying both sexes into six groups according to RHR, we found no significant difference in remaining lifespan between groups in either males or females. No significantly increased risk was demonstrated in groups with higher RHR. In very old people, elevated RHR is not associated with increased mortality.

Objectives: Although visual and hearing impairments have been found to be associated with cognitive decline in the old age, the mechanism underlying this relationship remains unclear. This study aimed at assessing the predictive role of visual and hearing difficulties on subsequent cognitive functioning., Method: From the cohort of the first (2002) and fifth waves (2010) of the English Longitudinal Study of Ageing (ELSA), 3,508 individuals aged 60 and older were included in the study. Five self-reported visual and hearing functioning items were used to assess sensory functioning at baseline. Cognition was assessed 8 years later by means of four measured tests covering immediate and delayed recall, verbal fluency, and processing speed. A Multiple Indicators Multiple Causes approach was used to assess the longitudinal associations of visual and hearing functioning with cognitive difficulties. A multigroup longitudinal measurement invariance was used to estimate latent change in cognitive difficulties across groups of participants presenting either visual, hearing, or dual sensory impairment (i.e., those reporting difficulties in both visual and hearing functioning items)., Results: Visual (β = 0.140, p < .001) and hearing (β = 0.115, p < .001) difficulties predicted cognitive difficulties 8 years later. The latent increase in cognitive difficulties was steeper in people with visual impairment (d = 0.52, p < .001), hearing impairment (d = 0.50, p < .001), and dual-sensory impairment (d = 0.68, p < .001) than those non-impaired (d = 0.12, p < .001)., Discussion: Visual and hearing difficulties were identified as predictors of subsequent cognitive decline in the old age. Interventions to prevent visual and hearing difficulties may have a substantial impact to slow down subsequent age-related cognitive decline., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively., Methods: We obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries., Results: We included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use., Conclusion: We confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk., (© 2019 American Academy of Neurology.)

Background: This study investigates the accuracy of the reporting of medication use by proxy- and self-respondents, and it compares the prognostic value of the number of medications from survey and registry data for predicting mortality across self- and proxy-respondents., Methods: The study is based on the linkage of the Longitudinal Study of Aging Danish Twins and the Danish 1905-Cohort Study with the Danish National Prescription Registry. We investigated the concordance between survey and registry data, and the prognostic value of medication use when assessed using survey and registry data, to predict mortality for self- and proxy-respondents at intake surveys., Results: Among self-respondents, the agreement was moderate (κ = 0.52-0.58) for most therapeutic groups, whereas among proxy-respondents, the agreement was low to moderate (κ = 0.36-0.60). The magnitude of the relative differences was, generally, greater among proxies than among self-respondents. Each additional increase in the total number of medications was associated with 7%-8% mortality increase among self- and 4%-6% mortality increase among proxy-respondents in both the survey and registry data. The predictive value of the total number of medications estimated from either data source was lower among proxies (c-statistic = 0.56-0.58) than among self-respondents (c-statistic = 0.74)., Conclusions: The concordance between survey and registry data regarding medication use and the predictive value of the number of medications for mortality were lower among proxy- than among self-respondents., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype., Research Design and Methods: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects ( n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes ( n = 2,454 vs. 968) and type 2 diabetes ( n = 2,779 vs. 10,396)., Results: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3 , encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes., Conclusions: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies., (© 2018 by the American Diabetes Association.)

Background & Aims: Studies of association between use of proton pump inhibitors (PPI) and dementia have yielded conflicting results. We investigated the effects of PPIs on cognitive decline in a study of middle-aged and elderly twins in Denmark., Methods: In a prospective study, we collected data from surveys of middle-aged individuals (46-67 years old; the Middle Aged Danish Twin study) and older individuals (the Longitudinal Study of Aging Danish Twins) who underwent cognitive assessments (a 5-component test battery) over a 10-year period (middle-age study, n = 2346) or a 2-year period (longitudinal study of aging: n = 2475). We determined cumulative use of PPIs 2 years prior study enrollment and during follow up, in defined daily doses (DDDs) of PPIs, using data from a nationwide prescription register. Multi-variable linear regression models were used to examine associations between cumulative PPI use and a composite score of cognitive function at baseline and decreases in scores during the follow-up periods., Results: Use of PPIs before study enrollment was associated with a slightly lower mean cognitive score at baseline in the middle age study. The adjusted difference in mean score of individuals with high consumption of PPIs (≥400 DDD) was lower than that of non-users in the middle-age study (mean crude score for high PPI use, 43.4 ± 13.1 vs for non-use, 46.8 ± 10.2; adjusted difference of 0.69 points; 95% CI, -4.98 to 3.61). In the longitudinal study of aging twins, individuals with high consumption of PPI had higher adjusted scores than non-users (mean crude score for high PPI use, 35.2 ± 10.8 vs for non-use, 36.2 ± 11.1; adjusted difference of 0.95 points; 95% CI, -1.88 to 3.79). In analyses of cognitive decline, among individuals with high consumption of PPIs in the longitudinal study of aging, the adjusted mean difference between baseline score and follow-up score was lower than that of non-users (mean crude score for high PPI use at baseline, 36.6 ± 10.1 and at follow up, 34.3 ± 12.3 vs for non-use at baseline, 38.1 ± 10.5 and at follow up, 37.6 ± 11.3; adjusted difference of -1.22 points; 95% CI, -3.73 to 1.29). In the middle-age study, users with the highest consumption of PPIs (≥1600 DDD) had slightly less cognitive decline than non-users (baseline mean crude score for high PPI use, 43.4 ± 10.1 and follow-up mean crude score, 41.3 ± 9.7 vs baseline score of 49.1 ± 10.2 for non-users and follow-up score of 46.3 ± 9.9 for non-users; adjusted difference of 0.94 points; 95% CI, -1.63 to 3.50). No stated differences in scores between PPI users and non-users were significant., Conclusions: In analyzing data from 2 large population-based studies of twins in Denmark, we found no association between PPI use and cognitive decline., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Latent Autoimmune Diabetes in Adults (LADA) is the second most common form of diabetes, but data on its clinical course and prognosis are scarce. We compared long-term risk of mortality and cardiovascular outcomes in patients with LADA, type 2 diabetes mellitus (T2D), and insulin deficient diabetes (IDD)., Methods: We conducted a cohort study of 4368 adults with diabetes referred to the Department of Endocrinology, Odense University Hospital, Denmark, between 1997 and 2012. Data on comorbidity, cardiovascular outcomes and death were obtained from prospective medical databases. We compared adjusted hazard ratios (HRs) of mortality and cardiovascular outcomes for patients with LADA, T2D and IDD, respectively., Results: We included 327 patients with LADA, 3539 with T2D and 502 with IDD. At diagnosis, patients with LADA were older (50 years (IQR 37-59)) than IDD patients (40 years (IQR 28-52)), but younger than patients with T2D (55 years (IQR 45-64)). During a median follow-up period of 6.6 years (IQR 3.4-9.4), patients with IDD had higher mortality than patients with LADA, age- and gender-adjusted HR 2.2 (95% CI, 1.5-3.2). T2D also conferred higher mortality than LADA, HR 1.4 (95% CI, 1.0-1.9). Compared with LADA patients, cardiovascular outcome rates were increased both with IDD, HR 1.2 (95% CI, 0.7-2.0) and T2D, HR 1.2 (95% CI, 0.8-1.8), with the strongest association observed for T2D vs. LADA and acute myocardial infarction HR 1.7 (95% CI, 0.8-3.5)., Conclusion: LADA seems to be associated with lower mortality and lower risk of cardiovascular events, compared with both T2D and IDD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To examine the association between exposure to surgery and 10-year change in cognitive functioning., Methods: Among 2351 middle-aged twins, a 10-year change in composite cognitive scores derived from five cognitive tests was compared between 903 (38%) twins exposed to surgery classified as major, minor, knee and hip replacement, and other, and a reference group of 1448 (62%) twins without surgery, using linear regression models adjusted for socioeconomic factors. Genetic and shared environmental confounding was addressed in intrapair analyses of 48 monozygotic and 74 dizygotic same-sexed twin pairs., Results: In individual-level analyses, twins with major surgery (mean difference, -0.37; 95% CI, -0.76 to 0.02) or knee and hip replacement surgery (mean difference, -0.54; 95% CI, -1.30 to 0.22) had a tendency of a negligibly higher rate of decline in cognitive score than the reference group. In the intrapair analyses, the surgery-exposed twin had a higher rate of cognitive decline than the co-twin in 55% (95% CI, 45% to 63%) of the pairs. The mean difference in cognitive decline within pairs was -0.21 (95% CI, -0.81 to 0.39)., Conclusions: No significant associations were found between exposure to surgery and change in cognitive score either in individual-level or in intrapair analyses., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: In order to examine the hypothesis that elevated resting heart rate (RHR) is associated with impaired cognitive score, we investigated the relationship between RHR and cognitive score in middle-aged, elderly and old Danish subjects from the general population., Methods: Composite cognitive scores derived from the result of 5 age-sensitive cognitive tests for a total of 7,002 individuals (Middle-aged Danish twin: n = 4,132, elderly Danish twins: n = 2,104 and Danish nonagenarian: n = 766) divided according to RHR and compared using linear regression models adjusted for sex, age, previous heart conditions and hypertension. RHR was assessed by palpating radial pulse. Genetic and shared environmental confounding was addressed in intrapair analyses of 2,049 twin pairs., Results: In unadjusted multivariate models and in multivariable models adjusting for age, sex, heart conditions and hypertension, RHR was not associated with cognitive function. Furthermore, the intrapair analyses showed that RHR was not associated with cognitive score testing within twin pairs, as measured by the proportion of twin pairs in which the twin with higher RHR also was the twin with the lowest composite cognitive score (1,049 pairs of 2,049 pairs [51% (95% CI 49-53), p < 0.289])., Conclusion: While elevated RHR has been shown to be associated with adverse health events and poor fitness level, RHR has no relation to cognitive function in the general population., (© 2018 S. Karger AG, Basel.)

Objective: Islet autoimmunity, age at onset and time to insulin treatment are often used to define subgroups of diabetes. However, the latter criterion is not clinical useful. Here, we examined whether an unbiased stratification of diabetes according to age at onset, fasting C-peptide and GAD autoantibodies (GADab) defines groups with differences in glycaemic control and markers of cardiometabolic risk., Design and Methods: A cohort of 4374 adults with relatively newly diagnosed diabetes referred to a Danish hospital during 1997-2012 was stratified according to age at onset above or below 30 years, fasting C-peptide above or below 300 pmol/l (CPEP high or CPEP low ), and presence or absence of GADab (GAD pos or GAD neg ). HbA 1c , BMI, blood pressure (BP), lipid profile, alanine aminotransferase (ALT) and creatinine were evaluated., Results: GADab were present in 13% of the cohort. Age at onset was not associated with major differences between groups. Patients with insulin deficient diabetes (CPEP low ; n = 503) had higher HbA 1c but otherwise lower cardiometabolic risk (lower BMI, BP, LDL, triacylglycerol, and ALT, and higher HDL) than both patients with latent autoimmune diabetes of adults (LADA defined as GAD pos CPEP high ; n = 327) and patients with type 2 diabetes (GAD neg CPEP high ; n = 3544). Patients with LADA defined an intermediate group with higher HbA 1c but otherwise lower cardiometabolic risk than patients with type 2 diabetes., Conclusions: Our results demonstrate that fasting C-peptide and GADab status, but not age at onset, define groups of patients with diabetes with clinically relevant differences in glycaemic control and cardiometabolic risk., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Type 2 diabetes, obesity and insulin resistance are characterized by hypertriglyceridemia and ectopic accumulation of lipids in liver and skeletal muscle. AGPAT6 encodes a novel glycerol-3 phosphate acyltransferase, GPAT4, which catalyzes the first step in the de novo triglyceride synthesis. AGPAT6-deficient mice show lower weight and resistance to diet- and genetically induced obesity. Here, we examined whether common or low-frequency variants in AGPAT6 associate with type 2 diabetes or related metabolic traits in a Danish population., Methods: Eleven variants selected by a candidate gene approach capturing the common and low-frequency variation of AGPAT6 were genotyped in 12,068 Danes from four study populations of middle-aged individuals. The case-control study involved 4,638 type 2 diabetic and 5,934 glucose-tolerant individuals, while studies of quantitative metabolic traits were performed in 5,645 non-diabetic participants of the Inter99 Study., Results: None of the eleven AGPAT6 variants were robustly associated with type 2 diabetes in the Danish case-control study. Moreover, none of the AGPAT6 variants showed association with measures of obesity (waist circumference and BMI), serum lipid concentrations, fasting or 2-h post-glucose load levels of plasma glucose and serum insulin, or estimated indices of insulin secretion or insulin sensitivity., Conclusions: Common and low-frequency variants in AGPAT6 do not significantly associate with type 2 diabetes susceptibility, or influence related phenotypic traits such as obesity, dyslipidemia or indices of insulin sensitivity or insulin secretion in the population studied.