Search

Competing Interests: This work was supported by the European Crohn's and Colitis Organization, paid to JS. OO was primary investigator for projects at Karolinska Institutet, financed by grants from Janssen, Pfizer, AbbVie, Galapagos–Alfasigma, Takeda, and Bristol Myer Squibb. JFL coordinated a study on behalf of the Swedish Inflammatory Bowel Disease Register, which received funding from Janssen; has received financial support from MSD; and has a research collaboration with Takeda. HA declares no competing interests.

Background: An increased risk of cardiovascular disease (CVD) has been reported in patients with diverticular disease (DD). However, there are knowledge gaps about specific risks of each major adverse cardiovascular event (MACE) component., Methods: This nationwide cohort study included Swedish adults with DD (1987-2017, N=52,468) without previous CVD. DD was defined through ICD codes in the National Patient Register and colorectal histopathology reports from the ESPRESSO study. DD cases were matched by age, sex, calendar year and county of residence to ≤5 population reference individuals (N=194,525). Multivariable-adjusted hazard ratios (aHRs) for MACE up until December 2021 were calculated using stratified Cox proportional hazard models., Results: Median age at DD diagnosis was 62 years and 61% were females. During a median follow-up of 8.6 years, 16,147 incident MACE occurred in individuals with DD, and 48,134 in reference individuals (incidence rates (IRs)=61.4 vs. 43.8/1,000 person-years) corresponding to an aHR of 1.24 (95%CI=1.22-1.27), equivalent to one extra case of MACE for every 6 DD patients followed for 10 years. The risk was increased for ischemic heart disease (IR=27.9 vs. 18.6; aHR=1.36, 95%CI=1.32-1.40), congestive heart failure (IR=23.2 vs. 15.8; aHR=1.26, 95%CI=1.22-1.31), and stroke (IR=18.0 vs. 13.7; aHR=1.15, 95%CI=1.11-1.19). DD was not associated with cardiovascular mortality (IR=18.9 vs. 15.3; aHR=1.01, 95%CI=0.98-1.05). Results remained robust in sibling-controlled analyses., Conclusions: Patients with DD had a 24% increased risk of MACE compared with reference individuals, but no increased cardiovascular mortality. Future research should confirm these data and examine underlying mechanisms and shared risk factors between DD and CVD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims/hypothesis: While the association between coeliac disease and type 1 diabetes is well documented, the association of coeliac disease with type 2 diabetes risk remains undetermined. We conducted a nationwide cohort and Mendelian randomisation analysis to investigate this link., Methods: This nationwide matched cohort used data from the Swedish ESPRESSO cohort including 46,150 individuals with coeliac disease and 219,763 matched individuals in the comparator group selected from the general population, followed up from 1969 to 2021. Data from 9053 individuals with coeliac disease who underwent a second biopsy were used to examine the association between persistent villous atrophy and type 2 diabetes. Multivariable Cox regression was employed to estimate the associations. In Mendelian randomisation analysis, 37 independent genetic variants associated with clinically diagnosed coeliac disease at p<5×10 -8 were used to proxy genetic liability to coeliac disease. Summary-level data for type 2 diabetes were obtained from the DIAGRAM consortium (80,154 cases) and the FinnGen study (42,593 cases)., Results: Over a median 15.7 years' follow-up, there were 6132 (13.3%) and 30,138 (13.7%) incident cases of type 2 diabetes in people with coeliac disease and comparator individuals, respectively. Those with coeliac disease were not at increased risk of incident type 2 diabetes with an HR of 1.00 (95% CI 0.97, 1.03) compared with comparator individuals. Persistent villous atrophy was not associated with an increased risk of type 2 diabetes compared with mucosal healing among participants with coeliac disease (HR 1.02, 95% CI 0.90, 1.16). Genetic liability to coeliac disease was not associated with type 2 diabetes in DIAGRAM (OR 1.01, 95% CI 0.99, 1.03) or in FinnGen (OR 1.01, 95% CI 0.99-1.04)., Conclusions/interpretation: Coeliac disease was not associated with type 2 diabetes risk., (© 2024. The Author(s).)

Background and Aims: Dysregulation of inflammatory and immune responses has been implicated in the pathogenesis of heart failure (HF). But even if inflammation is a prerequisite for inflammatory bowel disease (IBD), little is known about HF risk in IBD., Methods: In this Swedish nationwide cohort, patients with biopsy-confirmed IBD were identified between 1969 and 2017 [n = 81 749, Crohn's disease (CD, n = 24 303), ulcerative colitis (UC, n = 45 709), and IBD-unclassified (IBD-U, n = 11 737)]. Each patient was matched with up to five general population reference individuals (n = 382 190) and IBD-free full siblings (n = 95 239) and followed until 31 December 2019. Flexible parametric survival models estimated the adjusted hazard ratio (aHR) and standardized cumulative incidence for HF, with 95% confidence intervals (CI)., Results: There were 5582 incident HF identified in IBD patients (incidence rate [IR]: 50.3/10 000 person-years) and 20 343 in reference individuals (IR: 37.9) during a median follow-up of 12.4 years. IBD patients had a higher risk of HF than reference individuals (aHR 1.19, 95% CI 1.15-1.23). This increased risk remained significant ≥20 years after IBD diagnosis, leading to one extra HF case per 130 IBD patients until then. The increased risk was also observed across IBD subtypes: CD (IR: 46.9 vs. 34.4; aHR 1.28 [1.20-1.36]), UC (IR: 50.1 vs. 39.7; aHR 1.14 [1.09-1.19]), and IBD-U (IR: 60.9 vs. 39.0; aHR 1.28 [1.16-1.42]). Sibling-controlled analyses showed slightly attenuated association (IBD: aHR 1.10 [1.03-1.19])., Conclusions: Patients with IBD had a moderately higher risk of developing HF for ≥20 years after IBD diagnosis than the general population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Microscopic colitis (MC) is an inflammatory condition of the large intestine. Primarily diagnosed in middle-aged and older adults, the incidence of the disease has increased markedly during the past few decades. While MC is associated with a reduced quality of life, large-scale studies on the association with future psychiatric disorders are lacking., Methods: We conducted a nationwide matched cohort study in Sweden from 2006 to 2021. Through a nationwide histopathology database (the Epidemiology Strengthened by histoPathology Reports in Sweden study), we identified 5,816 patients with a colorectal biopsy consistent with MC. These patients were matched with 21,509 reference individuals from the general population all of whom with no previous record of psychiatric disorders., Results: From 2006 to 2021, 519 patients with MC (median age 64.4 years [interquartile range = 49.5-73.3]) and 1,313 reference individuals were diagnosed with psychiatric disorders (9.9 vs 6.5 events per 1,000 person-years), corresponding to 1 extra case of psychiatric disorder in 29 patients with MC over 10 years. After adjustments, the hazard ratio for psychiatric disorders was 1.57 (95% confidence interval = 1.42-1.74). We found significantly elevated estimates up to 10 years after MC diagnosis and a trend toward higher risk with increasing age. Specifically, we observed increased risks for unipolar depression, anxiety disorders, stress-related disorders, substance abuse, and suicide attempts. In sibling-controlled analysis, the adjusted hazard ratio was 1.76 (95% confidence interval = 1.44-2.15)., Discussion: Patients with MC are at increased risk of incident psychiatric disorders compared with the general population., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Microscopic colitis (MC) is an inflammatory disorder of the colon. To date, the relationship between inflammatory eye diseases and MC is unclear., Objective: To assess whether inflammatory eye disease (iridocyclitis and episcleritis) is a risk factor for MC., Methods: We conducted a nationwide matched case control study in Sweden leveraging the ESPRESSO-study (a Swedish database containing data on all biopsies from the gastrointestinal tract from 1965 to 2017). In total, we identified 14,338 patients with biopsy-verified MC (diagnosed from 1981 to 2017). Patients with MC were matched (by age, sex, county and year of birth) with 68,753 controls from the general population and the occurrence of preceding inflammatory eye diseases (defined as diagnosis of episcleritis or iridocyclitis) in the two groups was compared. Multivariable adjusted odds ratios (aORs) were calculated using conditional logistic regression conditioned on the matching variables., Results: A majority of patients with MC were women (71.9%) and the median age at MC diagnosis was 63.3 years (interquartile range (IQR) = 50.7-72.6). Some 225 (1.6%) MC patients had an earlier record of inflammatory eye disease compared with 614 (0.9%) in controls. These figures corresponded to an aOR of 1.77 (95% CI = 1.52-2.07) for inflammatory eye diseases in patients with MC. Compared to siblings, the aOR for previous inflammatory eye diseases in MC was 1.52 (95% CI = 1.17-1.98) and patients treated with budesonide, as a proxy for clinically significant disease, had a somewhat higher aOR for previous inflammatory eye diseases., Conclusion: Inflammatory eye diseases are more common in patients subsequently being diagnosed with MC. Our findings highlight that these conditions may have shared causes and inflammatory pathways and are of clinical interest to gastroenterologists, ophthalmologists and general practitioners., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites, increased therapeutic efficacy, and reduced adverse effects. Over the past few years, sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential. These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature. Inspired by their unique properties, thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine. In this review, the state-of-the-art developments in thermosensitive hydrogels for precision therapy are investigated, which covers from the thermo-gelling mechanisms and main components to biomedical applications, including wound healing, anti-tumor activity, osteogenesis, and periodontal, sinonasal and ophthalmic diseases. The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features., Competing Interests: 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., (© 2024 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Background: There are conflicting data on the risk of acute coronary syndrome (ACS) in patients with inflammatory bowel disease (IBD). Only a few previous reports include patients diagnosed during the last decade., Aim: To assess and compare the risk of ACS between patients with IBD and the general population., Methods: In this cohort study, we used nationwide registers to identify patients diagnosed with IBD in Sweden 2003-2021. Every patient was matched by birth year, sex, calendar year and area of residence with up to 10 general population comparators. The primary outcome was incident ACS. We used semi-parametric Cox proportional hazard models to estimate hazard ratios (HRs)., Results: We identified 76,517 patients with IBD (Crohn's disease [CD], N = 22,732; ulcerative colitis [UC], N = 42,194 and IBD-unclassified, N = 11,591) and 757,141 comparators. During a median follow-up of 8 years, 2546 patients with IBD (37.5/10,000 person-years) were diagnosed with ACS compared with 19,598 (28.0/10,000 person-years) among comparators (HR 1.30; 95% confidence interval 1.24-1.35) after adjustments for confounding factors, and approximately one extra case of ACS in 100 IBD patients followed for 10 years. The highest HRs for ACS were in patients with elderly onset IBD (≥60 years) and among patients with CD or UC with extra-intestinal manifestations. No increased HRs were observed in patients diagnosed with IBD before the age of 40., Conclusion: In this contemporary cohort of patients with IBD, exposed to modern IBD care, there was an increased risk for ACS compared with individuals from the general population., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Microscopic colitis (MC) has been associated with several immune-mediated diseases including psoriasis, but earlier research has been limited to psoriasis occurring before MC. Data from large-scale cohort studies investigating MC and risk of future psoriasis are lacking., Objective: To examine the association between MC and psoriasis., Methods: In a nationwide, population-based, matched cohort study in Sweden from 2007 to 2021, we identified 8404 patients with biopsy-verified MC (diagnosed in 2007-2017), 37,033 matched reference individuals, and 8381 siblings without MC. Information on MC was obtained through the ESPRESSO cohort (a Swedish histopathology database with nationwide coverage). Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for psoriasis up until 2021., Results: During a median follow-up of 9.2 years (interquartile range = 6.7-11.7), 179 MC patients and 440 reference individuals were diagnosed with psoriasis (241.1 vs 131.8 events per 100,000 person-years), corresponding to one extra case of psoriasis in 91 patients with MC over 10 years. After adjustment for the matching variables (birth year, sex, county of residence, and calendar period) and level of education, we computed an adjusted hazard ratio (aHR) of 1.82 (95% CI = 1.53-2.17). Stratified by sex, estimates were similar and when examining the aHR across different lengths of follow-up, we found significantly elevated estimates up to 10 years after MC diagnosis. Compared to MC-free siblings, the aHR was 1.85 (95% CI = 1.36-2.51)., Conclusion: Patients with MC are at an almost doubled risk of psoriasis compared to the general population. Clinicians need to consider psoriasis in MC patients with skin lesions., Competing Interests: Dr. Ludvigsson has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from the Janssen corporation. Dr Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. Dr. Ebrahimi has served as an advisory board member for Boehringer Ingelheim. Dr Svedbom has received consultancy fees from ICON plc, AbbVie, BMS, Novartis, and Eli Lilly. Dr Svedbom has received lecture fees from Janssen Cilag and UCB. Dr Ståhle has received lecture fees and consulted for Leo Pharma, AbbVie, Eli-Lilly, Lipidor, UCB Pharma, Bristol-Myers Squibb and Janssen. Dr Ståhle serves as scientific chairman in Swedish Dermatology Foundation (Hudfonden) receiving honoraria. The authors report no other conflicts of interest in this work., (© 2024 Bergman et al.)

Objectives: Despite a suggested link between inflammatory bowel disease (IBD) and myocarditis, the association has not been well-established. This study aimed to investigate the long-term risk of myocarditis in patients with IBD., Methods: This nationwide cohort involved all patients with biopsy-confirmed IBD in Sweden (1969-2017) (n=83,264, Crohn's disease [CD, n=24,738], ulcerative colitis [UC, n=46,409], and IBD-unclassified [IBD-U, n=12,117]), general population reference individuals (n=391,344), and IBD-free full siblings (n=96,149), and followed until 2019. Primary outcome was incident myocarditis and secondary outcome was severe myocarditis (complicated with heart failure, death, or readmission). Flexible parametric survival models were used to estimate adjusted hazard ratios (aHR) and cumulative incidence of outcomes, along with 95% confidence intervals (CIs)., Results: During a median follow-up of 12 years, there were 256 myocarditis cases in IBD patients (incidence rate [IR]=22.6/100,000 person-years) and 710 in reference individuals (IR=12.9), with an aHR of 1.55 (95%CI: 1.33 to 1.81). The increased risk persisted through 20 years after IBD diagnosis, corresponding to one extra myocarditis case in 735 IBD patients until then. This increased risk was observed in CD (aHR=1.48 [1.11 to 1.97]) and UC (aHR=1.58 [1.30 to 1.93]). IBD was also associated with severe myocarditis (IR: 10.1 vs. 3.5; aHR=2.44 [1.89 to 3.15]), irrespective of IBD subtypes (CD: aHR=2.39 [1.43 to 4.01], UC: aHR=2.82 [1.99 to 4.00], and IBD-U: aHR=3.14 [1.55 to 6.33]). Sibling comparison analyses yielded similar results., Conclusions: Patients with IBD had an increased risk of myocarditis, especially severe myocarditis, for ≥20 years after diagnosis, but absolute risks were low., (Copyright © 2024 by The American College of Gastroenterology.)

Objectives: Celiac disease (CeD) has been linked to an increased risk of other autoimmune diseases, yet the impact of delayed CeD diagnosis on risk of developing additional autoimmune diseases remains uncertain. We investigated this through a nationwide matched case-control study., Methods: Using the ESPRESSO cohort with histophatology data from Sweden's 28 pathology departments, we assessed 46,575 biopsy-confirmed CeD cases from 1964 to 2017. We extracted 225,295 matched controls without histopathology information from the Swedish Total Population Register. Autoimmune disease was defined through diagnostic codes in the National Patient Register. Through conditional logistic regression we estimated odds ratio (OR) of autoimmune disease up until CeD diagnosis/matching date comparing CeD cases to controls across different age strata., Results: A total of 3059 (6.6 %) CeD patients and 4076 (1.8 %) controls had earlier autoimmune disease. The overall OR for autoimmune disease in CeD was 3.50 (95%CI 3.32-3.70). The risk of autoimmune disease did not escalate with increasing age at CeD diagnosis. Compared with controls, the OR of autoimmune disease in CeD patients was 7.70 (95%CI 4.71-12.57) in those diagnosed with CeD in 0-4 years, 19.02 (95%CI 13.80-26.23) in 5-9 years, 6.18 (95%CI 5.14-7.44) in 10-14 years, 4.80 (95%CI 3.97-5.79) in 15-19 years, 4.24 (95%CI 3.55-5.07) in 20-29 years, 4.65 (95%CI 3.93-5.51) in 30-39 years, 3.67 (95%CI 3.30-4.09) in 40-59 years, and 1.67 (95%CI 1.50-1.85) in ≥60 years., Conclusions: This study revealed an increased risk of autoimmune disease among CeD patients compared with controls. However, older age at CeD diagnosis did not seem to escalate the risk of autoimmune diseases., Competing Interests: Declaration of competing interest Dr. Leffler is an employee of Takeda. Dr. Ludvigsson has coordinated an unrelated study for the Swedish IBD quality register (SWIBREG). That study received funding from Janssen Corporation. Dr. Ludvigsson has also received financial support from MSD, developing a paper reviewing national healthcare registers in China. Dr. Ludvigsson has an ongoing research collaboration with Takeda. The other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Data suggest atherosclerotic-related inflammation may play a role in the pathogenesis of inflammatory bowel disease (IBD), but large-scale studies are missing., Methods: In this nationwide case-control study, we used the Swedish Patient Register and the Epidemiology Strengthened by histoPathology Reports in Sweden cohort to identify adult cases of incident IBD between 2002 and 2021, with each case matched to up to 10 general population controls. We used conditional logistic regression to calculate odds ratios (OR) for exposure to an atherosclerotic-related condition (myocardial infarction, thromboembolic stroke, or atherosclerosis itself) before being diagnosed with IBD., Results: There were a total of 56,212 individuals with IBD and 531,014 controls. Of them, 2,334 (4.2%) cases and 18,222 (3.4%) controls had a prior diagnosis of an atherosclerotic-related condition, corresponding to an OR of 1.30 (95% confidence interval [CI] 1.24-1.37). Results were statistically significant for both Crohn's disease (OR 1.37, 95% CI 1.26-1.48) and ulcerative colitis (OR 1.27, 95% CI 1.20-1.35) and for individuals who developed IBD at 40-59 years of age and 60 years or older. In addition, associations persisted when adjusting for underlying comorbidities, including the presence of immune-mediated diseases and prior aspirin and/or statin use. The highest odds of an atherosclerotic-related condition were seen in the 6-12 months before IBD diagnosis, though odds were increased even ≥5 years before. A higher magnitude of odds was also observed when having 2 or more atherosclerotic-related conditions when compared with having only 1 condition., Discussion: A history of an atherosclerotic-related condition is associated with increased odds of developing IBD, particularly among older adults. Future studies should investigate whether drugs targeting atherosclerotic-related inflammation may prevent IBD in higher-risk individuals., (Copyright © 2023 by The American College of Gastroenterology.)

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown., Methods: This nationwide multigenerational cohort study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969-2017), and matched general population comparators. Using the Swedish Multi-generation Register, we identified 38,018 first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 spouses of patients with MASLD, as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality., Results: Over a median of 17.6 years, the rate of the primary outcome HCC was higher in MASLD FDRs vs. comparator FDRs (13 vs. 8/100,000 person-years [PY]; aHR 1.80, 95% CI 1.36-2.37). The HCC risk was further increased in FDRs of individuals with liver fibrosis/cirrhosis (aHR 2.14, 95% CI 1.07-4.27; P Heterogeneity  = 0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000 PY; aHR 1.52, 95% CI 1.36-1.69) and liver-related mortality (20 vs. 11/100,000 PY; aHR 2.14, 95% CI 1.67-2.74). MASLD FDRs with any concomitant chronic liver condition experienced accelerated progression of liver disease (aHR 1.47, 95% CI 1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000 PY; aHR 1.23, 95% CI 1.01-1.51) and liver-related mortality (25 vs. 19/100,000 PY; aHR 1.93, 95% CI 1.15-3.23), but not of HCC (aHR 1.43, 95% CI 0.87-2.35)., Conclusions: There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low., Impact and Implications: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigenerational cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of hepatocellular carcinoma in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Microscopic colitis (MC) has been linked to several autoimmune conditions. Results from previous studies on the association with rheumatoid arthritis (RA) have been inconsistent., Aim: To assess the risk of future RA in MC., Methods: We conducted a nationwide matched cohort study in Sweden of 8179 patients with biopsy-verified MC (diagnosed in 2007-2017), 36,400 matched reference individuals and 8202 siblings without MC, with follow-up until 2021. Information on MC was obtained from all of Sweden's regional pathology registers (n = 28) through the ESPRESSO cohort. Data on incident RA were collected from the National Patient Register. Using Cox regression, we calculated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs)., Results: During a median follow-up of 9.1 years (interquartile range = 6.7-11.7), 73 MC patients and 183 reference individuals from the general population were diagnosed with RA (99 vs. 55 events per 100,000 person-years), equivalent to one extra case of RA in 226 patients with MC followed for 10 years. These rates corresponded to an aHR of 1.83 (95% CI = 1.39-2.41). The aHR was highest during the first year of follow-up (2.31 [95% CI = 1.08-4.97]) and remained significantly elevated up to 5 years after MC diagnosis (aHR 2.16; 95% CI = 1.42-3.30). Compared to siblings, without MC, the aHR was 2.04 (95% CI = 1.18-3.56)., Conclusion: Patients with MC are at a nearly two-fold risk of developing RA compared to the general population. Knowledge of this increased risk may expedite evaluation for RA in patients with MC presenting with joint symptoms and/or arthralgia, thus preventing delay until RA diagnosis., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Purpose: Evidence has accumulated to support the early involvement of altered gastrointestinal (GI) function in neurodegenerative disease. However, risk of Alzheimer disease (AD) and Parkinson disease (PD) among individuals with a GI biopsy of normal mucosa or nonspecific inflammation is unknown., Methods: This matched cohort study included all individuals in Sweden with a GI biopsy of normal mucosa (n = 480,346) or nonspecific inflammation (n = 655,937) during 1965-2016 (exposed group) as well as their individually matched population references and unexposed full siblings. A flexible parametric model and stratified Cox model were used to estimate hazard ratio (HR) and its 95% confidence interval (CI)., Results: Individuals with normal mucosa or nonspecific inflammation had a higher risk of AD and PD during the 20 years after biopsy. Compared with the population references, individuals with normal mucosa had an increased risk of AD (incidence rate [IR] difference = 13.53 per 100,000 person-years, HR [95% CI] = 1.15 [1.11-1.20]) and PD (IR difference = 6.72, HR [95% CI] = 1.16 [1.10-1.23]). Elevated risk was also observed for nonspecific inflammation regarding AD (IR difference = 13.28, HR [95% CI] = 1.11 [1.08-1.14]) and PD (IR difference = 6.83, HR [95% CI] = 1.10 [1.06-1.14]). Similar results were observed in subgroup and sensitivity analyses and when comparing with their unexposed siblings., Conclusions: Individuals with a GI biopsy of normal mucosa or nonspecific inflammation had an increased risk of AD and PD. This adds new evidence of the early involvement of GI dysfunction in neurodegenerative disease., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Although previous evidence has suggested an increased risk of cardiovascular disease (CVD) in patients with inflammatory bowel disease (IBD), its association with arrhythmias is inconclusive. In this study, we aimed to explore the long-term risk of arrhythmias in patients with IBD., Methods and Findings: Through a nationwide histopathology cohort, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn's disease (CD: n = 24,954; median age at diagnosis: 38.4 years; female: 52.2%), ulcerative colitis (UC: n = 46,856; 42.1 years; 46.3%), and IBD-unclassified (IBD-U: n = 12,067; 43.8 years; 49.6%), as well as their matched reference individuals and IBD-free full siblings. Outcomes included overall and specific arrhythmias (e.g., atrial fibrillation/flutter, bradyarrhythmias, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest). Flexible parametric survival models estimated hazard ratios (aHR) with 95% confidence intervals (95% CIs), after adjustment for birth year, sex, county of residence, calendar year, country of birth, educational attainment, number of healthcare visits, and cardiovascular-related comorbidities. Over a median of approximately 10 years of follow-up, 1,904 (7.6%) patients with CD, 4,154 (8.9%) patients with UC, and 990 (8.2%) patients with IBD-U developed arrhythmias, compared with 6.7%, 7.5%, and 6.0% in reference individuals, respectively. Compared with reference individuals, overall arrhythmias were increased in patients with CD [54.6 versus 46.1 per 10,000 person-years; aHR = 1.15 (95% CI [1.09, 1.21], P < 0.001)], patients with UC [64.7 versus 53.3 per 10,000 person-years; aHR = 1.14 (95% CI [1.10, 1.18], P < 0.001)], and patients with IBD-U [78.1 versus 53.5 per 10,000 person-years; aHR = 1.30 (95% CI [1.20, 1.41], P < 0.001)]. The increased risk persisted 25 years after diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. Patients with IBD also had a significantly increased risk of specific arrhythmias, except for bradyarrhythmias. Sibling comparison analyses confirmed the main findings. Study limitations include lack of clinical data to define IBD activity, not considering the potential role of IBD medications and disease activity, and the potential residual confounding from unmeasured factors for arrhythmias., Conclusions: In this study, we observed that patients with IBD were at an increased risk of developing arrhythmias. The excess risk persisted even 25 years after IBD diagnosis. Our findings indicate a need for awareness of this excess risk among healthcare professionals., Competing Interests: ES has served as a speaker and/or advisory board member (all institutional grants) for Bayer, Bristol-Myers Squibb-Pfizer, Boehringer- Ingelheim, Johnson & Johnson, Merck Sharp & Dohme. JH served as speaker and/or advisory board member for AbbVie, Aqilion, BMS, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD and Takeda. JS reports stock ownership in Anagram kommunikation AB and Symptoms Europe AB, outside the current study. AF has served as a speaker and advisory board member for Janssen. OO has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Bristol Myer Squibb and Ferring, and Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, Galapagos, Bristol Myer Squibb, Takeda, and Pfizer. OO also reports grants from Pfizer, Janssen, Galapagos, and AbbVie in the context of a national safety monitoring programs. JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen corporation. JFL has also received financial support from MSD developing a paper reviewing national healthcare registers in China. JFL is currently discussing potential research collaboration with Takeda. The other authors have declared that no competing interests exist., (Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Antibiotics affect the gut microbiome. Preclinical studies suggest a role of gut dysbiosis in the development of nonalcoholic fatty liver disease (NAFLD), but data from large cohorts with liver histology are lacking., Methods: In this nationwide case-control study, Swedish adults with histologically confirmed early-stage NAFLD (total n = 2584; simple steatosis n = 1435; steatohepatitis (NASH) n = 383; non-cirrhotic fibrosis n = 766) diagnosed January 2007-April 2017 were included and matched to ≤5 population controls (n = 12 646) for age, sex, calendar year and county of residence. Data for cumulative antibiotic dispensations and defined daily doses were accrued until 1 year before the matching date. Using conditional logistic regression, multivariable-adjusted odds ratios (aORs) were calculated. In a secondary analysis, NAFLD patients were compared with their full siblings (n = 2837)., Results: Previous antibiotic use was seen in 1748 (68%) NAFLD patients versus 7001 (55%) controls, corresponding to 1.35-fold increased odds of NAFLD (95% CI = 1.21-1.51) in a dose-dependent manner (p for trend  < .001). Estimates were comparable for all histologic stages (p > .05). The highest risk of NAFLD was observed after treatment with fluoroquinolones (aOR 1.38; 95% CI = 1.17-1.59). Associations remained robust when patients were compared with their full siblings (aOR 1.29; 95% CI = 1.08-1.55). Antibiotic treatment was only linked to NAFLD in patients without metabolic syndrome (aOR 1.63; 95% CI = 1.35-1.91) but not in those with metabolic syndrome (aOR 1.09; 95% CI = 0.88-1.30)., Conclusions: Antibiotic use may be a risk factor for incident NAFLD, especially in individuals without the metabolic syndrome. The risk was highest for fluoroquinolones and remained robust in sibling comparisons with whom individuals share genetic and early environmental susceptibilities., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Chronic nonhealing diabetic wounds are becoming increasingly severe, with high rates of mortality and disability, owing to the difficulty in wound healing caused by hyperglycemia, blocked angiogenesis, biofilm infection, and excessive oxidative stress. A multicomponent enzyme-responsive natural polymer, a hyaluronic acid (HA) microneedle, embedded in a cerium/zinc-based nanomaterial (ZCO) for the treatment of diabetic wounds is reported. ZCO-HA can destroy the oxidation balance of bacteria, kill bacteria, and scavenge reactive oxygen species (ROS) to alleviate oxidative stress via the adjustable release of Zn 2+ and Ce 3+ / 4+ . Additionally, ZCO-HA exhibits good anti-inflammatory activity through the nuclear factor kappa-B (NF-κB) pathway, which reduces the inflammatory state of macrophages and promotes cell proliferation, migration, and angiogenesis. In vitro experiments shows that ZCO-HA accompanies mouse fibroblast migration, promoting human umbilical vein endothelial cell tube formation. In vivo studies in mice with streptozotocin-induced (STZ)-induced diabetes reveal that this microneedle accelerates wound healing without systemic toxicity. RNA transcriptome sequencing illustrates that the multicomponent HA microneedle accelerates wound healing in diabetes through cell migration and inhibits inflammatory reactions and oxidative damage in mice via the NF-κB signaling pathway., (© 2023 Wiley-VCH GmbH.)

Background: Statin use has been linked to a reduced risk of advanced colorectal adenomas, but its association with colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) - a high risk population for CRC - remains inconclusive., Methods: From a nationwide IBD cohort in Sweden, we identified 5273 statin users and 5273 non-statin users (1:1 propensity score matching) from July 2006 to December 2018. Statin use was defined as the first filled prescription for ≥30 cumulative defined daily doses and followed until December 2019. Primary outcome was incident CRC. Secondary outcomes were CRC-related mortality and all-cause mortality. Cox regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs)., Findings: During a median follow-up of 5.6 years, 70 statin users (incidence rate (IR): 21.2 per 10,000 person-years) versus 90 non-statin users (IR: 29.2) were diagnosed with incident CRC (rate difference (RD), -8.0 (95% CIs: -15.8 to -0.2 per 10,000 person-years); aHR = 0.76 (95% CIs: 0.61 to 0.96)). The benefit for incident CRC was duration-dependent in a nested case-control design: as compared to short-term use (30 days to <1 year), the adjusted odd ratios were 0.59 (0.25 to 1.43) for 1 to <2 years of use, 0.46 (0.21 to 0.98) for 2 to <5 years of use, and 0.38 (0.16 to 0.86) for ≥5 years of use ( P for tread  = 0.016). Compared with non-statin users, statin users also had a decreased risk for CRC-related mortality (IR: 6.0 vs. 11.9; RD, -5.9 (-10.5 to -1.2); aHR, 0.56 (0.37 to 0.83)) and all-cause mortality (IR: 156.4 vs. 231.4; RD, -75.0 (-96.6 to -53.4); aHR, 0.63 (0.57 to 0.69))., Interpretation: Statin use was associated with a lower risk of incident CRC, CRC-related mortality, and all-cause mortality. The benefit for incident CRC was duration-dependent, with a significantly lower risk after ≥2 years of statin use., Funding: This research was supported by Forte (i.e., the Swedish Research Council for Health, Working Life and Welfare)., Competing Interests: All authors have completed the ICMJE uniform disclosure form and declare: JH served as speaker and/or advisory board member for AbbVie, Aqilion, BMS, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma and received grant support from Janssen, MSD and Takeda. PL is an employee of GSK (received and purchased GSK stock). OO has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Bristol Myer Squibb and Ferring, and Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, Galapagos, Bristol Myer Squibb, Takeda, and Pfizer. OO also reports grants from Pfizer, Janssen, Galapagos, and AbbVie in the context of a national safety monitoring programs. JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen corporation. JFL has also received financial support from MSD developing a paper reviewing national healthcare registers in China. The other authors report no conflict of interest., (© 2023 The Author(s).)

Background and Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of thromboembolic events, but evidence on the long-term risk of stroke remains scarce. We aimed to explore whether patients with a biopsy-confirmed IBD had an increased long-term risk of stroke., Methods: This cohort included all patients with biopsy-confirmed IBD in Sweden between 1969 and 2019 and up to 5 matched reference individuals per patient who were randomly selected from the general population and IBD-free full siblings. The primary outcome was incident overall stroke; secondary outcomes were ischemic and hemorrhagic strokes. Stroke was identified from the Swedish National Patient Register by using both primary and secondary diagnoses. Adjusted hazard ratios (aHRs) for stroke were estimated by flexible parametric survival models., Results: A total of 85,006 patients with IBD (including Crohn disease [CD, n = 25,257], ulcerative colitis [UC, n = 47,354], and IBD-unclassified [IBD-U, n = 12,395]), 406,987 matched reference individuals, and 101,082 IBD-free full siblings were included in the analysis. We observed 3,720 incident strokes in patients with IBD (incidence rate [IR] 32.6 per 10,000 person-years) and 15,599 in reference individuals (IR 27.7; aHR 1.13, 95% CI 1.08-1.17). The elevated aHR remained increased even 25 years after diagnosis, corresponding to 1 additional stroke case per 93 patients with IBD until then. The excess aHR was mainly driven by ischemic stroke (aHR 1.14; 1.09-1.18) rather than hemorrhagic stroke (aHR 1.06; 0.97-1.15). The risk of ischemic stroke was significantly increased across IBD subtypes (CD [IR 23.3 vs 19.2; aHR 1.19; 1.10-1.29], UC [IR 25.7 vs 22.6; aHR 1.09; 1.04-1.16], and IBD-U [IR 30.5 vs 22.8; aHR 1.22; 1.08-1.37]). Similar results were found when patients with IBD were compared with their siblings., Discussion: Patients with IBD were at an increased risk of stroke, especially of ischemic events, irrespective of the IBD subtype. The excess risk persisted even 25 years after diagnosis. These findings highlight the need for clinical vigilance about the long-term excess risk of cerebrovascular events in patients with IBD., (© 2023 American Academy of Neurology.)

Background: Although evidence suggests a persistently decreased risk of colorectal cancer for up to 10 years among individuals with a negative endoscopic biopsy result (i.e., normal mucosa), concerns have been raised about other long-term health outcomes among these individuals. In this study, we aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa., Methods and Findings: In the present nationwide cohort study, we identified all individuals in Sweden with a lower or upper gastrointestinal (GI) biopsy of normal mucosa during 1965 to 2016 (exposed, n = 200,495 and 257,192 for lower and upper GI biopsy, respectively), their individually matched population references (n = 989,484 and 1,268,897), and unexposed full siblings (n = 221,179 and 274,529). Flexible parametric model estimated hazard ratio (HR) as an estimate of the association between a GI biopsy of normal mucosa and IBD as well as cumulative incidence of IBD, with 95% confidence interval (CI). The first 6 months after GI biopsy were excluded to avoid detection bias, surveillance bias, or reverse causation. During a median follow-up time of approximately 10 years, 4,853 individuals with a lower GI biopsy of normal mucosa developed IBD (2.4%) compared to 0.4% of the population references. This corresponded to an incidence rate (IR) of 20.39 and 3.39 per 10,000 person-years in the respective groups or 1 extra estimated IBD case among 37 exposed individuals during the 30 years after normal GI biopsy. The exposed individuals had a persistently higher risk of overall IBD (average HR = 5.56; 95% CI: 5.28 to 5.85), ulcerative colitis (UC, average HR = 5.20; 95% CI: 4.85 to 5.59) and Crohn's disease (CD, average HR = 6.99; 95% CI: 6.38 to 7.66) than their matched population references. In the sibling comparison, average HRs were 3.27 (3.05 to 3.51) for overall IBD, 3.27 (2.96 to 3.61) for UC, and 3.77 (3.34 to 4.26) for CD. For individuals with an upper GI biopsy of normal mucosa, the average HR of CD was 2.93 (2.68 to 3.21) and 2.39 (2.10 to 2.73), compared with population references and unexposed full siblings, respectively. The increased risk of IBD persisted at least 30 years after cohort entry. Study limitations include lack of data on indications for biopsy and potential residual confounding from unmeasured risk or protective factors for IBD., Conclusions: Endoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG) and that study received funding from Janssen corporation. OO has been PI on projects at Karolinska Institutet, financed by grants from Janssen, Takeda, AbbVie, Ferring, and Karolinska Institutet; has received fees for lectures and participation on advisory boards from Janssen, Ferring, Takeda, Bristol Myer Squibb, Galapagos, and Pfizer. OO also reports a grant from Pfizer in the context of a national safety monitoring program. JH served as speaker and/or advisory board member for AbbVie, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD and Takeda. HK is supported by the American College of Gastroenterology Senior Research Award and the Beker Foundation; HK has received consulting fees from Abbvie and Takeda; HK has also received grant funding from Pfizer and Takeda. The other authors report no conflict of interest., (Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Amyotrophic lateral sclerosis (ALS) is a relatively rare but fatal neurodegenerative disease with the progressive loss of both upper and lower motor neurons. Although electromyography, imaging and multi-omics technologies have suggested numerous functional, structural, circulating and microbiota markers for ALS, no clinically validated markers have, as yet, been identified. Here we summarize the advances to characterize markers underlying ALS pathophysiology as well as their potential use in diagnosis, prognosis and therapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Accumulating evidence suggests a higher risk for cardiovascular diseases among individuals with mental disorders, but very little is known about the risk for overall and specific groups of cardiovascular diseases in people with attention-deficit/hyperactivity disorder (ADHD). To fill this knowledge gap, we investigated the prospective associations between ADHD and a wide range of cardiovascular diseases in adults. In a nationwide population-based cohort study, we identified 5,389,519 adults born between 1941 and 1983, without pre-existing cardiovascular diseases, from Swedish registers. The study period was from January 1, 2001 to December 31, 2013. Incident cardiovascular disease events were identified according to ICD codes. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression model, with ADHD as a time-varying exposure. After an average 11.80 years of follow-up, 38.05% of individuals with ADHD versus 23.57% of those without ADHD had at least one diagnosis of cardiovascular disease (p<0.0001). ADHD was significantly associated with increased risk of any cardiovascular disease (HR=2.05, 95% CI: 1.98-2.13) after adjusting for sex and year of birth. Further adjustments for education level, birth country, type 2 diabetes mellitus, obesity, dyslipidemia, sleep problems and heavy smoking attenuated the association, which however remained significant (HR=1.84, 95% CI: 1.77-1.91). Further adjustment for psychiatric comorbidities attenuated but could not fully explain the association (HR=1.65, 95% CI: 1.59-1.71). The strongest associations were found for cardiac arrest (HR=2.28, 95% CI: 1.81-2.87), hemorrhagic stroke (HR=2.16, 95% CI: 1.68-2.77), and peripheral vascular disease/arteriosclerosis (HR=2.05, 95% CI: 1.76-2.38). Stronger associations were observed in males and younger adults, while comparable associations were found among individuals with or without psychotropic medications and family history of cardiovascular diseases. These data suggest that ADHD is an independent risk factor for a wide range of cardiovascular diseases. They highlight the importance of carefully monitoring cardiovascular health and developing age-appropriate and individualized strategies to reduce the cardiovascular risk in individuals with ADHD., (© 2022 World Psychiatric Association.)

Background: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections., Methods and Findings: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to 2.72, P < 0.001) and PD (OR = 1.41, 95% CI: 1.29 to 1.53, P < 0.001). The associations were primarily due to AD and PD diagnosed before 60 years (OR = 1.93, 95% CI: 1.89 to 1.98 for AD, P < 0.001; OR = 1.29, 95% CI: 1.22 to 1.36 for PD, P < 0.001), whereas no association was found for those diagnosed at 60 years or older (OR = 1.00, 95% CI: 0.98 to 1.01 for AD, P = 0.508; OR = 1.01, 95% CI: 0.99 to 1.03 for PD, P = 0.382). No association was observed for ALS (OR = 0.97, 95% CI: 0.92 to 1.03, P = 0.384), regardless of age at diagnosis. Excluding infections experienced within 10 years before diagnosis of neurodegenerative disease confirmed these findings. Study limitations include the potential misclassification of hospital-treated infections and neurodegenerative diseases due to incomplete coverage of the National Patient Register, as well as the residual confounding from unmeasured risk or protective factors for neurodegenerative diseases., Conclusions: Hospital-treated infections, especially in early- and mid-life, were associated with an increased risk of AD and PD, primarily among AD and PD cases diagnosed before 60 years. These findings suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age. However, due to the observational nature of the study, these results do not formally prove a causal link., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JL coordinates a study (independent of the present study) on behalf of the Swedish IBD quality register (SWIBREG). That study has received funding from Janssen Corporation. Other authors declared no competing interests.

Background: While individuals with normal gastrointestinal (GI) mucosa on endoscopy have a lower risk of colorectal cancer, risks of other cancers remain unexplored., Methods: Through Sweden's 28 pathology departments, we identified 415,092 individuals with a first GI biopsy with histologically normal mucosa during 1965-2016 and no prior cancer. These individuals were compared to 1,939,215 matched reference individuals from the general population. Follow-up began 6 months after biopsy, and incident cancer data were retrieved from the Swedish Cancer Register. Flexible parametric model was applied to estimate cumulative incidences and hazard ratios (HRs) for cancers. We also used full siblings (n = 441,534) as a secondary comparison group., Results: During a median follow-up of 10.9 years, 40,935 individuals with normal mucosa (incidence rate: 82.74 per 10,000 person-years) and 177,350 reference individuals (incidence rate: 75.26) developed cancer. Restricting the data to individuals where follow-up revealed no cancer in the first 6 months, we still observed an increased risk of any cancer in those with a histologically normal mucosa (average HR = 1.07; 95%CI = 1.06-1.09). Although the HR for any and specific cancers decreased shortly after biopsy, we observed a long-term excess risk of any cancer, with an HR of 1.08 (95%CI = 1.05-1.12) and a cumulative incidence difference of 0.93% (95%CI = 0.61%-1.25%) at 30 years after biopsy. An elevated risk of gastric cancer, lung cancer, and hematological malignancy (including lymphoproliferative malignancy) was also observed at 20 or 30 years since biopsy. Sibling analyses confirmed the above findings., Conclusion: Individuals with a histologically normal mucosa at biopsy and where follow-up revealed no cancer in the first 6 months, may still be at increased risk of cancer, although excess risks are small., (© 2022. The Author(s).)

Background: To assess the association of hospital-treated infections with the subsequent risk of two Epstein-Barr virus (EBV)-related malignancies, namely Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC)., Methods: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with HL or NPC during 1994-2016 in Sweden, according to the Swedish Cancer Register. For each case, we randomly selected five controls individually matched to the case on sex and year of birth from the general Swedish population. Hospital-treated infections (i.e., infections requiring either inpatient or outpatient hospital care) were identified from the Swedish Patient Register. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HL and NPC, in relation to hospital-treated infections, after adjustment for age, sex, calendar period, educational achievement, and region of residence., Results: The study included a total of 890 cases of HL and 306 cases of NPC. A hospital-treated infection three years ago or earlier was associated with a higher risk of HL (OR = 1.49, 95%CI: 1.26-1.75) as well as NPC (OR = 1.36; 95%CI: 1.01-1.83). The positive association was noted for both bacterial and viral infections and primarily for respiratory and skin infections. A monotonous dose-response relationship was found between a number of hospital-treated infections and the risk of HL ( p = 0.02) but less compelling for NPC ( p = 0.06). Using a 5-year lag time rendered similar results (OR = 1.43, 95%CI: 1.21-1.70 for HL; OR = 1.43, 95%CI: 1.05-1.95 for NPC)., Conclusions: These findings suggest that infections requiring hospital treatment might contribute to the carcinogenesis of malignancies potentially related to EBV.

Background: Studying whether medications act as potential risk factors for amyotrophic lateral sclerosis (ALS) can contribute to the understanding of disease etiology as well as the identification of novel therapeutic targets. Therefore, we conducted a systematic review to summarize the existing evidence on the association between medication use and the subsequent ALS risk., Methods: A systematic review was conducted in Medline, Embase, and Web of Science from the date of database establishment to December 10, 2021. References of identified articles were further searched for additional relevant articles. Studies were included if (1) published in English, (2) explored medication use as exposure and development of ALS as outcome, and (3) the design was a human observational study. Clinical trials, reviews, comments, editorials, and case reports were excluded. Quality assessment was performed using a pre-validated tool for non-randomized studies, the Newcastle-Ottawa Assessment Scale (NOS)., Results: Of the 4760 studies identified, 25 articles, including 13 case-control studies, five nested case-control studies, six cohort studies, and one retrospective chart review, were included in the review. Among these studies, there were 22 distinct study populations that included 171,407 patients with ALS, seven classes of medication examined, and 23 studies with a NOS ≥ 5. There was a general lack of agreement between studies on the associations of cholesterol-lowering drugs, anti-inflammatory drugs, immunosuppressants, antibiotics, oral contraceptives (OCs) or hormone replacement therapy (HRT), antihypertensive drugs, antidiabetics, and drugs for psychiatric and neurological disorders with the subsequent risk of ALS. However, it appeared that statins, aspirin, OCs/HRT, antihypertensives, and antidiabetics were unlikely related to a higher risk of ALS. The positive associations noted for antibiotics, antidepressants, and skeletal muscle relaxants might be attributable to prodromal symptoms of ALS., Conclusions: There is currently no strong evidence to link any medication use with ALS risk., (© 2022. The Author(s).)

Importance: Adults with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for unemployment. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but whether it helps to reduce the unemployment rate among adult patients remains unclear., Objective: To investigate the association between use of ADHD medication and long-term unemployment in working-age adults with ADHD., Design, Setting, and Participants: Data for this population-based cohort study were extracted from Swedish national registers. Among 25 358 individuals with ADHD born from 1958 to 1978, 12 875 middle-aged adults among the workforce were included. The longitudinal cohort was followed up from January 1, 2008, to December 31, 2013. Data were analyzed from March 1, 2020, through May 31, 2021., Exposures: Use of medication for ADHD during the previous 2 years was the main exposure, as both categorical and continuous variables., Main Outcomes and Measures: Yearly accumulated unemployed days were derived from the Public Employment Service, and long-term unemployment was defined as 90 or more days of unemployment per year. Overall and sex-specific relative risks (RRs) with 95% CIs were estimated using generalized estimating equations., Results: Among 12 875 individuals with ADHD (5343 women [41.50%] and 7532 men [58.50%]; mean [SD] age, 37.9 [5.6] years), the use of ADHD medications during the previous 2 years was associated with a 10% lower risk of long-term unemployment in the following year (adjusted RR, 0.90 [95% CI, 0.87-0.95]). An association between use of ADHD medications and long-term unemployment was found among women (RR, 0.82 [95% CI, 0.76-0.89]) but not men (RR, 0.96 [95% CI, 0.91-1.01]). Longer treatment duration was associated with a lower risk of subsequent long-term unemployment among women (RR for use of 1-6 months, 0.86 [95% CI, 0.78-0.95]; RR for use of 18-24 months, 0.72 [95% CI, 0.58-0.90]; P < .001 for trend). Within-individual comparisons showed that the long-term unemployment rate was lower during periods of ADHD medication treatment compared with nontreatment periods (RR, 0.89; 95% CI, 0.85-0.94)., Conclusions and Relevance: The findings of this cohort study suggest that the use of ADHD medication is associated with a lower risk of subsequent long-term unemployment for middle-aged women. These findings should be considered together with the existing knowledge of risks and benefits of ADHD medication when developing treatment plans for working-age adults.

Amyotrophic lateral sclerosis (ALS), characterized by a loss of motor neurons in the brain and spinal cord, is a relatively rare but currently incurable neurodegenerative disease. The global incidence of ALS is estimated as 1.75 per 100,000 person-years and the global prevalence is estimated as 4.1-8.4 per 100,000 individuals. Contributions from outside the central nervous system to the etiology of ALS have been increasingly recognized. Gut microbiome is one of the most quickly growing fields of research for ALS. In this article, we performed a comprehensive review of the results from existing animal and human studies, to provide an up-to-date summary of the current research on gut microbiome and ALS. In brief, we found relatively consistent results from animal studies, suggesting an altered gut microbiome composition in experimental ALS. Publication bias might however be a concern. Findings from human studies are largely inconclusive. A few animal and human studies demonstrated the usefulness of intervention with microbial-derived metabolites in modulating the disease progression of ALS. We discussed potential methodological concerns in these studies, including study design, statistical power, handling process of biospecimens and sequencing data, as well as statistical methods and interpretation of results. Finally, we made a few proposals for continued microbiome research in ALS, with the aim to provide valid, reproducible, and translatable findings., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: The death of a child is an extreme life event with potentially long-term health consequences. Knowledge about its association with ischemic heart diseases (IHDs) and acute myocardial infarction (AMI), however, is very limited. We investigated whether the death of an offspring is associated with the risk of IHD and AMI., Methods and Findings: We studied parents of live-born children recorded in the Danish (1973 to 2016) and the Swedish (1973 to 2014) Medical Birth Registers (n = 6,711,952; mean age at baseline 31 years, 53% women). We retrieved information on exposure, outcomes, and covariates by linking individual-level information from several nationwide registers. We analyzed the abovementioned associations using Poisson regression. A total of 126,522 (1.9%) parents lost at least 1 child during the study period. Bereaved parents had a higher risk of IHD and AMI than the nonbereaved [incidence rate ratios (IRRs) (95% confidence intervals (CIs)): 1.20 (1.18 to 1.23), P < 0.001 and 1.21 (1.17 to 1.25), P < 0.001, respectively]. The association was present not only in case of losses due to CVD or other natural causes, but also in case of unnatural deaths. The AMI risk was highest in the first week after the loss [IRR (95% CI): 3.67 (2.08 to 6.46), P < 0.001], but a 20% to 40% increased risk was observed throughout the whole follow-up period. Study limitations include the possibility of residual confounding by socioeconomic, lifestyle, or health-related factors and the potentially limited generalizability of our findings outside Scandinavia., Conclusions: The death of an offspring was associated with an increased risk of IHD and AMI. The finding that the association was present also in case of losses due to unnatural causes, which are less likely to be confounded by cardiovascular risk factors clustering in families, suggests that stress-related mechanisms may also contribute to the observed associations., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KDL received research grants from the Swedish Council for Working Life and Social Research, the Swedish Heart and Lung Foundation, the Karolinska Institutet’s Research Foundation, the Clas Groschinsky Memorial Foundation and the Swedish Society of Medicine during the past five years. RL is employed at the Swedish Medical Products Agency, Uppsala, Sweden. The views expressed in this paper do not necessarily represent the views of the Government agency. The remaining authors have nothing to disclose.

Background and Purpose: Results from previous studies that linking vitamin B12 to risk of chronic diseases or mortality are inconsistent. We hereby explore the association between serum concentration of vitamin B12 and all-cause mortality risk in elderly adults., Methods: Participants aged over 65 years in the Chinese Longitudinal Healthy Longevity Survey were included in present prospective cohort study. Serum vitamin B12 was assessed at the 2011-2012 and 2014 wave, respectively. Participants were divided into three groups based on two cut-off points - 10th and 90th percentiles of vitamin B12 concentrations - in the whole population. Cox regression model was used to calculate the hazard ratio (HR) and 95 % confidence intervals (95 % CIs), and restricted cubic spline function was further modelled to investigate their dose-response associations., Results: Among 2,086 participants [mean ± SD: 87.74 ± 11.24 years, 908 (43.53 %) males], 943 (45.21 %) died during an average follow-up of 3.34 (SD: 1.63) years. Comparing with participants with middle concentration of serum vitamin B12, participants with high concentration had an increased risk of all-cause mortality [HR (95 %CIs): 1.30 (1.03-1.64)], whereas participants with low concentration had an insignificantly decreased risk of all-cause mortality (0.96, 0.76-1.20). The positive association between high concentration of serum vitamin B12 and all-cause mortality was also observed among the male and in a series of sensitivity analyses. In the dose-response analysis, a J-shape pattern was observed, but the non-linear association was only significant in males (P non-linearity = 0.0351)., Conclusions: High concentration of serum vitamin B12 was associated with an increased risk of all-cause mortality in a J-shaped pattern. The precise mechanisms underlying the association remain to be explored., (© 2021. The Author(s).)

Mild cognitive impairment (MCI) is a symptomatic predementia phase of the trajectory of cognitive decline, and its prevalence increases with age. Although the relationship between oral health and MCI have been explored previously, it is uncertain whether individuals with different tooth loss rates have altered MCI risks. We hereby conducted a longitudinal study by using data from the Chinese Longitudinal Healthy Longevity Survey to investigate the association. Tooth loss rate was defined as the difference of teeth between two interview waves divided by years of interval; participants were then grouped into four categories: stable, no tooth loss; mild, 0-1 tooth loss; middle, 1-2 tooth loss; and severe, more than 2 tooth loss per year. Cognitive function was assessed by the Chinese version of Mini-Mental State Examination. We used the generalized estimating equation model to estimate the odds ratio (OR) and the 95% confidence intervals (CIs) and applied the restricted cubic spline function to explore the dose-response association. Among 11,862 participants, 3,966 developed MCI in a median follow-up time of 5.93 years. Higher tooth loss rate was associated with an increased risk of MCI in elderly subjects. Compared with subjects with stable tooth, the corresponding ORs (95% CIs) were 0.94 (0.85-1.03), 1.16 (1.04-1.29) and 1.28 (1.17-1.40) for subjects with the mild, middle and severe rate of tooth loss. A nonlinear dose-response relationship was detected ( P non-linearity = 0.0165). Similar results were observed in the subgroup analyses stratified by sex, age at baseline, and number of teeth at baseline. The positive association was only observed among denture nonwearers (OR middle vs stable : 1.19; 1.06-1.35; OR severe vs stable : 1.35; 1.22-1.50), but not among denture wearers. In conclusion, among elderly population in China, higher rate of tooth loss may be associated with an increased risk of MCI, while denture wearers may be less likely to develop MCI.

Background: Evidence has accumulated to support the involvement of gastrointestinal (GI) dysfunction, possibly via gut microbial dysbiosis and alterations in the enteric nervous system, in the pathophysiology of different neurodegenerative diseases. However, whether patients with GI dysfunction have altered risk of amyotrophic lateral sclerosis (ALS) remains unknown. Methods: Based on a historical nationwide cohort study-ESPRESSO-in Sweden, we compared the risk of ALS among individuals with a previous GI biopsy finding of normal mucosa or non-specific inflammation, as two conditions of GI dysfunction, to that of individuals without any GI biopsy. We identified all individuals with a GI biopsy result of either normal mucosa ( n  = 483,442) or non-specific inflammation ( n  = 566,663) during 1965-2016 in Sweden as the exposed groups. For each exposed individual, we randomly selected up to five controls from the general Swedish population after individual matching by age and sex. Both the exposed and unexposed individuals were followed from date of biopsy (exposed individuals) or date of selection (unexposed individuals) until ALS diagnosis, emigration out of Sweden, death, or 31 December 2016, whichever came first. Stratified Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). Results: Compared to individuals without GI biopsy, individuals with a GI biopsy result of normal mucosa had an increased risk of ALS (HR = 1.22; 95%CI: 1.04-1.42) after excluding the first 2 years of follow-up to alleviate concern of surveillance bias. This increased risk was noted among male (HR = 1.20; 95%CI: 0.94-1.51) and female (HR = 1.23; 95%CI: 1.01-1.50), as well as among younger (<60 years; HR = 1.17; 95%CI: 0.94-1.44) and older (≥60 years; HR = 1.24; 95%CI: 0.99-1.56) individuals. In contrast, no association was observed for a GI biopsy result of non-specific inflammation (HR = 1.00; 95%CI: 0.88-1.15). Neither of the GI biopsy results was related to the mortality risk after ALS diagnosis. Conclusions: Individuals with a GI biopsy result of normal mucosa-representing potentially a distinct type of GI dysfunction-had a higher future risk of ALS. No association was however noted for a GI biopsy result of non-specific inflammation. Further studies are needed to validate this finding and to understand the underlying reasons for the contrasting result pattern.

As a symptomatic predementia stage with progressive cognitive decline, mild cognitive impairment (MCI) is common with aging. How changes in self-reported sleep duration affect MCI risk in the older adults remains unclear. Participants aged ≥ 65 years and enrolled at least two waves in the Chinese Longitudinal Healthy Longevity Survey were included in present longitudinal study. Changes in sleep duration were calculated as the difference between two waves and categorized into five groups: decreased >2 h, decreased 0-2h, stable, increased 0-2 h, and increased >2 h. MCI was measured by the Chinese version of the Mini-Mental State Examination. Generalized estimating equation model and restricted cubic spline function was applied to investigate the association. Among 9,005 participants (mean age, 81.19 years; 4,391 male), 2,877 developed MCI. Comparing with individuals with stable sleep duration, MCI risk [odds ratio (95% confidence intervals)] was: 1.15 (0.99-1.34) for decreased >2 h, 0.99 (0.87-1.13) for decreased 0-2h, 1.09 (0.95-1.24) for increased 0-2 h, and 1.57 (1.36-1.81) for increased >2 h, respectively. Similar patterns were observed among subgroup analyses by sex, age, and sleep quality at baseline. For participants with long sleep duration at baseline (>8h), further increased >2 h was associated with higher MCI risk [2.23 (1.55-3.21)]. Either in the whole or subgroup population, a U-shaped association was observed ( P non-linearity <0.05). In conclusion, changes in self-reported sleep duration were associated with MCI risk in a U-shaped pattern. Strategies that shifting sleep duration into normal range and keeping it stable are essential to prevent MCI in clinical practice.

Background: Although a U-shaped association between sleep duration and all-cause mortality has been found in general population, its association in the elderly adults, especially in the oldest-old, is rarely explored., Methods: In present cohort study, we prospectively explore the association between sleep duration and all-cause mortality among 15,092 participants enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from 2005 to 2019. Sleep duration and death information was collected by using structured questionnaires. Cox regression model with sleep duration as a time-varying exposure was performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). The dose-response association between them was explored via a restricted cubic spline function., Results: During an average follow-up of 4.51 (standard deviation, SD: 3.62) years, 10,768 participants died during the follow-up period. The mean (SD) age of the participants was 89.26 (11.56) years old. Compared to individuals with moderate sleep duration (7-8 hours), individuals with long sleep duration (> 8 hours) had a significantly higher risk of all-cause mortality (HR: 1.13, 95%CI: 1.09-1.18), but not among individuals with short sleep duration (≤ 6 hours) (HR: 1.02, 95%CI: 0.96-1.09). Similar results were observed in subgroup analyses based on age and gender. In the dose-response analysis, a J-shaped association was observed., Conclusions: Sleep duration was associated with all-cause mortality in a J-shaped pattern in the elderly population in China.

With age-related functional deterioration, sensory impairment including vision impairment (VI), hearing impairment (HI), and dual sensory impairment (DSI) usually occurred among the elderly population, causing a decrease in functional capacity and quality of life. The study aimed to explore how sensory impairment is associated with the risk of all-cause mortality among the elderly adults in China. We prospectively investigated the association among 37,076 participants enrolled from 1998 to 2019 in the Chinese Longitudinal Healthy Longevity Survey. We also, as a sensitivity analysis, explored the association among 11,365 newly incident sensory impairment participants. Cox regression model with sensory impairment as a time-varying exposure was performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with participants without sensory impairment, those with VI (HR=1.20, 95% CI: 1.15-1.24), HI (HR=1.26, 95% CI: 1.21-1.31), and DSI (HR: 1.46, 95% CI=1.41-1.52) had significant higher risk of all-cause mortality after adjusting for potential confounders. These associations were robust among subgroup analyses stratified by sex and entry age, and sensitivity analyses performed among newly incident sensory impairment participants. In conclusion, sensory impairment was associated with higher mortality risk among the elderly adults in China.

Serum creatinine and C-reactive protein have been proposed as potential biomarkers for neurodegenerative diseases, including amyotrophic lateral sclerosis, multiple sclerosis and Parkinson's disease. However, longitudinal studies investigating temporal patterns of these biomarkers, including the phase before diagnosis, are rare. We performed a case-control study including all newly diagnosed patients with amyotrophic lateral sclerosis ( N  = 525), multiple sclerosis ( N  = 1815) or Parkinson's disease ( N  = 3797) during 2006-2013 in Stockholm, Sweden, who participated in the Stockholm CREAtinine Measurements (SCREAM) project. For each case, we randomly selected up to five controls from SCREAM that were individually matched to the case by age, sex and county of residence ( N  = 2625 for amyotrophic lateral sclerosis, N  = 9063 for multiple sclerosis and 18 960 for Parkinson's disease). We collected for both the cases and the controls testing results of serum creatinine and C-reactive protein performed by healthcare providers in Stockholm during the study period. Median levels of creatinine and C-reactive protein were visualized using locally weighted smoothing curves among cases and controls. A linear mixed model was also applied to explore temporal changes within an individual. Compared to controls, patients with amyotrophic lateral sclerosis had lower levels of creatinine from 2 years before diagnosis onwards. In contrast, patients with amyotrophic lateral sclerosis had lower levels of C-reactive protein before diagnosis but higher levels after diagnosis, compared to controls. Focusing the 2 years before to 2 years after diagnosis, patients with amyotrophic lateral sclerosis displayed statistically significantly decreasing level of creatinine from 1 year before diagnosis until 2 years after diagnosis, whereas increasing level of C-reactive protein from diagnosis until 2 years after diagnosis. There were no similar patterns noted among patients with multiple sclerosis or Parkinson's disease, or the controls of the three patient groups. Patients with amyotrophic lateral sclerosis display distinct temporal patterns of creatinine and C-reactive protein before and after diagnosis, compared to amyotrophic lateral sclerosis-free controls or patients with multiple sclerosis and Parkinson's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The use of proton pump inhibitors (PPIs) has been proposed as a potential risk factor for neurodegenerative diseases, but little is known regarding its role in amyotrophic lateral sclerosis (ALS). We therefore aimed to assess the association of PPI use with the subsequent risk of ALS, and performed a register-based nationwide nested case-control study, including 2,484 ALS cases diagnosed during July 2006-December 2013 in Sweden and 10 population controls per case that were individually matched to the case by sex, age, and area of residence. Dispenses and cumulative defined daily doses (cDDDs) of PPIs were extracted from the Swedish Prescribed Drug Register. The association of PPI use with the risk of ALS was assessed using conditional logistic regression, after applying different lag windows to avoid reverse causation. ALS patients were more likely to be dispensed with PPIs before diagnosis than controls. However, previous PPI use was not associated with an increased risk of ALS (OR = 1.08, 95% CI 0.97-1.19), and there was no dose-response relationship between cDDDs of PPIs and ALS risk (p = 0.0874), after excluding dispenses during the year before ALS diagnosis. The results were similar after excluding dispenses during the 2 or 3 years before ALS diagnosis.