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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. In a population-based, sibling-controlled cohort study Jiangwei Sun and colleagues explore the long-term risk of arrhythmias in patients with inflammatory bowel disease. Author summary: Why was this study done?: Although previous studies have explored the associations between inflammatory bowel disease (IBD) and arrhythmias, earlier findings are inconclusive and unaddressed issues remain. For example, except for atrial fibrillation, data on the risk of other specific arrhythmias in patients with IBD is lacking. Until now, the long-term risk of overall and specific arrhythmias in patients with IBD remains unclear. What did the researchers do and find?: In this population-based, sibling-controlled cohort study, we identified patients with biopsy-confirmed IBD in Sweden during 1969 to 2017, including Crohn's disease (CD) (n = 24,954), ulcerative colitis (UC) (n = 46,856), and IBD-unclassified (IBD-U) (n = 12,067), as well as their matched reference individuals and IBD-free full siblings. Patients with IBD were at a higher risk of developing overall arrhythmias than their matched reference individuals; the increased risk may persist even 25 years after IBD diagnosis, corresponding to 1 extra arrhythmia case per 80 CD, 58 UC, and 29 IBD-U cases over the same period. The risks of specific arrhythmias were also increased in patients with IBD, including atrial fibrillation/flutter, other supraventricular arrhythmias, and ventricular arrhythmias/cardiac arrest. What do these findings mean?: Healthcare professionals should be aware of the long-term increased risk of arrhythmias in patients with IBD. For those patients, a risk assessment of modifiable and established cardiovascular disease (CVD) risk factors could be considered. Study limitations include the absence 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. [ABSTRACT FROM AUTHOR]

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 (pfor 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. [ABSTRACT FROM AUTHOR]

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. Jiangwei Sun and colleagues investigate the long-term risk of inflammatory bowel disease after endoscopic biopsy with normal mucosa in a Swedish cohort. Author summary: Why was this study done?: As the most frequent gastrointestinal (GI) histologic finding on endoscopy, a negative endoscopic result (i.e., normal mucosa) has been associated with a persistently decreased risk of colorectal cancer for up to 10 years. However, concerns have been raised about other long-term health outcomes among these individuals. We aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa. What did the researchers find?: In this population-based, sibling-controlled cohort study, we identified individuals with a lower (n = 200,495) or upper (n = 257,192) GI biopsy of normal mucosa, their individually matched general population references (n = 989,484 and 1,268,897, respectively), and unexposed full siblings (n = 221,179 and 274,529, respectively). Compared with population references and unexposed full siblings, individuals with a lower GI biopsy of normal mucosa had a persistently higher risk of overall IBD (average HR = 5.56 and 3.27, respectively), ulcerative colitis (UC, average HR = 5.20 and 3.27, respectively), and Crohn's disease (CD, average HR = 6.99 and 3.77, respectively). Individuals with an upper GI biopsy of normal mucosa were also at an increased risk of CD (average HR = 2.93 and 2.39, respectively). The elevated risk of IBD persisted at least 30 years after a biopsy with normal mucosa. What do these findings mean?: Our findings suggest a substantial symptomatic period before IBD diagnosis. Clinicians should be aware of the long-term increased risk of IBD in those with symptoms requiring GI investigation but with a finding of histologically normal mucosa. [ABSTRACT FROM AUTHOR]

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. In a nested case-control study, Jiangwei Sun and colleagues investigate the relationship between hospital-treated infections and risk of a diagnosis for Alzheimer's disease, Parkinson's disease, and ALS using nationwide registry data from 1970-2016 in Sweden. Author summary: Why was this study done?: Experimental studies suggest that infection plays a role in neurodegenerative disease development. Supporting evidence in humans is, however, scarce. Due to the long preclinical stage of neurodegenerative diseases, it is still unclear whether infection constitutes a risk factor or is merely a comorbidity or secondary event. No study has explored the association of infections treated in specialized care (i.e., hospital in- and outpatient care) with the subsequent risk of common neurodegenerative diseases (i.e., Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) in a single population. What did the researchers find?: Infections treated in specialized care were associated with an increased subsequent risk of AD and PD—primarily AD and PD diagnosed before 60 years, but not ALS. These positive associations remained after excluding infections experienced within 10 years before diagnosis of AD or PD. Increased risks of AD and PD were observed for bacterial, viral, and other infections, and across different sites of infection, including gastrointestinal and genitourinary infections. Individuals with repeated infections in early- and mid-life had the greatest risk increment of AD and PD. What do these findings mean?: The underlying mechanisms for the link between infections and neurodegenerative disease may not be specific to certain pathogens or affected organs but possibly occur at the systemic level. 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 among individuals with disease predisposition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein–Barr virus (EBV) is associated with the risk of several human malignancies, including Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). However, as EBV infection is widely spread across human populations, whereas only a small proportion of the infected individuals eventually develop such malignancies, additional component causes are likely needed in the development of EBV-related malignancies. We performed a national register-based study in Sweden to examine the role of infections that required hospital treatment on the subsequent risk of HL and NPC. We found that previous hospital-treated infections were associated with a higher risk of HL and NPC and that a positive association was observed for both bacterial and viral infections, especially for respiratory and skin infections. A dose-response relationship was also noted between the number of infections and the risk of HL. These findings suggest that infectious events might contribute to the carcinogenesis of malignancies potentially related to EBV. 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. [ABSTRACT FROM AUTHOR]

Background: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown. Methods: We identified 466,987 individuals with a first GI biopsy 1965– 2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death. Results: During a median follow-up of ∼ 11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20– 1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged < 40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32– 1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01– 1.03), cancer (HR = 1.58; 95% CI: 1.56– 1.61), GI disease (HR = 1.65; 95% CI: 1.58– 1.71), and other causes (HR = 1.10; 95% CI: 1.08– 1.11). Sibling comparisons yielded similar results. Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (Pnon-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The authors investigate the shape memory effect (SME) and microstructure evolution of the Fe-25Mn, Fe-25Mn-6Co, and Fe-25Mn-6Si alloys before and after deformation at room temperature (RT) through ex situ optical observation. After deformation, the stress-induced reverse transformation of thermal ϵ martensite, an unrecovered deformation mode, can be easily observed in the Fe-25Mn and Fe-25Mn-6Co alloys, but it can be hardly observed in the Fe-25Mn-6Si alloy. The lower values of chemical driving force for ϵ → γ transformation at RT lead to the occurrence of the stress-induced reverse transformation of thermal ϵ martensite and the poorer SME in the Fe-Mn and Fe-Mn-Co alloys than in the Fe-Mn-Si alloy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In order to improve the shape-memory effect (SME) in Co-Ni alloys, the influence of ausforming temperature on the SME, microstructures, and mechanical behavior in a Co-31Ni-3Si alloy was studied. The results show that the ausforming at 1073 K (800 °C) could remarkably improve the SME in Co-31Ni-3Si alloy. A large recovery strain of 2.3 pct was obtained after bent by 3.7 pct at 77 K (−196 °C). The increase of yield strength and the decrease of the critical stress for the stress-induced gamma to epsilon martensitc transformation are responsible for the remarkable improvement of SME. The results indirectly showed that the SME in Co-Ni alloys results from the stress-induced gamma to epsilon martensitic transformation, and their low yield strength account for their poor SME. It can be expected that the strengthening of matrix by other methods, such as solution, dispersion, and grain refinement hardening, will improve the SME of Co-Ni alloys. [ABSTRACT FROM AUTHOR]