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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]

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: 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]

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: 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]

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]

Abstract The microstructures and mechanical properties of cast and extruded Al-4Cu-1Li-0.4Mg-0.1Zr- x Zn alloys were investigated and the amount of Zn additions was up to 1.1 wt%. The results showed that Zn addition could bring additional MgZn 2 phases at the grain boundary and slightly refine the grain size in the as-cast alloy. The mechanical properties of extruded Al-4Cu-1Li-0.4Mg-0.1Zr -x Zn alloy increased gradually with the Zn content under different conditions. The yield strength (YS) and ultimate tensile strength (UTS) of T8 treated (stretched by 4% and aged at 150 °C for 32 h) 1.1 Zn alloy could reach 639 MPa and 666 MPa, while elongation (EL) remained at 10.9%. For alloys peak-aged at 175 °C for 32 h (T6 treated), Zn could effectively promote the precipitation of T 1 phases (Al 2 CuLi) but decrease the volume fraction of θ′ phases (Al 2 Cu) in the matrix. The coarsening of T 1 phases could be obviously suppressed by the addition of Zn under overaged condition. However, the precipitate of T 1 phases promoted by Zn under the T8 condition is not as obvious as the T6 condition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. 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. [Display omitted] • Nationwide multigenerational study of 292,274 family members of people with biopsy-confirmed MASLD and comparators. • MASLD first-degree relatives had increased hazards of HCC, major adverse liver outcomes and liver-related mortality. • The absolute risk of HCC was low, with only one extra case per 900 first-degree relatives over 20 years of follow-up. • Spouses of individuals with MASLD also had a higher relative risk of developing major adverse liver outcomes. • Liver disease progressed more rapidly in MASLD first-degree relatives with concomitant liver diseases. [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: 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 this paper, mechanical properties and microstructures of the cast and extruded Al- x Cu-1Li-0.4Mg–1Zn-0.1Zr alloys (x = 2.0, 3.0, 4.0, 4.5, 5.5, 6.5 wt%) were investigated. The results showed that the as-cast micrographs of alloys with different Cu content primarily consist of dendritic α-Al grains, and the intermetallic phases at the grain boundaries were Cu and Zr rich phases. After solution treatment, no recrystallization took place in extruded alloys, and the alloys mainly represented mixed textures composed of <111> and <100> fibers. Cu significantly affected the precipitation behavior of the extruded alloys. Only T 1 (Al 2 CuLi) phases were observed in T6 (aging at 175 °C for 32 h) and T8 (3% pre-strain followed by aging at 150 °C for 32 h) treated alloy with 2 wt% Cu. Further increasing Cu contents (4.5 and 6.5 wt%) enabled the co-precipitation of T 1 and θ' (Al 2 Cu) phases, as well as increased their density. In addition, the microstructures of grain boundaries of alloys with different Cu content showed dramatic differences. T 1 phases precipitated at the grain boundaries of alloy containing 2 wt% Cu, while rare precipitation of T 1 phases was observed at the grain boundaries of alloy with 6.5 wt% Cu. The yield strength (YS) of the alloys increased with the Cu content and the elongation (EL) showed an opposite trend. A good combination of ultra-high strength (YS = 684 MPa, ultimate tensile strength = 726 MPa) and ductility (EL = 6.3%) was obtained in T8 treated alloy containing 4.5 wt% Cu. The presence of the undesired coarse T 2 (Al 6 CuLi 3) phases at the grain boundaries resulted in the premature failure of the high Cu content alloys. [ABSTRACT FROM AUTHOR]

In this work, a novel Al-4.7Cu–1Li-0.5Mg-0.1Zr–1Zn alloy was designed with the purpose of developing ultra-high strength and low-cost Al–Cu–Li alloy. The mechanical properties and microstructure evolution of the studied alloy under T6, T8, and two-stage aged conditions were investigated. The alloy showed a non-recrystallization feature during solution treatment. A strong <111> fiber texture was presented in the as-quenched alloy. The yield strength (YS), ultimate tensile strength (UTS), and elongation (EL) of the alloy was largely depended on the aging process parameters. A good combination of ultra-high strength (YS = 731 MPa, UTS = 753 MPa) and ductility (EL = 5.5%) were obtained in the T8 treated specimen (pre-stretched by 3% and aged at 150 °C for 32 h). The pre-strain prior to artificial aging and aging temperature significantly affect the distribution, density, and size of precipitates. Strengthening mechanism of the alloy was discussed in detail. The strong <111> texture preserved in the as-quenched alloy and the finely dispersed T 1 (Al 2 CuLi) phases distributed in the T8 treated specimens could account for the ultra-high strength of the present alloy. Image 1 • Zn is a candidate for Ag to develop cost-effective high strength Al–Cu–Li alloys. • A novel ultra-high strength Al-4.7Cu–1Li-0.5Mg-0.1Zr–1Zn alloy was designed. • The mechanical properties and microstructure of the alloy under different aging conditions were systematically investigated. • A high density of fine T 1 phases was distributed in the T8 treated alloy. • The introduction of pre-strain and improving the aging temperature could promote the precipitation of S' phases. [ABSTRACT FROM AUTHOR]

• Trend of condensation HTC with vapor velocity in the range of 20–100 m/s. • The influence of pipe inclination on condensation in the vapor velocity range of 20–100 m/s. • Modified empirical correlation for heat transfer calculations with vapor velocities of 80–100 m/s. Heat pipe is widely used as an efficient built-in heat exchanger for thermal management of high pulse and heat flux power supplies. Enhanced heat dissipation at the condensing side is an important issue in heat pipe research, where vapor velocity is an essential factor affecting the condensing heat transfer characteristics. This study adopted the CFD method to numerically simulate the condensation heat transfer of R134a flowing in a smooth pipe. The flow condensation heat transfer characteristics, such as film thickness and heat transfer coefficient (HTC), were investigated under vapor velocities v = 20–100 m/s and tube inclinations β =-90–90° Geometric and numerical heat transfer modeling is established in high vapor velocity flow condensation. The error of numerical simulation results and model validation is 10%. The HTC increases rapidly with the change in vapor velocity under 60 m/s, increasing the rate to 0.4. When the vapor velocity exceeds 60 m/s, the growth trend slows to 0.15, 37.5% of the original increase. At high vapor velocities above 60 m/s, the effect of pipe inclination on condensation heat transfer coefficient can be almost negligible. A modified empirical correlation suitable for high vapor velocities is proposed, which has higher predictive accuracy when the vapor velocity exceeds 80 m/s. [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]

Fast pyrolysis of waste biomass is a cross-coupling pyrolysis of its components (cellulose, lignin, hemicellulose and ash), resulting in the complex composition of bio-oil. Here, microwave-assisted organosolv fractionation (MOF) of waste biomass combined with decoupling pyrolysis is first proposed to overcome this challenge. MOF of waste eucalyptus was conducted in different solvents (organic acid, glycerol or ethylene glycol (EG)). The derived fractions were first characterized by Fourier transform infrared (FTIR) spectroscopy and two-dimensional heteronuclear single-quantum coherence nuclear magnetic resonance (2D HSQC NMR) and then pyrolyzed via thermogravimetric analyzer-mass spectrometry (TG-MS) and a pyro-probe reactor to exam their pyrolysis behaviors. The experimental results demonstrated that waste eucalyptus can be rapidly divided into xylose, high purity organosolv lignins (OL) and cellulose-rich fractions (CF) by MOF under mild conditions. Compared with the fast pyrolysis of raw waste eucalyptus, the decoupling pyrolysis of CF produced higher yields of levoglucosan, whereas the decoupling pyrolysis of OL can result in decreases in the yields of some phenols. MOF can boost the levoglucosan yields from CF by 464–502% compared to that of raw waste eucalyptus. The rank order of the solvents for the improvement in the levoglucosan yield was organic acid < glycerol < EG. This work proposed an efficient, integrated process for selectively producing platform chemicals from waste biomass that can compete with hydrolysis and catalytic conversion processes. [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: 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]

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. 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. 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. 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. • The diagnosis of celiac disease peaked at age 2 and subsequently declined as age progresses. • Celiac disease patients exhibited a higher prevalence of autoimmune diseases compared to their controls. • The risk of autoimmune disease did not escalate with increasing age at the celiac disease diagnosis. [ABSTRACT FROM AUTHOR]

In this work, the influence of Sc content on the microstructure and mechanical properties of cast Al-2Li-2Cu-0.5Mg-0.2Zr alloy was investigated. It was found that the grain size of As-cast alloy was significantly reduced in steps with the increase of Sc addition, accompanied by the arising and increasing of cubic primary Al 3 (Sc, Zr) phases. No evidence for the presence of the ternary W (Al 8−x Cu 4+x Sc) phase was obtained. The volume fraction of nanoscale Al 3 (Sc, Zr) dispersoids was improved with the increase of Sc content, and the presence of Sc was observed to refine the S′ (Al 2 CuMg) morphology during ageing. The addition of Sc lowered the growth rates of δ′ (Al 3 Li) particles and δ′-Precipitate-free zones (δ′-PFZs) of the base alloy. The tensile property results showed that, with the increasing Sc content and ageing times, the yield strength (YS) and ultimate tensile strength (UTS) were continuously increased, and the highest elongation of 6.0% was obtained in the 0.2Sc-containing alloy aged for 32 h at 175 °C. The results indicated that the optimal Sc addition in cast Al-2Li-2Cu-0.5Mg-0.2Zr alloy was 0.2 wt%. [ABSTRACT FROM AUTHOR]

The microstructure, electrical conductivity and mechanical properties of cast Al-2Li-2Cu-0.5Mg-0.2Zr alloy during heat treatment were investigated. The results indicated that a population of secondary phases enriched along grain boundaries in as-cast studied alloy, most of which dissolved into the α-Al matrix after solution treatment. Profound enhancement in mechanical properties of the studied alloy was obtained after T6 heat treatment. TEM observations revealed competitive precipitation of T 1 (Al 2 CuLi) and S′ (Al 2 CuMg) phases during ageing, while no θ′ (Al 2 Cu) phase was observed. The anomalous decrease in conductivity observed during ageing was attributed to the precipitation of T 1 phases. Fine δ′ (Al 3 Li) particles were homogeneously distributed after quenching, gradual coarsening of which was observed with prolonged ageing time. As ageing proceeded, the δ′ coarsened and δ′-Precipitate-Free Zones (PFZs) developed, resulting in diminishing ductility observed from as-quenched to peak-aged state. Precipitation and continuous coarsening of T 1 phases kept on at the expense of gradual δ′ dissolution. The improvements of ductility observed in over-aged samples arose mainly from the presence of T 1 , S′ phases, Al 3 (Li,Zr) composite precipitates and progressive δ′ dissolution. Moreover, continuous coarsening of T 1 and S′ phases contributed primarily to the strength loss in over-aged studied alloy. [ABSTRACT FROM AUTHOR]

• The hydrogen peroxide (H 2 O 2) can be used as an effective target for tumor therapy. • Efficacy can be improved by regulation of H 2 O 2 in tumor microenvironment. • H 2 O 2 delivery via exogenous and endogenous factors were highlighted. Due to the rapid proliferation of tumors, the hydrogen peroxide (H 2 O 2) concentration of tumor cells is higher than that of normal cells, which can be used as an effective target for tumor therapy to differentiate normal tissues and produce differential therapeutic effects. By modulating the generation or decomposition of H 2 O 2 in the tumor microenvironment, target molecules with more killing effects can be produced, to enhance the efficiency of tumor treatment. However, intracellular H 2 O 2 is not sufficient to obtain satisfactory therapeutic results. In this review, we will focus on how to modulate H 2 O 2 -related strategies from two aspects, firstly by direct delivery of exogenous factors, and secondly by amplifying endogenous genes, which show that H 2 O 2 regulation-based anticancer strategies are producing increasingly successful results. Finally, we discuss the obstacles that need to be solved and the bright future in the process of H 2 O 2 modulation. [ABSTRACT FROM AUTHOR]

Heat treatment process is one of the key methods to improve the mechanical properties of age-hardening Al–Cu–Li alloy, and pre-stretching can further increase nucleation sites of precipitates by introducing dislocations. In this study, the effects of solution treatment, artificial ageing, and 4% pre-stretching on the microstructure evolution, mechanical properties, and fracture mechanism of extruded 2050 Al–Cu–Li alloy were investigated. The results indicated that the residual secondary phase, including Al 2 Cu and Al 2 CuLi, precipitated in hot extrusion were dissolved and a non-recrystallization characteristic for the 2050 alloy was presented after solution treated at 530 °C for 90 min. During artificial ageing at 150 °C, the precipitation sequence of the alloy without pre-stretching was: SSS → GP zone + δ′/β'→ θ' + T 1. Pre-stretching led to denser dislocations thus a higher nucleation rate of T 1 phase in compared with the alloy without pre-stretching. Additionally, the segregations of non-Cu atom at dislocations inhibited the formation of GP zones in the early ageing state, thereby providing sufficient Cu atoms for accelerating the growth of T 1 phases. After pre-stretched by 4% and aged at 150 °C for 12 h, a good combination of strength (YS = 671 MPa, UTS = 682 MPa) and ductility (EL = 10.3%) was obtained. The fracture mode changed from transgranular fracture to intergranular fracture with increasing ageing time due to the dislocation density and the distribution, size, and number density of the precipitates. [ABSTRACT FROM AUTHOR]

The influence of Cr addition on the microstructure and stress corrosion cracking behavior of Al-6.5Zn-2Cu-1.5 Mg-0.05Ti alloy was investigated by microscopy characterization and slow strain rate tensile tests. In Cr-containing alloys, E (Al 18 Mg 3 Cr 2) phases precipitated from the matrix, which could serve as energetically preferred heterogeneous nucleation sites for η (Mg(Zn, Cu) 2) phases. Due to the decrease of η' (MgZn 2) strengthening phases and the formation of η' (MgZn 2) precipitate free zones, the strength of Cr-containing alloys was reduced to some extent. However, the crack propagation could be suppressed by the discrete distribution of grain boundary precipitates and the inhibition of recrystallization, leading to the increase of the elongation and the stress corrosion cracking resistance. With the addition of 0.15 wt% Cr, the comprehensive performance of Al-6.5Zn-2Cu-1.5 Mg-0.05Ti alloy was improved. Compared with the base alloy, the susceptibility index of stress corrosion cracking (I SCC) decreased by 82% and the elongation increased by 42% at the expense of partial strength (less than 5%). • With the addition of 0.15 wt% Cr, the comprehensive performance of Al-6.5Zn-2Cu-1.5 Mg-0.05Ti alloy was improved. • E (Al 18 Mg 3 Cr 2) phases could serve as energetically preferred heterogeneous nucleation sites for η (Mg(Zn, Cu) 2) phases. • Crack propagation of Cr-containing alloys was suppressed by the discrete distribution of GBPs and the inhibition of recrystallization. [ABSTRACT FROM AUTHOR]

• The Sc doping induced a more than 50% reduction in the grain size and enhanced the grain growth resistance. • Both Al 3 (Sc, Zr) and Al 3 Sc cores of composite particles can be observed in the Sc-containing alloys. • The coarsening exponent (n−1) of the core-shell precipitates is about 0.11 probably due to the unreached quasi-steady-state. In the present study, microstructure and mechanical properties of casting Al-3Li-2Mg-1Zn-0.1Zr alloys modified by Sc additions have been investigated. As-aged Al-3Li-2Mg-1Zn-0.2Sc-0.1Zr alloy possesses a desirable comprehensive mechanical performance. The YS, UTS and El reach 253 MPa, 406 MPa and 7.4% respectively. With the addition of Sc, a more than 50% reduction in the grain size was achieved by the promoted heterogeneous nucleation on primary Al 3 (Sc, Zr) phases and the grain growth resistance was enhanced by the Zener pinning. After the heat treatment, core-shell composite particles precipitated from the matrix. The shell consists entirely of Al 3 Li phases. In contrast, both Al 3 (Sc, Zr) and Al 3 Sc cores can be observed in the Sc-containing alloys. Increasing the Sc content from 0.1 wt% to 0.2 wt%, the mean radius of cores increases, while the mean width of shells and the number density of particles seem not to be affected. With the passage of ageing time, the coarsening of composite particles occurred, though the dimension of the core remained almost constant. The kinetics follows the KV model and the exponent (n−1) is about 0.11, which is lower than the expected value (0.33) probably due to the unreached quasi-steady-state at the present low temperature. [ABSTRACT FROM AUTHOR]

• There are two kinds of grains zone including micro-grained regions and coarse-grained regions. • The crack initiation appears from around Mg-Zn-Er phases to along grain boundaries with extrusion temperature increasing. • The yield strength of the Mg-10Li-5Zn-0.5Er alloy extruded at above 200 °C is higher than this of the extruded ZK60 alloy. Role of extrusion temperature on the microstructure evolution and tensile properties of an ultralight Mg-10Li-5Zn-0.5Er alloy was studied. The results indicate that the second phases and grains are all refined after extrusion. It is firstly reported that there are two kinds of grains zone including micro-grained region and coarse-grained region in the as-extruded Mg-Li alloys with high Li content (≥ 9 wt%). As the extrusion temperature increases from 150 °C to 300 °C, the volume of micro-grained region decreases and finally almost disappears. The grain size of coarse-grained region increases as well. The amount of Mg-Li-Zn precipitates along the boundaries decreases and their quantity in the grains increases with grain coarsening. The strength rises slightly and the elongation decreases notably with the enhancement of extrusion temperature. As the extrusion temperature increases, the crack initiation appears from mainly around the bulky Mg-Zn-Er phases to mainly along the grain boundaries. Due to the grain refinement, the second phases strengthening, and the abundant slip systems of β -Li phase, the comprehensive properties of the as-extruded alloys have leading position in the field of wrought Mg-Li alloys and the optimum comprehensive tensile properties are gained in the alloy extruded at 275 °C. [ABSTRACT FROM AUTHOR]

Ultralight cast Al-3Li- X Mg-0.1Zr alloys (X = 1, 2, 3, 4) were studied by microscopy methods and tensile tests. Increasing the addition of Mg, grains in as-cast alloys were refined as a result of the intensified constitutional supercooling. After the low-to-high two-stage solution heat treatment, coarse δ′-Al 3 Li, Al 12 Mg 17 , δ-AlLi and S 1 -Al 2 MgLi second phases were dissolved into the α-Al matrix. Meanwhile, plenty of fine δ′-Al 3 Li phases and some core-shell Al 3 (Zr, Li) composite particles were precipitated. During the following ageing procedure, δ′ phases were coarsened following LSW theory while the size of composite particles kept almost unchanged due to the low diffusion rate of zirconium in aluminum. Magnesium was found to be able to promote not only the precipitation but also the coarsening of δ′-Al 3 Li phases in Al Li alloys. After ageing heat treatment at 175 °C for 32 h, Al-3Li-2 Mg-0.1Zr alloy presented optimum comprehensive mechanical performance with the ultimate tensile strength, yield strength and elongation equal to 368 MPa, 247 MPa and 4.7% respectively under the synthetic effect of grain refinement, promoted solution strengthening and the relatively narrow δ′-Al 3 Li precipitate free zones. • δ′ kinetic rate constant K was calculated to be 56.8 nm3 h−1 for Al-3Li-2 Mg-0.1Zr alloy aged at 175 °C. • Magnesium was found to be able to promote the coarsening of δ′-Al 3 Li phases in Al Li alloys. • Grain refinement and solution strengthening were promoted while PFZs widened with the increase of Mg. • The optimum Mg content of ultralight cast Al-3Li- X Mg-0.1Zr alloys (X = 1, 2, 3, 4) was found to be 2 wt%. [ABSTRACT FROM AUTHOR]

The influence of Zn addition on microstructure evolution and mechanical performance of a novel cast Al-Li-Cu-Mg alloy is studied in detail. The results reveal that Zn modifies the precipitation behaviors and improves the tensile strength effectively. As Zn content increases to 1 wt%, the precipitation of T 1 (Al 2 CuLi) phase is greatly enhanced at the expense of S′ (Al 2 CuMg) phase. Zn atoms are observed to enrich in T 1 phase by using high-angle annular dark field-scanning transmission electron microscope (HADDF-STEM), possibly attributed to some Cu atoms being substituted by Zn atoms. The precipitation of δ′ (Al 3 Li) is increased as Zn addition, suppressing the widening of δ′-precipitation-free zones. A more uniformly distribution of S'is also observed in the Zn-containing alloys. With the collaborative effect of both T 1 and δ′ precipitates, the optimal ultimate tensile strength of 504 MPa is obtained in 1 wt% Zn-containing alloy aged at 175 °C for 64 h, which is the highest value in cast Al-Li alloy field at present. • The alloys studied in this study are high Li-containing cast Al-Li alloys with low density. • The optimal Zn content significantly promotes content of T 1 precipitation. • The mechanism of Zn in aging process is analyzed in detail by microstructure characterization. • The UTS of 504MPa obtained in this study is the highest value in all the cast Al-Li-Cu alloys at present. [ABSTRACT FROM AUTHOR]