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Background: Co-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes, but evidence on their bidirectional associations remain scarce. This study aims to investigate their bidirectional associations. Methods: A nationwide matched cohort and case-control study with IBD patients identified between 1987 and 2017. The cohort study included 20,314 IBD patients (≤28 years; Crohn's disease [CD, n = 7277], ulcerative colitis [UC, n = 10,112], and IBD-unclassified [IBD-U, n = 2925]) and 99,200 individually matched reference individuals, with a follow-up until December 2021. The case-control study enrolled 87,001 IBD patients (no age restriction) and 431,054 matched controls. We estimated adjusted hazard ratio (aHR) of incident T1D in the cohort study with flexible parametric survival model and adjusted odds ratio (aOR) of having a prior T1D in the case-control study with conditional logistic regression model, with 95% confidence intervals (CI). Findings: During a median follow-up of 14 years, 116 IBD patients and 353 reference individuals developed T1D. Patients with IBD had a higher hazard of developing T1D (aHR = 1.58 [95% CI = 1.27-1.95]). The hazard was increased in UC (aHR = 2.02 [1.51-2.70]) but not in CD or IBD-U. In the case-control study, a total of 1018 (1.2%) IBD patients and 3496 (0.8%) controls had been previously diagnosed with T1D. IBD patients had higher odds of having prior T1D (aOR = 1.36 [1.26-1.46]). Such positive association was observed in all IBD subtypes. The sibling comparison analyses showed similar associations between IBD and T1D (aHR = 1.44 [0.97-2.15] and aOR = 1.32 [1.18-1.49]). Interpretation: Patients with IBD had a moderately increased hazard of developing T1D and higher odds of having prior T1D. Their bidirectional associations may be partially independent of shared familial factors. Funding: European Crohn's and Colitis Organisation, Stiftelsen Professor Nanna Svartz Fond, SSMF (project#: PG-23-0315-H-02), Ruth and Richard Julin Foundation; and FORTE (project#: 2016-00424).

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Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide and is increasingly being diagnosed at younger ages, affecting more than one-third of young people with obesity. Objective: To evaluate associations between perinatal conditions and risk of MASLD and associated progressive liver disease. Design, Setting, and Participants: This nationwide, population-based case-control study included all biopsy-confirmed cases of MASLD in Sweden. Individuals aged 25 years or younger (hereafter, young individuals) with biopsy-proven MASLD between January 1, 1992, and December 31, 2016, were matched to up to 5 general population control individuals. Granular data on maternal and perinatal characteristics were retrieved from the Swedish Medical Birth Register. Data were analyzed from June 2023 to June 2024. Exposures: Birth weight (low [<2500 g], reference [2500 to <4000 g], or high [≥4000 g]), gestational age (GA), and birth weight for GA (small for GA [SGA; <10th percentile], appropriate for GA [10th-90th percentile], or large for GA [LGA; >90th percentile]), compared between patients and matched controls. Main Outcomes and Measures: The main outcome was odds of biopsy-proven MASLD and MASLD-associated progressive liver disease (ie, liver fibrosis or cirrhosis) according to birth weight, GA, and birth weight for GA, adjusted for matching factors. Results: In total, 165 young individuals with biopsy-proven MASLD (median age at diagnosis: 12.0 years [IQR, 4.4-16.9 years]; 100 [60.6%] male) were matched with 717 controls. There was an association between low birth weight and future development of MASLD (adjusted odds ratio [AOR], 4.05; 95% CI, 1.85-8.88) but no association between high birth weight and odds of MASLD (AOR, 0.64; 95% CI, 0.38-1.08) compared with the reference birth weight. An association was seen for SGA (AOR, 3.36; 95% CI, 2.00-5.64) compared with appropriate size for GA (reference category) but not for LGA (AOR, 0.57; 95% CI, 0.27-1.20). Progressive liver disease was more common in individuals born with low birth weight (AOR, 6.03; 95% CI, 1.66-21.87) or SGA (AOR, 4.90; 95% CI, 2.15-11.14). Conclusions and Relevance: In this nationwide study of young individuals with biopsy-proven MASLD, low birth weight and SGA were associated with development of MASLD and progressive liver disease, suggesting a need for structured screening measures to diagnose these conditions early in high-risk individuals.

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Diaryl-substituted vinyl boronates as potent building modules are challenging to synthesize. Herein, we present a convenient strategy based on a gold-catalyzed Hiyama arylation of (Z)-ß-(borylvinyl)silanes which are easily accessible by hydroboration of silylalkynes. By exploiting the highly electronegative nature of the Au(III) intermediate (which is accessed by the light-assisted oxidation with aryl diazonium salts), a selective activation of the silyl group in the presence of the boron moiety is achieved. This opens a route to selectively synthesize diaryl-substituted vinyl boronates. The reaction shows a broad substrate range, excellent functional group tolerance and perfect chemo-selectivity. Experimental studies and DFT calculations allowed us to elucidate the mechanism of the reaction, the synthetic potential was demonstrated by downstream transformations providing a facile route to bifunctional phenanthrenes and triaryl-substituted olefins.

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The menaquinone-pathway (men) is widespread in bacteria and key to the biosynthesis of intriguing small molecules such as the essential vitamin menaquinone and the natural dye lawsone. The violet molecule brevinic acid is another proposed product of men, but its direct biosynthetic precursor has remained doubtful. In this study, we isolated brevinic acid from E. coli and confirmed its non-enzymatic formation from lawsone and homocysteine involving an intermediate acetylation or phosphorylation step. We furthermore compared our proposed substrates in a non-enzymatic assay against the previously hypothesized precursor DHNA and showed that the reaction with activated lawsone derivatives proceeded faster, more selective, and with complete turnover. This supports our proposed biosynthesis of brevinic acid from lawsone and enables a cost effective, larger-scale synthesis of brevinic acid.

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

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INTRODUCTION: We aimed to assess the risk of serious infection in patients with inflammatory bowel disease (IBD) treated with vedolizumab compared with those treated with anti-tumor necrosis factors (TNF) and the general population. METHODS: In this Swedish cohort study, treatment episodes were identified from nationwide health registers. We used Cox regression with propensity score-matched cohorts to estimate hazard ratios (HRs) for incident serious infections, defined as infections requiring hospital admission. RESULTS: During 1,376 treatment episodes in Crohn's disease, the rate of serious infections per 100 person-years (PY) was 5.18 (95% CI = 3.98-6.63) with vedolizumab vs 3.54 (95% CI = 2.50-4.85) with anti-TNF; HR = 1.72 (95% CI = 1.12-2.65), partly explained by more gastrointestinal infections. Compared with the rate of 0.75/100 PY (95% CI = 0.59-0.92) in a matched general population cohort, vedolizumab demonstrated higher risk (HR = 7.00; 95% CI = 5.04-9.72). During 1,294 treatment episodes in ulcerative colitis, the corresponding rates were 3.74/100 PY (95% CI = 2.66-5.11) with vedolizumab vs 3.42/100 PY (95% CI = 2.31-4.89) with anti-TNF; HR = 0.80 (95% CI = 0.47-1.36) during the initial 1.1 years and HR = 2.03 (95% CI = 0.65-6.32) after 1.1 years (truncated due to nonproportional hazards). Pneumonia accounted for 40% of all infections among anti-TNF, whereas no case was observed among vedolizumab episodes. Compared with the rate of 0.69/100 PYs (95% CI = 0.53-0.87) in a matched general population cohort, vedolizumab showed an HR of 5.45 (95% CI = 3.67-8.11). DISCUSSION: Vedolizumab was associated with increased risks of serious infections compared with anti-TNF in Crohn's disease but not in ulcerative colitis. Nonetheless, the panorama of serious infections seemed to differ between the drugs. Our findings underscore the importance of clinical awareness of infections and the safety profile of the 2 therapies.

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

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Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies has been extensively investigated in the past, the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.

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

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INTRODUCTION: Leather has been a significant source of chromium (Cr) allergy in Denmark since the 1990s. More recently, cobalt (Co) allergy has been identified in leather as a source of allergic contact dermatitis. OBJECTIVES: To measure Cr and Co levels in Danish leather goods. METHODS: A total of 87 leather samples were collected, all tanned in Europe. Handheld X-ray fluorescence (XRF) device was used to screen for the presence of Cr and Co. The 20 leather samples with the highest concentrations of Co and Co were tested using International Organization for Standardization (ISO)-standards. RESULTS: XRF analysis showed Cr in 78/87 (83.9%) samples and Co in 52/87 (59.7%), with average concentrations of 41 mg/kg (range: 0.0-77 mg/kg) and 0.22 mg/kg (range: 0.0-2.9 mg/kg), respectively. ISO 10195 and 17 075-1 testing identified Cr (VI) in 7 out of 20 samples (1.4; 0.3-4.2 mg/kg), while ISO 17072-1 detected Co in 6 of 20 samples, averaging 3.95 mg/kg (range: 0.22-7.9 mg/kg). CONCLUSION: Most leather samples contained Cr, which was expected, while Cr (VI) was detectable in seven out of twenty tested samples but only detected in one product above the regulatory limit of 3 mg/kg. A potentially significant concentration was found for Co.

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Palladium-catalyzed cross-couplings of aryl chlorides usually call for bulky, electron-rich ligands such as phosphines or heterocyclic carbenes. We have now found that similarly powerful cross-coupling catalysts are obtained by the reaction of palladium salts with alkynyllithium reagents. The species initially formed in this process was characterized as a dilithium tetraalkinyl palladate complex. It catalyzes the coupling of aryl chlorides with the lithium salts of various terminal alkynes to give alkynyl arenes. The isolated Li-alkynyl-Pd complex also efficiently promotes the reaction of aryl, and allyl chlorides with (hetero)aryl-, alkyl-, and allyllithium compounds as well as lithium amides. None of these reactions proceeded in the presence of palladium salts alone. The preparative utility of this approach was demonstrated by the synthesis of 49 molecules, including pharmaceutically relevant compounds.

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Mitochondria react to infection with sub-lethal signals in the apoptosis pathway. Mitochondrial signals can be inflammatory but mechanisms are only partially understood. We show that activation of the caspase-activated DNase (CAD) mediates mitochondrial pro-inflammatory functions and substantially contributes to host defense against viral infection. In cells lacking CAD, the pro-inflammatory activity of sub-lethal signals was reduced. Experimental activation of CAD caused transient DNA-damage and a pronounced DNA damage response, involving major kinase signaling pathways, NF-κB and cGAS/STING, driving the production of interferon, cytokines/chemokines and attracting neutrophils. The transcriptional response to CAD-activation was reminiscent of the reaction to microbial infection. CAD-deficient cells had a diminished response to viral infection. Influenza virus infected CAD-deficient mice displayed reduced inflammation in lung tissue, higher viral titers and increased weight loss. Thus, CAD links the mitochondrial apoptosis system and cell death caspases to host defense. CAD-driven DNA damage is a physiological element of the inflammatory response to infection.

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Baeyer-Villiger monooxygenases (BVMOs) play crucial roles in the core-structure modification of natural products. They catalyze lactone formation by selective oxygen insertion into a carbon-carbon bond adjacent to a carbonyl group (Baeyer-Villiger oxidation, BVO). The homologous bacterial BVMOs, BraC and PxaB, thereby process bicyclic dihydroindolizinone substrates originating from a bimodular nonribosomal peptide synthetase (BraB or PxaA). While both enzymes initially catalyze the formation of oxazepine-dione intermediates following the identical mechanism, the final natural product spectrum diverges. For the pathway involving BraC, the exclusive formation of lipocyclocarbamates, the brabantamides, was reported. The pathway utilizing PxaB solely produces pyrrolizidine alkaloids, the pyrrolizixenamides. Surprisingly, replacing pxaB within the pyrrolizixenamide biosynthetic pathway by braC does not change the product spectrum to brabantamides. Factors controlling this product selectivity have remained elusive. In this study, we set out to solve this puzzle by combining the total synthesis of crucial pathway intermediates and anticipated products with in-depth functional in vitro studies on both recombinant BVMOs. This work shows that the joint oxazepine-dione intermediate initially formed by both BVMOs leads to pyrrolizixenamides upon nonenzymatic hydrolysis, decarboxylative ring contraction, and dehydration. Brabantamide biosynthesis is enzyme-controlled, with BraC efficiently transforming all the accepted substrates into its cognate final product scaffold. PxaB, in contrast, shows only considerable activity toward brabantamide formation for the substrate analog with a natural brabantamide-type side chain structure, revealing substrate-controlled product selectivity.

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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.

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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.

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