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Aims/hypothesis: The potential impact of childhood bereavement-a severe psychological stressor-on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact., Methods: We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (<18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics)., Results: During follow-up, 86,226 children (2.4%) lost a family member, and 18,817 children (0.52%) were diagnosed with type 1 diabetes (median age at onset 9.1 years). We did not detect any overall association between childhood bereavement and type 1 diabetes (adjusted HR 1.04; 95% CI 0.93, 1.17). We found no influence of age at loss, cause of death, familial relationship to the deceased, and time since loss., Conclusions/interpretation: In this large population-based Swedish study, we observed no evidence supporting a link between childhood bereavement and type 1 diabetes., Competing Interests: Acknowledgements: A previous version of this manuscript, based on a part of this cohort, was included in a PhD thesis by M.-L. Wernroth, Uppsala University, available from https://www.diva-portal.org/smash/get/diva2:1646525/FULLTEXT06 , and a short oral discussion was presented at the EASD Annual Meeting in September 2021. Data availability: Restrictions apply to the availability of these data, which were used under licence and ethical approval and are not publicly available. However, data are available from the authors upon reasonable request and with written permission from the Swedish Ethical Review Authority, subject to legal contracts regarding the general data protection regulations (GDPR) and personal data processing agreements between Uppsala University and the recipient research entity. Funding: Open access funding provided by Uppsala University. We acknowledge financial support from the European Research Council (ERC-STG-2018-801965 to TF), the Swedish Research Council (VR 2019-01471 to TF and 2018-02640 and 2023-02327 to CA), the Swedish Heart–Lung Foundation (20190505 to TF and 20210416 to CA), Forte (2020–00372 to TF) and the Strategic Research Program in Epidemiology at the Karolinska Institutet. Authors’ relationships and activities: TF is a member of the editorial board of Diabetologia. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: The study was designed by M-LW, BK, KF, BS, CA and TF. M-LW performed the statistical analysis, and wrote the first draft. All authors contributed with invaluable support for data analyses, interpretation of findings and critical revision of the article, and approved the final version for publication. TF is the guarantor of this work, and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s).)

Aims/hypothesis: Parenting a child with type 1 diabetes has been associated with stress-related symptoms. This study aimed to elucidate the potential impact on parental risk of major cardiovascular events (MCE) and death., Methods: In this register-based study, we included the parents of 18,871 children, born 1987-2020 and diagnosed with type 1 diabetes in Sweden at <18 years. The median parental age at the child's diagnosis was 39.0 and 41.0 years for mothers and fathers, respectively. The cohort also encompassed 714,970 population-based matched parental control participants and 12,497 parental siblings. Cox proportional hazard regression models were employed to investigate the associations between having a child with type 1 diabetes and incident MCE and all-cause death, and, as secondary outcomes, acute coronary syndrome and ischaemic heart disease (IHD). We adjusted for potential confounders including parental type 1 diabetes and country of birth., Results: During follow-up (median 12 years, range 0-35), we detected no associations between parenting a child with type 1 diabetes and MCE in mothers (adjusted HR [aHR] 1.02; 95% CI 0.90, 1.15) or in fathers (aHR 1.01; 95% CI 0.94, 1.08). We noted an increased hazard of IHD in exposed mothers (aHR 1.21; 95% CI 1.05, 1.41) with no corresponding signal in fathers (aHR 0.97; 95% CI 0.89, 1.05). Parental sibling analysis did not confirm the association in exposed mothers (aHR 1.01; 95% CI 0.73, 1.41). We further observed a slightly increased hazard of all-cause death in exposed fathers (aHR 1.09; 95% CI 1.01, 1.18), with a similar but non-significant estimate noted in exposed mothers (aHR 1.07; 95% CI 0.96, 1.20). The estimates from the sibling analyses of all-cause death in fathers and mothers were 1.12 (95% CI 0.90, 1.38) and 0.73 (95% CI 0.55, 0.96), respectively., Conclusions/interpretation: Having a child diagnosed with type 1 diabetes in Sweden was not associated with MCE, but possibly with all-cause mortality. Further studies are needed to disentangle potential underlying mechanisms, and to investigate parental health outcomes across the full lifespan., (© 2024. The Author(s).)

Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used 16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life., (© 2022. The Author(s).)

Clinical utility of cisplatin based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is limited because of lack of tools that can guide for a better patient selection. We aim to explore if a combination of biomarkers is superior to a single marker. Pretreatment tumor specimens and clinical data from two randomized trials including 250 patients with T2-T4 urothelial bladder cancer, were used. The information on the expressions on tumor tissue of four biomarkers; CCTα, emmprin, survivin, and BCL-2, detected by immunohistochemistry in our previous studies, was used. Cox proportional hazard models, including treatment-by-biomarker interaction terms, were used to assess the predictive value of the biomarkers for efficacy of NAC on overall survival. CCTα provided predictive information about the efficacy of NAC (interaction P=0.009). None of the other biomarkers provided statistically significant information additional to CCTα. The adjusted hazard ratio for NAC treated versus no-NAC was 0.42 (95% CI: 0.27-0.64) for patients with negative CCTα expression, when adding information about emmprin it decreased to 0.33 (95% CI: 0.19-0.56) for patients with both negative CCTα and emmprin. This corresponds to a decrease in number needed to treat from 4 to 3 patients. The combination of CCTα with survivin or BCL-2 yielded similar results. In a group of patients with muscle invasive bladder cancer a combination of two biomarkers might improve the possibility to identify patients most likely to benefit from the use of NAC. Further studies designed to have sufficient power to detect an interaction effect are needed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To analyze (1) associations between postoperative atrial fibrillation (POAF) after CABG and long-term cardiovascular outcome, (2) whether associations were influenced by AF during follow-up, and (3) if morbidities associated with POAF contribute to mortality., Methods: An observational cohort study of 7145 in-hospital survivors after isolated CABG (1996-2012), with preoperative sinus rhythm and without AF history. Incidence of AF was compared with matched controls. Time-updated covariates were used to adjust for POAF-related morbidities during follow-up, including AF., Results: Thirty-one percent of patients developed POAF. Median follow-up was 9.8 years. POAF patients had increased AF compared with matched controls (HR 3.03; 95% CI 2.66-3.49), while AF occurrence in non-POAF patients was similar to controls (1.00; 0.89-1.13). The observed AF increase among POAF patients compared with controls persisted over time (> 10 years 2.73; 2.13-3.51). Conversely, the non-POAF cohort showed no AF increase beyond the first postoperative year. Further, POAF was associated with long-term AF (adjusted HR 3.20; 95% CI 2.73-3.76), ischemic stroke (1.23; 1.06-1.42), heart failure (1.44; 1.27-1.63), overall mortality (1.21; 1.11-1.32), cardiac mortality (1.35; 1.18-1.54), and cerebrovascular mortality (1.54; 1.17-2.02). These associations remained after adjustment for AF during follow-up. Adjustment for other POAF-associated morbidities weakened the association between POAF and overall mortality, which became non-significant., Conclusions: Patients with POAF after CABG had three times the incidence of long-term AF compared with both non-POAF patients and matched controls. POAF was associated with long-term ischemic stroke, heart failure, and corresponding mortality even after adjustment for AF during follow-up. The increased overall mortality was partly explained by morbidities associated with POAF.

Objective: The effect of early-life antibiotic treatment on the risk of type 1 diabetes is debated. This study assessed this question, applying a register-based design in children up to age 10 years including a large sibling-control analysis., Research Design and Methods: All singleton children ( n = 797,318) born in Sweden between 1 July 2005 and 30 September 2013 were included and monitored to 31 December 2014. Cox proportional hazards models, adjusted for parental and perinatal characteristics, were applied, and stratified models were used to account for unmeasured confounders shared by siblings., Results: Type 1 diabetes developed in 1,297 children during the follow-up (median 4.0 years [range 0-8.3]). Prescribed antibiotics in the 1st year of life (23.8%) were associated with an increased risk of type 1 diabetes (adjusted hazard ratio [HR] 1.19 [95% CI 1.05-1.36]), with larger effect estimates among children delivered by cesarean section ( P for interaction = 0.016). The association was driven by exposure to antibiotics primarily used for acute otitis media and respiratory tract infections. Further, we found an association of antibiotic prescriptions in pregnancy (22.5%) with type 1 diabetes (adjusted HR 1.15 [95% CI 1.00-1.32]). In general, sibling analysis supported these results, albeit often with statistically nonsignificant associations., Conclusions: Dispensed prescription of antibiotics, mainly for acute otitis media and respiratory tract infections, in the 1st year of life is associated with an increased risk of type 1 diabetes before age 10 years, most prominently in children delivered by cesarean section., (© 2020 by the American Diabetes Association.)

Objectives: Type 1 diabetes mellitus (T1DM), resulting from an immune-associated destruction of insulin-secreting pancreatic β-cells, has been reported in a few earlier studies to be inversely associated with schizophrenia, but not with schizophrenia-like psychoses. The aim of this study was to verify this finding by carrying out a Swedish register study., Methods: Data from the Total Population- and Medical Birth-Registers were used to create a cohort of all individuals born in Sweden 1987-2004. The cohort individuals were linked with the Inpatient- and Outpatient-Registers and followed from birth to 2017 to identify onset of T1DM, schizophrenia and schizoaffective disorder. Cox proportional hazard regression models were used to assess the association between T1DM and risk of developing schizophrenia or schizoaffective disorder during a follow-up from age 13., Results: The study population included 1 745 977 individuals and the length of follow-up was maximally 18.0 (median 9.7) years. During the follow-up, 1 280 individuals developed schizophrenia and 649 individuals schizoaffective disorder. The risk of developing schizophrenia was significantly lower among individuals with, than among individuals without, a diagnosis of T1DM, whereas the risk of developing schizoaffective disorder did not differ among individuals with or without a T1DM diagnosis [adjusted hazard ratio (95% confidence interval); schizophrenia: 0.29 (0.09-0.91), p=0.0338, schizoaffective disorder: 1.50 (0.71-3.16), p=0.2909]., Conclusions: This study, in line with previous studies, shows that a diagnosis of T1DM is associated with a decreased risk of schizophrenia. This finding of an inverse association between T1DM and schizophrenia may bring an interesting piece, related to autoimmunity, into the schizophrenia-aetiology puzzle.

Background: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH., Methods and Results: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO 2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders)., Conclusions: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO 2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To describe treatment patterns in the Swedish early psoriatic arthritis cohort (SwePsA) of the mono-/oligo-arthritic (M/O) and polyarthritis (P) and identify early predictive factors for treatment with disease-modifying anti-rheumatic (DMARD), non-steroidal anti-inflammatory drugs (NSAID), and tumour necrosis factor inhibition (TNFi) after 5 years., Methods: Data for 198 M/O and P PsA were obtained within the programme for SwePsA. Multinomial and binary logistic regression analyses were used to assess the association between early predictive factors and treatment after 5 years adjusted for age at inclusion. The analysis of DMARD/NSAID was adjusted for medication at inclusion., Results: After inclusion visit, DMARD was prescribed in 30% of M/O and 56% of P PsA; mainly methotrexate. TNFi was not prescribed at inclusion, but 23 patients were treated at 5-year follow-up. The adjusted OR (95% CI) for treatment with both DMARD and NSAID after 5 years was 3.65 (1.34 - 9.89) (p=0.010) for Disease Activity Score 28 (DAS28) >3.2 and 2.90 (1.20-6.99) (p=0.038) for Disease Activity Index in Psoriatic Arthritis (DAPSA) >14 at inclusion. TNFi treatment was, after adjusting for age, associated with high erythrocyte sedimentation rate (p=0.0043), high C-reactive protein (p=0.013), DAPSA (p<0.001), not reaching minimal disease activity (p=0.001) high health assessment questionnaire (p=0.001), patient's overall assessment on the visual analogue scale (VAS) (p=0.009), high pain VAS (p=0.007), and high number of tender and swollen joints (p=0.031) at inclusion., Conclusions: Disease activity in early M/O and P PsA is to be considered in deciding the level of health care assessment and future pharmacological treatment. DAS28 >3.2 and DAPSA>14 early in the disease predict subsequent treatment with DMARD. For prediction of biological treatment, not reaching MDA at onset of disease, would be the composite index of choice.

Objectives: In an earlier interview study, we found that more men with familial schizophrenia had undergone inguinal hernia operation, than men with sporadic schizophrenia. However, there are no other studies published specifically on inguinal hernia and schizophrenia. Therefore, the aim of this study was to carry out a Swedish register-based cohort study on the association between inguinal hernia and schizophrenia or related psychosis., Methods: Data from the Total Population- and Medical Birth-Registers were used to create a cohort of all individuals born in Sweden 1987-1999 (n=1 406 168). The cohort individuals were linked with the In- and Out-patient Registers and followed from birth to 2015 to identify onset of schizophrenia, schizoaffective disorder and inguinal hernia. Cox proportional hazards regression models were used to assess the association between inguinal hernia before age 13 and risk of developing schizophrenia or schizoaffective disorder during a follow-up from age 13., Results: Inguinal hernia before age 13 was identified in 21 095 individuals, and during the follow-up in total 1314 individuals developed schizophrenia or schizoaffective disorder. The risk of schizophrenia or schizoaffective disorder was higher among individuals with inguinal hernia before age 13, than among individuals without such a diagnosis, especially among the men [adjusted hazard ratio (95% confidence interval); all: 1.44 (1.01-2.06), p=0.0452, men: 1.46 (1.01-2.12), p=0.0460, women: 0.56 (0.14-2.27), p=0.4173]., Conclusions: This study shows that early-onset inguinal hernia is associated with increased risk of developing schizophrenia or schizoaffective disorder, especially in men. Such an association may point to a common biological basis for the development of inguinal hernia and schizophrenia or related psychosis.

Importance: The association between early exposure to animals and type 1 diabetes in childhood is not clear., Objective: To determine whether exposure to dogs during the first year of life is associated with the development of type 1 diabetes in childhood., Design, Setting, and Participants: A nationwide cohort study utilizing high-quality Swedish national demographic and health registers was conducted. A total of 840 593 children born in Sweden from January 1, 2001, to December 31, 2010, were evaluated. Type 1 diabetes was identified using diagnosis codes from hospitals and dispensed prescriptions of insulin. Cox proportional hazards regression models were used to assess the association between exposure to dogs and risk of type 1 diabetes in childhood. The possible association was further investigated by performing dose-response and breed group-specific analyses. The cohort was followed up until September 30, 2012. Data analysis was conducted from October 15, 2015, to February 8, 2017., Exposures: Having a parent who was registered as a dog owner during the child's first year of life., Main Outcomes and Measures: Childhood-onset type 1 diabetes., Results: Of the 840 593 children reviewed, 408 272 (48.6%) were girls; mean (SD) age at diagnosis of type 1 diabetes was 5.1 (2.6) years. Dog exposure was identified in 102 035 children (12.1%). Follow-up started at age 1 year, and the children were followed up for as long as 10.7 years (median, 5.5 years). During follow-up, 1999 children developed type 1 diabetes. No association was found between exposure to dogs (adjusted hazard ratio [HR], 1.00; 95% CI, 0.86-1.16) and type 1 diabetes in childhood. The size of the dog (adjusted HR per 10-cm increase in height, 0.96; 95% CI, 0.86-1.06) or number of dogs in the household (1 dog: adjusted HR, 1.07; 95% CI, 0.91-1.26; 2 dogs: 0.79; 95% CI, 0.54-1.15; ≥3 dogs: 0.50; 95% CI, 0.23-1.12; compared with nonexposed children) also was not associated with type 1 diabetes risk. An analysis of children whose parent had type 1 diabetes (210 events) yielded an adjusted HR of 0.71 (95% CI, 0.43-1.17) for dog exposure., Conclusions and Relevance: In a nationwide study, no evidence supporting an association of register-derived measures of dog exposure with childhood type 1 diabetes was identified.

Objective: The aim of this study was to investigate the use of clinical laboratory tests in primary care and to evaluate if it is possible to improve the cost-effectiveness of laboratory testing by a short-term education programme. Our main goal has been to lower the total costs of care., Design: An education programme that was monitored by laboratory test ratios., Setting: Primary health care., Subjects: 63 primary care doctors at 19 primary care centres in the county of Uppsala, Sweden., Main Outcome Measures: The effects of the education programme were monitored by laboratory test ratios (e.g. ASAT/ALAT) of individual doctors before and after the education programme., Results: The education programme resulted in significant changes for the majority of the ratios studied. The savings on direct laboratory costs were approximately SEK 400,000 for assays that were recommended to decrease. The increased cost for assays that were recommended to increase was approximately SEK 140,000 but was considered cost-effective., Conclusion: It is possible to achieve significant changes in clinical chemistry test ordering habits of primary care doctors with a 2 day education programme. It resulted in cost savings and a better use of clinical chemistry tests in primary care. The effects were sustained for at least 6 months.