Gut Inflammation Markers, Diet, and Risk of Islet Autoimmunity in Finnish Children - A Nested Case-Control Study.

BACKGROUND: Gut dysbiosis and increased intestinal permeability have been reported to precede type 1 diabetes-related autoimmunity. The role of gut inflammation in autoimmunity is not understood. OBJECTIVES: This study aimed to assess whether gut inflammation markers are associated with risk of islet autoimmunity and whether diet is associated with gut inflammation markers. METHODS: A nested case-control sample of 75 case children with islet autoimmunity and 88 control children was acquired from the Finnish Type 1 Diabetes Prediction and Prevention cohort. Diet was assessed with 3-d food records, and calprotectin and human ß-defensin-2 (HBD-2) were analyzed from stool samples at 6 and 12 mo of age. Conditional logistic regression analysis was used in a matched case-control setting to assess risk of autoimmunity. Analysis of variance, independent samples t test, and a general linear model were used in secondary analyses to test associations of background characteristics and dietary factors with inflammation markers. RESULTS: In unadjusted analyses, calprotectin was not associated with risk of islet autoimmunity, whereas HBD-2 in the middle (odds ratio [OR]: 3.23; 95% confidence interval [CI]: 1.03, 10.08) or highest tertile (OR: 3.02; 95% CI: 1.05, 8.69) in comparison to the lowest at 12 mo of age showed borderline association (P-trend = 0.063) with higher risk of islet autoimmunity. Excluding children with cow milk allergy in sensitivity analyses strengthened the association of HBD-2 with islet autoimmunity, whereas adjusting for dietary factors and maternal education weakened it. At age 12 mo, higher fat intake was associated with higher HBD-2 (ß: 0.219; 95% CI: 0.110, 0.328) and higher intake of dietary fiber (ß: -0.294; 95% CI: -0.510, -0.078), magnesium (ß: -0.036; 95% CI: -0.059, -0.014), and potassium (ß: -0.003; 95% CI: -0.005, -0.001) with lower HBD-2. CONCLUSIONS: Higher HBD-2 in infancy may be associated with higher risk of islet autoimmunity. Dietary factors play a role in gut inflammatory status.

Impact of previous treatment history and B-cell depletion treatment duration on infection risk in relapsing-remitting multiple sclerosis: a nationwide cohort study.

BACKGROUND: B-cell depletion displays striking effectiveness in relapsing-remitting multiple sclerosis (RRMS), but is also associated with increased infection risk. To what degree previous treatment history, disease-modifying therapy (DMT) switching pattern and time on treatment modulate this risk is unknown. The objective here was to evaluate previous DMT use and treatment duration as predictors of infection risk with B-cell depletion. METHODS: We conducted a nationwide RRMS cohort study leveraging data from the Swedish MS registry and national demographic and health registries recording all outpatient-treated and inpatient-treated infections and antibiotics prescriptions from 1 January 2012 to 30 June 2021. The risk of infection during treatment was compared by DMT, treatment duration, number and type of prior treatment and adjusted for a number of covariates. RESULTS: Among 4694 patients with RRMS on B-cell depletion (rituximab), 6049 on other DMTs and 20 308 age-sex matched population controls, we found higher incidence rates of inpatient-treated infections with DMTs other than rituximab used in first line (10.4; 95% CI 8.1 to 12.9, per 1000 person-years), being further increased with rituximab (22.7; 95% CI 18.5 to 27.5), compared with population controls (6.6; 95% CI 6.0 to 7.2). Similar patterns were seen for outpatient infections and antibiotics prescriptions. Infection rates on rituximab did not vary between first versus later line treatment, type of DMT before switch or exposure time. CONCLUSION: These findings underscore an important safety concern with B-cell depletion in RRMS, being evident also in individuals with shorter disease duration and no previous DMT exposure, in turn motivating the application of risk mitigation strategies.

Risk factors for dropout from psychological substance use disorder treatment programs in criminal justice settings.

BACKGROUND: Substance use disorders are highly prevalent in people within the criminal justice system. Psychological programs are the most common type of treatment available and have been shown to decrease recidivism, but dropping out of treatment is common. Risk factors associated with treatment dropout remain unclear in this setting, and whether the risk factors differ by treatment form (group-based vs. individual). METHODS: Outcome (treatment dropout) was defined as not finishing the program due to client's own wish, misbehavior, no-shows, or because program leader found client to be unsuitable. Predictors of treatment dropout included a comprehensive set of individual-level clinical, socioeconomic, and crime-related pre-treatment characteristics. Multivariable regression models were used to estimate the associations between predictors and dropout. FINDINGS: The study cohort included 5239 criminal justice clients who participated in a psychological treatment program (group-based or individual). Multivariable logistic regression models showed that female sex (OR=1.64, 95% CI 1.20-2.25), age (0.99, [0.97-1.00]), sentence length (0.98, [0.97-0.98]), higher education (0.54, [0.28-1.00]), number of violent offenses (1.03, [1.01-1.05]), and anxiety disorders (1.32, [1.01-1.72]) were associated with dropout from the individual treatment program. For the group-based program, age (OR=0.98, 95% CI 0.96-1.00), sentence length (OR=0.96, 95% CI 0.94-0.98), stimulant use disorder (OR=1.48, 95%, 1.00-2.19), and self-harm (OR 1.52, 95% CI 1.00-2.34) were associated with dropout. CONCLUSIONS: We identified certain sociodemographic, crime-related, and clinical characteristics that were particularly important in predicting dropout from psychological treatment. Further, we find that there are similarities and differences in predictors of dropout from group-based and individual treatment forms.

Effectiveness of substance use disorder treatment as an alternative to imprisonment.

INTRODUCTION: Drug courts are criminal justice programs to divert people with substance use disorders from incarceration into treatment. Drug courts have become increasingly popular in the US and other countries. However, their effectiveness in reducing important public health outcomes such as recidivism and substance-related health harms remains ambiguous and contested. We used nationwide register data from Sweden to evaluate the effectiveness of contract treatment sanction, the Swedish version of drug court, in reducing substance misuse, adverse somatic and mental health outcomes, and recidivism. METHODS: In this prospective cohort study, two quasi-experimental designs were used: difference-in-differences and the within-individual design. In the latter, we compared the risk of outcomes during time on contract treatment to, 1) parole after imprisonment and, 2) probation. RESULTS: The cohort included 11,893 individuals (13% women) who underwent contract treatment. Contract treatment was associated with a reduction of 7 percentage points (95% CI: -.088, -.055) in substance misuse, 5 percentage points (-.064, -.034) in adverse mental health events, 9 percentage points (-.113, -.076) in adverse somatic health events, and 3 fewer charges (-3.16, -2.85) for crime in difference-in-differences analyses. Within-individual associations suggested that the same individual had longer times-to-event for all outcomes during contract treatment than on parole or on probation. CONCLUSIONS: Contract treatment is an effective intervention from both public health and criminal justice perspective. Our findings suggest that it is a superior alternative to incarceration in its target group. Further, we find that an implementation approach that is less punitive and more inclusive than what is typical in the US can be successful.

The prevalence of substance use disorders among people in Norwegian, Danish and Swedish prisons: A multi-national cohort study, 2010-19.

AIMS: We estimated the prevalence of substance use disorders (SUDs) in the Norwegian, Danish and Swedish prison populations and compared the prevalence of SUDs in the national prison populations with country-specific general population prevalence rates. DESIGN: A multi-national cohort study using data from the National Prison Registries linked to the National Patient Registries in Norway, Denmark and Sweden. SETTING AND PARTICIPANTS: We used data from the PriSUD-Nordic study, including national prison populations aged 19 years and older in Norway (2010-19), Denmark (2010-18) and Sweden (2010-13). A total of 119 507 Individuals (108 971 men and 10 536 women) contributing to 191 549 incarcerations were included in the study (Norway: 45432 men; 5429 women, Denmark: 42 162 men; 3370 women, Sweden: 21 377 men; 1737 women). MEASUREMENT: We calculated a study prevalence and prevalence at entry to prison for all types of SUDs before imprisonment each consecutive year of observation in each prison population. We also extracted country-specific 1-year prevalence rates from the Global Burden of Diseases database to calculate comparative national prevalence ratios. FINDINGS: The study prevalence of any SUD was approximately 40% [Norway: 44.0%, 95% confidence interval (CI) = 43.6-44.5%; Denmark: 39.9%, CI = 39.5-40.4%; Sweden: 39.1%, CI = 38.4-39.7%] in all three countries. Women had a significantly higher study prevalence of any SUD compared with men (Norway: 55.8 versus 42.6%, P < 0.001; Denmark 43.1 versus 39.7%, P = 0.004; Sweden: 51.7 versus 38.0%, P < 0.001). Prevalence estimates were higher for SUDs among people in prison than in the general population. We observed an increasing proportion of people with SUDs entering prison in Norway (P = 0.003), while the proportion was more stable in Denmark and Sweden. CONCLUSIONS: Substance use disorders (SUDs) appear to be highly prevalent among the Scandinavian prison populations compared with the general population, especially among women. In Norway, there was a relative increase in SUDs from 2010 to 2019.

Periodic mobile application (eMOM) with self-tracking of glucose and lifestyle improves treatment of diet-controlled gestational diabetes without human guidance: a randomized controlled trial.

BACKGROUND: Digitalization with minimal human resources could support self-management among women with gestational diabetes and improve maternal and neonatal outcomes. OBJECTIVE: This study aimed to investigate if a periodic mobile application (eMOM) with wearable sensors improves maternal and neonatal outcomes among women with diet-controlled gestational diabetes without additional guidance from healthcare personnel. STUDY DESIGN: Women with gestational diabetes were randomly assigned in a 1:1 ratio at 24 to 28 weeks' gestation to the intervention or the control arm. The intervention arm received standard care in combination with use of the periodic eMOM, whereas the control arm received only standard care. The intervention arm used eMOM with a continuous glucose monitor, an activity tracker, and a food diary 1 week/month until delivery. The primary outcome was the change in fasting plasma glucose from baseline to 35 to 37 weeks' gestation. Secondary outcomes included capillary glucose, weight gain, nutrition, physical activity, pregnancy complications, and neonatal outcomes, such as macrosomia. RESULTS: In total, 148 women (76 in the intervention arm, 72 in the control arm; average age, 34.1±4.0 years; body mass index, 27.1±5.0 kg/m2) were randomized. The intervention arm showed a lower mean change in fasting plasma glucose than the control arm (difference, -0.15 mmol/L vs -2.7 mg/mL; P=.022) and lower capillary fasting glucose levels (difference, -0.04 mmol/L vs -0.7 mg/mL; P=.002). The intervention arm also increased their intake of vegetables (difference, 11.8 g/MJ; P=.043), decreased their sedentary behavior (difference, -27.3 min/d; P=.043), and increased light physical activity (difference, 22.8 min/d; P=.009) when compared with the control arm. In addition, gestational weight gain was lower (difference, -1.3 kg; P=.015), and there were less newborns with macrosomia in the intervention arm (difference, -13.1 %; P=.036). Adherence to eMOM was high (daily use >90%), and the usage correlated with lower maternal fasting (P=.0006) and postprandial glucose levels (P=.017), weight gain (P=.028), intake of energy (P=.021) and carbohydrates (P=.003), and longer duration of the daily physical activity (P=.0006). There were no significant between-arm differences in terms of pregnancy complications. CONCLUSION: Self-tracking of lifestyle factors and glucose levels without additional guidance improves self-management and the treatment of gestational diabetes, which also benefits newborns. The results of this study support the use of digital self-management and education tools in maternity care.

Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

PURPOSE: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. METHODS: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. RESULTS: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D.  CONCLUSION: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA.

Post-discharge pharmacological treatment discontinuation of forensic psychiatric patients in Sweden.

Introduction: Most forensic psychiatric patients have chronic psychiatric disorders that require long-term pharmacological treatment even after discharge from care. However, the prevalence and correlates of post-discharge medication discontinuation in this patient group remain unclear. Objective: The aim of this study was to investigate the prevalence and correlates of post-discharge discontinuation of pharmacological treatment in forensic psychiatric patients in Sweden. Methods: Data on individuals discharged from forensic psychiatric care between 2009 and 2018 (n = 1,142) with ongoing pharmacological treatment at the time of discharge (n = 856) were identified from the Swedish National Forensic Psychiatric Register. Cox regression models were used to estimate the association between patient characteristics and medication discontinuation. Results: Of the 856 individuals with pharmacological treatment at discharge, 488 (57%) discontinued treatment within 2 years of discharge. Factors associated with an increased risk of treatment discontinuation varied between different types of psychotropic medications: the most important correlate was comorbidity between psychosis and personality disorder. Higher age at discharge, longer length of stay, having a history of several psychiatric care episodes, having a trustee, having a limited guardian, and a residing in a supported living accommodation at the time of discharge were associated with a decreased rate of medication discontinuation. This applied for antipsychotics, antidepressants, antiepileptics, and any psychotropic medication, but not for psychostimulants or drugs used in addictive disorders. Conclusion: For many former forensic psychiatric patients, there are situational factors associated with medication discontinuation. This insight holds significance for professionals who are involved in pre-discharge planning within forensic psychiatric care and those who interact with this cohort of former patients post-discharge.

The prevalence and comorbidity of mental health and substance use disorders in Scandinavian prisons 2010-2019: a multi-national register study.

BACKGROUND: Mental health disorders are common among people in prison, but their prevalence in the Scandinavian prison population remain unclear. In this multinational register study, we examined the prevalence of mental health disorders and the comorbidity of substance use disorders (SUDs) with other mental health disorders in this population. Further, we investigated how the prevalence of mental disorders at prison entry had changed in Norway, Denmark, and Sweden over the study period. METHODS: The three study cohorts included all individuals, aged 19 or older, whom had been imprisoned in Norway (2010-2019), Denmark (2011-2018), and Sweden (2010-2013). Mental disorders were defined as ICD-10 diagnoses (F-codes) registered in the national patient registers. The study prevalence was estimated based on recorded diagnoses during the entire study follow-up period in each respective country. The one-year prevalence of mental disorders was estimated for each calendar year for individuals entering prison during that year. RESULTS: The Scandinavian prison cohorts included 119 507 individuals released 191 549 times during the study period. Across all three countries a high proportion of both women (61.3%-74.4%) and men (49.6%-57.9%) had at least one mental health disorder during the observation period. The most prevalent disorders were SUDs (39.1%-44.0%), depressive disorder (8.1%-17.5%), and stress related disorder (8.8%-17.1%). Women (31.8%-41.1%) had higher levels of mental health and substance use comorbidities compared to men (20.8%-27.6%). The one-year prevalence of any mental health disorder increased over time with a 33% relative increase in Norway, 8% in Denmark, and 10% in Sweden. The proportion of individuals entering prison with a comorbid SUD and other mental disorder had also increased. CONCLUSIONS: While the incarceration rate has been decreasing during the past decade in the Scandinavian countries, an increasing proportion of people entering prison have a diagnosed mental health disorder. Our results suggest that prisons should provide adequate treatment and scale up services to accommodate the increasing proportion of people with complex health needs among incarcerated people.

Detecting potential outliers in longitudinal data with time-dependent covariates.

BACKGROUND: Outliers can influence regression model parameters and change the direction of the estimated effect, over-estimating or under-estimating the strength of the association between a response variable and an exposure of interest. Identifying visit-level outliers from longitudinal data with continuous time-dependent covariates is important when the distribution of such variable is highly skewed. OBJECTIVES: The primary objective was to identify potential outliers at follow-up visits using interquartile range (IQR) statistic and assess their influence on estimated Cox regression parameters. METHODS: Study was motivated by a large TEDDY dietary longitudinal and time-to-event data with a continuous time-varying vitamin B12 intake as the exposure of interest and development of Islet Autoimmunity (IA) as the response variable. An IQR algorithm was applied to the TEDDY dataset to detect potential outliers at each visit. To assess the impact of detected outliers, data were analyzed using the extended time-dependent Cox model with robust sandwich estimator. Partial residual diagnostic plots were examined for highly influential outliers. RESULTS: Extreme vitamin B12 observations that were cases of IA had a stronger influence on the Cox regression model than non-cases. Identified outliers changed the direction of hazard ratios, standard errors, or the strength of association with the risk of developing IA. CONCLUSION: At the exploratory data analysis stage, the IQR algorithm can be used as a data quality control tool to identify potential outliers at the visit level, which can be further investigated.

Antidepressant Use and Risk of Manic Episodes in Children and Adolescents With Unipolar Depression.

Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania. Design, Setting, and Participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included. Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days. Main Outcomes and Measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline. Results: The cohort included 43 677 patients (28 885 [66%] girls); 24 573 in the treatment group and 19 104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks. Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.

Fruit, berry, and vegetable consumption and the risk of islet autoimmunity and type 1 diabetes in children-the Type 1 Diabetes Prediction and Prevention birth cohort study.

BACKGROUND: Prospective studies investigating the association among fruit, berry, and vegetable consumption and the risk of islet autoimmunity (IA) and type 1 diabetes (T1D) are few. OBJECTIVES: In this cohort study, we explored whether the consumption of fruits, berries, and vegetables is associated with the IA and T1D development in genetically susceptible children. METHODS: Food consumption data in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available from 5674 children born between September 1996 and September 2004 in the Oulu and Tampere University Hospitals. Diet was assessed with 3-d food records at the age of 3 and 6 mo and annually from 1 to 6 y. The association between food consumption and the risk of IA and T1D was analyzed using joint models adjusted for energy intake, sex, human leukocyte antigen (HLA) genotype, and a family history of diabetes. RESULTS: During the 6-y follow-up, 247 children (4.4%) developed IA and 94 (1.7%) T1D. Furthermore, 64 of 505 children with at least 1 repeatedly positive autoantibody (12.7%) progressed from islet autoantibody positivity to T1D. The consumption of cruciferous vegetables was associated with decreased risk of IA [hazard ratio (HR): 0.83; 95% credible intervals (CI): 0.72, 0.95, per 1 g/MJ increase in consumption] and the consumption of berries with decreased risk of T1D (0.60; 0.47, 0.89). The consumption of banana was associated with increased risk of IA (1.08; 1.04, 1.12) and T1D (1.11; 1.01, 1.21). Only the association between banana and IA remain significant after multiple testing correction. CONCLUSIONS: In children genetically at risk for T1D, the consumption of cruciferous vegetables was associated with decreased risk of IA and consumption of berries with decreased risk of T1D. In addition, the consumption of banana was associated with increased risk of IA and T1D.

Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk.

BACKGROUND: Higher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. OBJECTIVES: This study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. METHODS: Data was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. RESULTS: At age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). CONCLUSIONS: Dietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

Association between incident depression and clinical outcomes in patients with chronic kidney disease.

Background: Depression is highly prevalent and related to increased morbidity and mortality in patients on dialysis, but less is known among patients with earlier stages of CKD. This study investigated the associations between depression and clinical outcomes in patients with CKD not receiving dialysis. Methods: We identified 157 398 adults with CKD stages 3-5 not previously diagnosed with depression from the Stockholm CREAtinine Measurements (SCREAM) project. The primary outcomes included hospitalization, CKD progression (>40% decline in eGFR, initiation of kidney replacement therapy, or death due to CKD), major adverse cardiovascular events (MACE; myocardial infarction, stroke, or cardiovascular death), and all-cause mortality. Survival analyses were used to estimate the associations between incident depression and adverse health outcomes, adjusting for socio-demographics, kidney disease severity, healthcare utilization, comorbidities, and concurrent use of medications. Results: During a median follow-up of 5.1 (interquartile range: 2.3-8.5) years, 12 712 (8.1%) patients received an incident diagnosis of depression. A total of 634 471 hospitalizations (4 600 935 hospitalized days), 42 866 MACEs, and 66 635 deaths were recorded, and 9795 individuals met the criteria for CKD progression. In the multivariable-adjusted analyses, incident depression was associated with an elevated rate of hospitalized days [rate ratio: 1.77, 95% confidence interval (CI): 1.71-1.83], as well as an increased rate of CKD progression [hazard ratio (HR): 1.38, 95% CI: 1.28-1.48], MACE (HR: 1.22, 95% CI: 1.18-1.27), and all-cause mortality (HR: 1.41, 95% CI: 1.37-1.45). The association with CKD progression was more evident after one year of depression diagnosis (HR: 1.47, 95% CI: 1.36-1.59). Results were robust across a range of sensitivity analyses. Conclusion: Among patients with nondialysis-dependent CKD stages 3-5, incident depression is associated with poor prognosis, including hospitalization, CKD progression, MACE, and all-cause mortality.

Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies.

INTRODUCTION: Type 1 diabetes (T1D) is an autoimmune disease in which pro-inflammatory and cytotoxic signaling drive the death of the insulin-producing ß cells. This complex signaling is regulated in part by fatty acids and their bioproducts, making them excellent therapeutic targets. AREAS COVERED: We provide an overview of the fatty acid actions on ß cells by discussing how they can cause lipotoxicity or regulate inflammatory response during insulitis. We also discuss how diet can affect the availability of fatty acids and disease development. Finally, we discuss development avenues that need further exploration. EXPERT OPINION: Fatty acids, such as hydroxyl fatty acids, ω-3 fatty acids, and their downstream products, are druggable candidates that promote protective signaling. Inhibitors and antagonists of enzymes and receptors of arachidonic acid and free fatty acids, along with their derived metabolites, which cause pro-inflammatory and cytotoxic responses, have the potential to be developed as therapeutic targets also. Further, because diet is the main source of fatty acid intake in humans, balancing protective and pro-inflammatory/cytotoxic fatty acid levels through dietary therapy may have beneficial effects, delaying T1D progression. Therefore, therapeutic interventions targeting fatty acid signaling hold potential as avenues to treat T1D.

The edible plant microbiome: evidence for the occurrence of fruit and vegetable bacteria in the human gut.

Diversity of the gut microbiota is crucial for human health. However, whether fruit and vegetable associated bacteria contribute to overall gut bacterial diversity is still unknown. We reconstructed metagenome-assembled genomes from 156 fruit and vegetable metagenomes to investigate the prevalence of associated bacteria in 2,426 publicly available gut metagenomes. The microbiomes of fresh fruits and vegetables and the human gut are represented by members in common such as Enterobacterales, Burkholderiales, and Lactobacillales. Exposure to bacteria via fruit and vegetable consumption potentially has a beneficial impact on the functional diversity of gut microbiota particularly due to the presence of putative health-promoting genes for the production of vitamin and short-chain fatty acids. In the human gut, they were consistently present, although at a low abundance, approx. 2.2%. Host age, vegetable consumption frequency, and the diversity of plants consumed were drivers favoring a higher proportion. Overall, these results provide one of the primary links between the human microbiome and the environmental microbiome. This study revealed evidence that fruit and vegetable-derived microbes could be found in the human gut and contribute to gut microbiome diversity.

HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study.

OBJECTIVE: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children. RESULTS: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4-5.9 months compared with later in the U.S. was associated with an increased risk of IA. CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study.

Predicting risk of suicidal behaviour after initiation of selective serotonin reuptake inhibitors in children, adolescents and young adults: protocol for development and validation of clinical prediction models.

INTRODUCTION: There is concern regarding suicidal behaviour risk during selective serotonin reuptake inhibitor (SSRI) treatment among the young. A clinically useful model for predicting suicidal behaviour risk should have high predictive performance in terms of discrimination and calibration; transparency and ease of implementation are desirable. METHODS AND ANALYSIS: Using Swedish national registers, we will identify individuals initiating an SSRI aged 8-24 years 2007-2020. We will develop: (A) a model based on a broad set of predictors, and (B) a model based on a restricted set of predictors. For the broad predictor model, we will consider an ensemble of four base models: XGBoost (XG), neural net (NN), elastic net logistic regression (EN) and support vector machine (SVM). The predictors with the greatest contribution to predictive performance in the base models will be determined. For the restricted predictor model, clinical input will be used to select predictors based on the top predictors in the broad model, and inputted in each of the XG, NN, EN and SVM models. If any show superiority in predictive performance as defined by the area under the receiver-operator curve, this model will be selected as the final model; otherwise, the EN model will be selected. The training and testing samples will consist of data from 2007 to 2017 and from 2018 to 2020, respectively. We will additionally assess the final model performance in individuals receiving a depression diagnosis within 90 days before SSRI initiation.The aims are to (A) develop a model predicting suicidal behaviour risk after SSRI initiation among children and youths, using machine learning methods, and (B) develop a model with a restricted set of predictors, favouring transparency and scalability. ETHICS AND DISSEMINATION: The research is approved by the Swedish Ethical Review Authority (2020-06540). We will disseminate findings by publishing in peer-reviewed open-access journals, and presenting at international conferences.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/Objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI. Research Design and Methods: Genetically at-risk children (n = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually. Of these, 495 (9.7%) children developed IA. Mediation analysis for time-varying covariates (BMI z-score) and exposure (energy intake) was conducted. Cox proportional hazard method was used in sensitivity analysis. Results: We found an indirect effect of total energy intake (estimates: indirect effect 0.13 [0.05, 0.21]) and energy from protein (estimates: indirect effect 0.06 [0.02, 0.11]), fat (estimates: indirect effect 0.03 [0.01, 0.05]), and carbohydrates (estimates: indirect effect 0.02 [0.00, 0.04]) (kcal/day) on the development of IA. A direct effect was found for protein, expressed both as kcal/day (estimates: direct effect 1.09 [0.35, 1.56]) and energy percentage (estimates: direct effect 72.8 [3.0, 98.0]) and the development of GAD autoantibodies (GADA). In the sensitivity analysis, energy from protein (kcal/day) was associated with increased risk for GADA, hazard ratio 1.24 (95% CI: 1.09, 1.53), p = 0.042. Conclusions: This study confirms that higher total energy intake is associated with higher BMI, which leads to higher risk of the development of IA. A diet with larger proportion of energy from protein has a direct effect on the development of GADA.