Reference Individuals Research Articles

Exercise-induced troponin I elevation is associated with alterations in regional longitudinal strain

Abstract Background Mechanisms of exercise-induced troponin elevation in healthy individuals are unclear. This study aimed to determine if exercise-induced cardiac troponin elevation (cTn) is associated with alterations in the myocardial response to physical stress. Methods This study assessed regional and global myocardial function by strain echocardiography at rest and following exercise of increasing workloads in individuals with either a high- or a normal cTnI response to exercise. High-cTnI responders (n=34) were individuals with a previous exercise-induced cTnI level above the 92.5% limit (cTnI > 200 ng/L) in the NEEDED population (n= 1002). Normal-cTnI responders comprised 25 reference individuals with a post-exercise cTnI < 200 ng/L. All study participants were healthy individuals with normal CT coronary angiography. The first exercise was a cardiopulmonary exercise test (CPET) of 43 (40,45) minutes. The second exercise was a 91 km recreational mountain bike race of 230 (210, 245) minutes. Myocardial function was assessed by echocardiography before and within 10 minutes and 24 hours after both exercises. Results Study individuals were 51±10 years old, and 46 (74 %) were male. At baseline, there were no differences between the High- and Normal-cTnI responders regarding demographics, training condition, cardiac risk factors, peak oxygen consumption and conventional echocardiographic parameters. Maximal cTnI levels 3 hours after exercise were significantly higher in the High- compared with Normal-cTnI responders: CPET: cTnI 13 (9-32) vs 9 (5-17) ng/L (p 0.027) and Race: cTnI: 101 (76-198) vs 37 (25-69) ng/L (p <0.001). Following exercise, there were no differences in global ventricular function between the two groups, assessed as left ventricular (LV) global longitudinal strain (GLS) and right ventricular (RV) GLS. When comparing regional longitudinal strain between the two groups, High-cTnI responders had significantly lower regional strain values in the anteroseptal segments following both exercises (p-values 0.005-0.041, 8-14% relative difference, Figure 1 and 2). The changes were more profound after the most intensive exercise (the Race). Conclusion High-cTnI responders have larger reductions in post-exercise systolic longitudinal strain in anteroseptal segments than Normal -cTnI responders. The reduction in regional strain was most profound following the highest workload (the Race). These findings suggest that highly elevated exercise-induced cTnI levels may reflect vulnerable regional alterations in the myocardial response to increasing workloads.Figure 1CPETFigure 2Race

Risk of Anxiety, Depression, and Attention-Deficit/Hyperactivity Disorder in Pediatric Patients With Inflammatory Bowel Disease: A Population-Based Cohort Study.

Inflammatory bowel disease (IBD) is associated with depression and anxiety in adults, but data are scarce on risk of psychiatric diseases in children with IBD. We aimed to estimate the risk of anxiety, depression, or attention-deficit/hyperactivity disorder (ADHD) in patients with pediatric-onset IBD. We performed a nationwide, register-based cohort study including all patients with pediatric-onset IBD diagnosed in Denmark during 1998-2018, resulting in 3,559 patients matched 1:5 on age, sex, municipality of residence, and time period, resulting in 17,795 reference individuals. We used Cox regression to calculate hazard ratios for each outcome after a diagnosis with IBD. Patients with pediatric-onset IBD had an increased risk of depression (hazard ratio [HR] 1.50; 95% confidence interval [CI] 1.26-1.80) and of using antidepressants (HR, 1.54; 95% CI, 1.39-1.71) and, surprisingly, a reduced risk of using methylphenidate (HR, 0.75; 95% CI, 0.58-0.98). Patients with both IBD subtypes (Crohn's disease and ulcerative colitis) had an increased risk of using antidepressants and developing depression, which was particularly high in patients with Crohn's disease (HR, 1.73; 95% CI, 1.35-2.22). Patients with ulcerative colitis had reduced risk of using methylphenidate (HR, 0.63; 95% CI, 0.43-0.93) and a reduced-although not statistically significant-risk of being diagnosed with ADHD compared with the background population. Patients with pediatric-onset IBD have a 50% increased risk of developing depression, which is important for healthcare providers to be aware of and manage. Remarkably, we found a reduced risk of receiving methylphenidate and being diagnosed with ADHD, which merits further investigation.

Sample‐based robust model reduction for non‐linear systems biology models

AbstractComplex non‐linear systems biology models comprise relevant knowledge on processes of pharmacological interest. They are, however, too complex to be used in inferential settings, for example, to allow for the estimation of patient‐specific parameters for individual dose optimisation. Thus, there is a need for simple models with interpretable components to infer the drug effect in a clinical setting. In particular, it is essential to accurately quantify and simulate the interindividual variability in the drug response in order to account for covariates like body weight, age and genetic disposition. To this end, non‐linear model order reduction and simplification methods can be used if they maintain model interpretability during reduction and consider an entire population rather than just a single reference individual. We present a sample‐based approach for robust model order reduction and propose two improvements for efficiency. In particular, we introduce a new sampling method to generate the virtual population based on transformed latin hypercube sampling. Thereby, the sample is stratified in the relevant parameter‐space directions, which are identified using empirical observability Gramians. We illustrate our approach in application to a blood coagulation pathway model, where we reduce the complexity from a 62‐dimensional highly non‐linear to a six‐dimensional and a nine‐dimensional system of ordinary differential equations for two scenarios, respectively.

Long-term risk of arrhythmias in patients with inflammatory bowel disease: A population-based, sibling-controlled cohort study.

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. 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. 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.

The impact of stroke on spousal and family income: a difference-in-difference study from Swedish national registries

ABSTRACT Aim To investigates the financial consequences in the overall population spouses of persons with stroke in Sweden as well as for subgroups based on spouses age, sex and modified Rankin Scale (mRS) of the person with stroke. Methods The study population consists of spouses aged ≤ 60 during the year of their partner’s stroke event. Each spouse was matched to four reference individuals. This longitudinal registry data covers spouses and a reference population between 2005 and 2016. We use difference-in-differences to estimate the impact on individual income from paid work, disposable individual income, and disposable family income. Results The primary analysis shows a small and statistically insignificant decrease on spouses’ individual income from paid work and disposable individual income. In the subgroup analysis based on mRS, the largest effect is seen in mRS 4–5, where spouses’ individual income from paid work and disposable individual income increases after their partner’s stroke. Further, younger female spouses’ individual income from paid work decreases by 1 614 EUR (p = 0.008) on average. Conclusion The financial consequences are small in the overall population of spouses. However, for some subgroups, younger women, and spouses of persons with stroke and mRS 4–5, the financial consequences are more prominent.

Association of major depressive disorder and increased risk of irritable bowel syndrome: A population-based cohort study and a two-sample Mendelian randomization study in the UK biobank

ObjectiveTo examine the association between depression and the risk of incident irritable bowel syndrome (IBS). MethodsWe included 98,564 participants free of IBS in the UK biobank. Depression was defined by self-report and Hospital Episode Statistics. The main outcome was incident IBS. Cox proportional hazards regression models and two-sample mendelian randomization were performed to estimate the risk of incident IBS. ResultsAmong 98,564 participants, 8770 (8.9 %) participants had a depression diagnosis at baseline. During a median of 12.9-year follow-up, 224 cases of incident IBS were identified in patients with depression (2.0 per 1000 person-years), compared with 1625 cases in reference individuals (1.5 per 1000 person-years). After adjustment, the hazard ratio of incident IBS associated with depression was 1.26 (95 % CI: 1.01–1.41). Sensitivity analysis indicated similar results. The two-sample mendelian randomization based on the inverse variance weighted method provided evidence for the harmful role of depression in an increased risk of IBS with an OR of 1.57 (95 % CI: 1.24–1.99). LimitationsDepression was mainly measured by self-report online CIDI-SF in the current study, rather than the gold diagnostic criteria including clinical structured interview, which might lead to potential measurement error. Lifestyle behaviors might change during the long-term follow-up, and time-varying covariates (i.e., smoking and alcohol status) may bias the estimate. ConclusionsDepression is associated with an increased risk of incident IBS. Further studies are warranted to confirm the role of depression on incident IBS and elucidate the underlying mechanisms.

FREE-RANGING OCELOTS (LEOPARDUS PARDALIS): HEMATOLOGY AND SERUM CHEMISTRY REFERENCE VALUES.

Acquiring baseline physiologic data for animals from a free-ranging wildlife species is an elusive objective. Between 1990 and 2020, a monitoring program on the last population of ocelot (Leopardus pardalis) to inhabit public land in the United States yielded 139 blood samples from 67 individual animals. Ocelots were live trapped and anesthetized for census and radiotelemetric studies. The protocol included morphometrics, photographs, electronic identification, and blood collection. Complete blood count and serum chemistry were performed, and after sorting of the data to remove unhealthy individuals and occasional outliers, the dataset provided sufficient information to compute reliable reference intervals (RI). According to the American Society of Veterinary Clinical Pathology consensus guidelines, RI should be elaborated by using data from each reference individual only once. RI by random selection was determined when several measurements were available over time from one same animal. Second, RI were also computed allowing repeat measurements for reference individuals, exclusively to characterize and quantify the effect on the data distribution and on the generated RI. A summary of published RI for various species of wild felids is also presented. The variations observed between species is due not only to species differences but also to variation in measurement methods and RI study design. Overall, accurate blood work interpretation requires RI generated from a healthy population, with defined measurement methods and state-of-the-art RI study design. Of note, calcium is typically tightly regulated in all mammals, as illustrated by the narrow RI (8.5-10.8 mg/dl); conversely, finding a narrow RI in calcium across as many as 49 healthy individuals suggests a high-quality design study.

B-123 Utilization of Five Data Mining Algorithms Combined with Simplified Preprocessing to Establish Reference Intervals of Thyroid Related Hormones for Nonelderly Adults

Abstract Background Despite the extensive research on data mining algorithms, there is still a lack of a standard protocol to evaluate the performance of the existing algorithms. Therefore, the study aims to provide a novel procedure that combines data mining algorithms and simplified preprocessing to establish reference intervals (RIs), with the performance of five algorithms assessed objectively as well. Methods The Test data set and the Reference data set are the two data sets derived from the population undergoing a physical examination. After the thyroid-related hormone including thyroid stimulating hormone (TSH), free triiodo-thyronine (FT3), total triiodo-thyronine (TT3), free thyroxine(FT4), and total thyroxine (TT4) were measured by an ADVIA Centaur XP chemiluminescence immunoassay analyzer, five data algorithms were used to calculated RIs. Hoffmann, Bhattacharya, Expectation Maximum (EM), kosmic, and refineR algorithms combined with two-step data preprocessing respectively were implemented in the Test data set to establish RIs for thyroid-related hormones. The first step is to conduct a random sampling strategy to balance the ratio of sex and age, and the second step is to identify the outliers of variables in each subgroup by the Tukey method. Algorithm-calculated RIs were compared with the standard RIs calculated by transformed parametric method from the Reference data set in which reference individuals were selected following strict inclusion and exclusion criteria. RIs partition were comprehensively determined by the multiple linear regression and variance component analysis. Objective assessment of the methods is implemented by the bias ratio (BR) matrix, of which the BR threshold was set to 0.375. Results The levels of the all five thyroid-related hormones are significantly different in sex, with the male having lower TSH and higher FT3, FT4, TT3, and TT4 compared to the female. Further analysis indicates the establishment of sex-specific RIs for FT3 and FT4. Standard RIs derived from the Reference data set by transformed parametric method are 0.801–4.221 μIU/L for TSH, 2.58–3.82 pg/mL for FT3, 0.98–1.53 ng/dL for FT4, 0.80–1.38 ng/mL for TT3, 5.46–10.05 g/dL for TT4, respectively. There is a high consistency between TSH RIs established by the EM algorithm and the standard TSH RIs (BR = 0.063), although EM algorithms seems to perform poor on other hormones with the BR higher than 0.375. RIs calculated by Hoffmann, Bhattacharya, and refineR methods for free and total triiodo-thyronine, free and total thyroxine respectively are close and matched the standard RIs. Conclusion An effective approach for objectively evaluating the performance of the algorithm based on the BR matrix is established. EM algorithm combined with simplified preprocessing can handle data with significant skewness, but its performance is limited in other scenarios. The other four algorithms perform well for data with Gaussian or near-Gaussian distribution. Using the appropriate algorithm based on the data distribution characteristics is recommended.

Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD

Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD. We conducted a cohort study with data from Swedish university hospitals. Patients (n= 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n= 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression. MALO occurred in 111 (8.8%, incidence rate= 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate= 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio= 6.6; 95% CI= 5.2-8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72at 10 years). This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy. Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

Microscopic colitis and risk of incident rheumatoid arthritis: A nationwide population-based matched cohort study.

Microscopic colitis (MC) has been linked to several autoimmune conditions. Results from previous studies on the association with rheumatoid arthritis (RA) have been inconsistent. To assess the risk of future RA in MC. 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). 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). 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.

Screening for elevated blood lead levels using single hair strands: Accounting for external contamination

Hair has long been explored as a potential biomarker of lead exposure since lead is readily adsorbed into hair's keratinous matrix; however, the utility of hair as a biomarker for lead exposure is hampered by its susceptibility to external contamination: lead particles attach to the exposed hair surface, confounding estimates of endogenous concentrations. This study describes the development of a hair screening tool, in which the confounding influence of external contamination are mitigated by focusing on the unexposed hair root, to predict elevated blood lead levels (BLLs). This tool requires a single strand of scalp hair, which is analyzed using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Forty-four (44) workers with high potential for lead exposure, and 63 reference individuals (with no known lead exposure) volunteered for the study. Hair lead level (HLL) thresholds were developed using methods from clinical assessment to screen exceedances of BLL thresholds at 10 and 15 µg/dL. Hair from both groups showed significantly lower lead concentrations in below-scalp portions compared to above the scalp (above-scalp was 11.2 times higher in workers, and 3.7 times higher in reference group). Hair lead concentrations below the scalp in workers significantly predicted BLLs. HLL thresholds for screening BLLs were 0.60 mg/kg and 0.75 mg/kg for BLLs of 10 µg/dL and 15 µg/dL, respectively. These HLL thresholds yielded high sensitivity (>85%), and slightly lower specificity (67% and 33%, for BLL thresholds of 10 µg/dL and 15 µg/dL, respectively). This study provides reference HLLs in non-contaminated portions of hair (<0.097 mg/kg), shows the significance of external contamination on exposed portions of hair even in a reference population, and assesses the effectiveness of below-scalp hair as a biomarker of elevated lead exposure. This hair screening tool effectively predicted BLL exceedances and could be considered as a non-invasive alternative to blood sampling.

Four-fold increased mortality rate in patients with Wilson's disease: A population-based cohort study of 151 patients.

Few studies have investigated mortality rates in patients with Wilson's disease and compared these to the general population. Here, we examined several clinical outcomes (including cardiovascular, psychiatric, neurologic conditions) in a population-based study of patients with Wilson's disease. We used nationwide registers to identify all patients with a first diagnosis of Wilson's disease between 2002 and 2020 in Sweden. Each patient was matched by age, sex, and municipality with up to 10 reference individuals from the general population. Validated registers were used to investigate outcomes up to 19years after baseline in patients and reference individuals. We identified 151 patients with Wilson's disease matched with 1441 reference individuals. Median age at baseline was 26years (IQR 17-42) and 50% were males. During a median follow-up of 6.6years (IQR 2.9-12.9), 10 (6.6%) patients with Wilson's disease died compared with 31 (2.2%) reference individuals. This translated to a hazard ratio (HR) of 3.8 (95%CI=1.8-8.1). Mortality was higher among Wilson's disease patients with baseline neuropsychiatric diagnoses (HR 7.9, 95%CI=2.9-21.8). Cumulative mortality over 10years was 9.3% (95%CI=5.0-16.8) in Wilson's disease, compared to 2.4% (95%CI=1.6-3.6) in reference individuals. We observed significantly elevated risks in the Wilson's disease group for incident cardiovascular disease, and incident psychiatric and neurological conditions when considering liver transplantation or death from other causes as competing events. In this large population-based cohort study, patients with Wilson's disease had an almost four-fold increased mortality rate compared with matched individuals from the general population.

Personalized and Population-Based Reference Intervals for 48 Common Clinical Chemistry and Hematology Measurands: A Comparative Study.

Personalized reference intervals (prRIs) have the potential to improve individual patient follow-up as compared to population-based reference intervals (popRI). In this study, we estimated popRI and prRIs for 48 clinical chemistry and hematology measurands using samples from the same reference individuals and explored the effect of using group-based and individually based biological variation (BV) estimates to derive prRIs. 143 individuals (median age 28 years) were included in the study and had fasting blood samples collected once. From this population, 41 randomly selected subjects had samples collected weekly for 5 weeks. PopRIs were estimated according to Clinical Laboratory Standards Institute EP28 and within-subject BV (CVI) were estimated by CV-ANOVA. Data were assessed for trends and outliers prior to calculation of individual prRIs, based on estimates of (a) within-person BV (CVP), (b) CVI derived in this study, and (c) publically available CVI estimates. For most measurands, the individual prRI ranges were smaller than the popRI range, but overall about half the study participants had a prRI wider than the popRI for 5 or more out of 48 measurands. The dispersion of prRIs based on CVP was wider than that of prRIs based on CVI. The prRIs derived in our study varied significantly between different individuals, especially if based on CVP. Our results highlight the limitations of popRIs in interpreting test results of individual patients. If sufficient data from a steady-state situation are available, using prRI based on CVP estimates will provide a RI most specific for an individual patient.

Fasting plasma insulin in normal-weight apparently healthy adults in a Nigerian population: Reference intervals and influence of age, gender and anthropometric variables

Introduction: In Nigeria, there is paucity of data regarding indigenously established reference intervals for fasting plasma or serum insulin concentrations in the local populations. This study was designed to establish the reference interval of fasting plasma insulin (FPI) among apparently healthy young and middle-aged adults in a Nigerian population. The influence of age, gender, and anthropometric variables on FPI concentration were examined. Materials and Methods: The study was a cross-sectional descriptive study involving 210 reference individuals aged 18 to 64 years. Physical, anthropometric and biochemical variables were measured including FPI and fasting plasma glucose (FPG). The reference interval for FPI was determined using the non-parametric percentile method. Correlation studies between FPI and age, anthropometric indices, and HOMA-IR were carried out. Results: The study involved a total of 210 healthy normal-weight non-diabetic adults consisting of 110 males (52.4%) and 100 females (47.6%) as reference individuals. Reference intervals for FPI for the male, female, and total study participants were 0.1 –11.1mIU/L, 1.3 –13.2mIU/L and 0.1 – 13.03mIU/L respectively. There were statistically significant positive correlations between FPI and age (r = 0.001), WC (r = 0.0.302, p = 0.0001), WHR (r = 0.220, p = 0.0001), SBP (r = 0.137, p = 0.047) FPG (r = 0.165, p = 0.017) and HOMA-IR (r = 0.985, p = 0.0001). Conclusion: The reference interval of FPI using the Biointecho human insulin ELISA kit is 0.1–13.0mIU/L. This is not much at variance with 0.7–9.0mIU/L quoted by the kit manufacturer, but valued widely with that of other commercially available insulin assay kits from different manufacturers. Similar to reports of similar studies, FPI correlated positively with FPG, BMI. WC, BP and age.

Micronuclei frequency and exposure to chemical mixtures in three Colombian mining populations

The Colombian mining industry has witnessed significant growth. Depending on the scale and mineral extracted, complex chemical mixtures are generated, impacting the health of occupationally exposed populations and communities near mining projects. Increasing evidence suggests that chromosomal instability (CIN) is an important link between the development of certain diseases and exposure to complex mixtures. To better understand the effects of exposure to complex mixtures we performed a biomonitoring study on 407 healthy individuals from four areas: three located in municipalities exploiting different-scale mining systems and a reference area with no mining activity. Large, medium, and small-scale mining systems were analyzed in Montelibano (Córdoba), artisanal and small-scale mining (ASGM) in Nechí (Antioquia), and a closed mining system in Aranzazu (Caldas). The reference area with no mining activity was established in Montería (Córdoba). ICP-MS measured multi-elemental exposure in hair, and CIN was evaluated using the cytokinesis-block micronucleus technique (MNBN). Exposure to mixtures of chemical elements was comparable in workers and residents of the mining areas but significantly higher compared to reference individuals. In Montelibano, increased MNBN frequencies were associated with combined exposure to Se, Hg, Mn, Pb, and Mg. This distinct pattern significantly differed from other areas. Specifically, in Nechí, Cr, Ni, Hg, Se, and Mg emerged as the primary contributors to elevated frequencies of MNBN. In contrast, a combination of Hg and Ni played a role in increasing MNBN in Aranzazu. Interestingly, Se consistently correlated with increased MNBN frequencies across all active mining areas. Chemical elements in Montelibano exhibit a broader range compared to other mining zones, reflecting the characteristics of the high-impact and large-scale mining in the area. This research provides valuable insights into the effects of exposure to chemical mixtures, underscoring the importance of employing this approach in the risk assessment of communities, especially those from residential areas.

Elite female endurance athletes are at increased risk of atrial fibrillation compared to the general population: a matched cohort study

ObjectivePrevious studies have found that endurance sport activity is associated with an increased risk of atrial fibrillation (AF) in men. However, it remains unclear whether endurance sports also influence the...

Risk of vascular diseases in patients with dermatitis herpetiformis and coeliac disease: a long-term cohort study

Introduction Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease. Increased cardiovascular morbidity has been reported in coeliac disease, but in DH only little is known about this. In this cohort study with a long-term follow-up, the risk for vascular diseases in patients with dermatitis herpetiformis (DH) and coeliac disease was assessed. Methods The study consisted of 368 DH and 1072 coeliac disease patients with biopsy-proven diagnosis performed between 1966 and 2000. For each DH and coeliac disease patient three matched reference individuals were obtained from the population register. Data regarding all outpatient and inpatient treatment periods between 1970 and 2015 were reviewed for diagnostic codes of vascular diseases from the Care Register for Health Care. Cox proportional hazard model was used to assess the risks for the diseases studied and the HRs were adjusted for diabetes mellitus (aHR). Results The median follow-up time of DH and coeliac disease patients was 46 years. The risk for cardiovascular diseases did not differ between DH patients and their references (aHR 1.16, 95% CI 0.91–1.47), but among coeliac disease patients, the risk was increased (aHR 1.36, 95% CI 1.16–1.59). The risk for cerebrovascular diseases was found to be decreased in DH patients when compared with references (aHR 0.68, 95% CI 0.47–0.99) and increased in coeliac disease patients (aHR 1.33, 95% CI 1.07–1.66). The risk for venous thrombosis was increased in coeliac disease patients (aHR 1.62, 95% CI 1.22–2.16) but not in DH. Conclusions The risk for vascular complications appears to differ between DH and coeliac disease. In DH the risk for cerebrovascular diseases seems to be decreased, while in coeliac disease an elevated risk for cerebrovascular and cardiovascular diseases was observed. These differing vascular risk profiles between the two manifestations of the same disease merit further investigation.

Early Life Oral Antibiotics Are Associated With Pediatric-Onset Inflammatory Bowel Disease-A Nationwide Study.

Early-life environmental triggers are thought to play a larger role in pediatric-onset inflammatory bowel disease (pIBD) compared to adult-onset IBD. We aimed to assess the risk of developing pIBD after exposure to oral antibiotics during the first 5 years of life. In a nation-wide cohort study, we identified all patients diagnosed with pIBD (<18 years at diagnosis) in Denmark between 1995 and 2018 from the National Patient Registry and matched them with up to 10 reference individuals. Antibiotic exposure was defined as being prescribed antibiotics during first 5 years of life. Data were retrieved from the National Prescription Register. Outcome was developing pIBD. Risk estimates are presented by hazard ratios (HR) with 95% confidence intervals (CI). We identified 1927 pIBD patients and 18,318 reference individuals. Oral antibiotic exposure during the first 5 years of life was associated with a higher risk of developing pIBD (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). The risk was also increased if patients had ≥4 antibiotic prescriptions compared to no antibiotics (HR = 1.33 [95% CI: 1.2-1.5], P <0.0001). Broad-spectrum antibiotics increased the risk of pIBD compared to narrow-spectrum antibiotics (HR = 1.29 [95% CI: 1.2-1.4], P < 0.0001). When stratified by IBD subtypes, only Crohn disease was significantly associated with exposure to antibiotics (HR = 1.37 [95% CI: 1.1-1.7], P = 0.002). In this nationwide registry-based study, we found that oral antibiotic exposure during first 5 years of life was associated with an increased risk of pIBD. Repeated antibiotic exposures increased risk estimates.

Long-term Risk of Stroke in Patients With Inflammatory Bowel Disease: A Population-Based, Sibling-Controlled Cohort Study, 1969-2019.

Patients with inflammatory bowel disease (IBD) are at an increased risk of thromboembolic events, but evidence on the long-term risk of stroke remains scarce. We aimed to explore whether patients with a biopsy-confirmed IBD had an increased long-term risk of stroke. This cohort included all patients with biopsy-confirmed IBD in Sweden between 1969 and 2019 and up to 5 matched reference individuals per patient who were randomly selected from the general population and IBD-free full siblings. The primary outcome was incident overall stroke; secondary outcomes were ischemic and hemorrhagic strokes. Stroke was identified from the Swedish National Patient Register by using both primary and secondary diagnoses. Adjusted hazard ratios (aHRs) for stroke were estimated by flexible parametric survival models. A total of 85,006 patients with IBD (including Crohn disease [CD, n = 25,257], ulcerative colitis [UC, n = 47,354], and IBD-unclassified [IBD-U, n = 12,395]), 406,987 matched reference individuals, and 101,082 IBD-free full siblings were included in the analysis. We observed 3,720 incident strokes in patients with IBD (incidence rate [IR] 32.6 per 10,000 person-years) and 15,599 in reference individuals (IR 27.7; aHR 1.13, 95% CI 1.08-1.17). The elevated aHR remained increased even 25 years after diagnosis, corresponding to 1 additional stroke case per 93 patients with IBD until then. The excess aHR was mainly driven by ischemic stroke (aHR 1.14; 1.09-1.18) rather than hemorrhagic stroke (aHR 1.06; 0.97-1.15). The risk of ischemic stroke was significantly increased across IBD subtypes (CD [IR 23.3 vs 19.2; aHR 1.19; 1.10-1.29], UC [IR 25.7 vs 22.6; aHR 1.09; 1.04-1.16], and IBD-U [IR 30.5 vs 22.8; aHR 1.22; 1.08-1.37]). Similar results were found when patients with IBD were compared with their siblings. Patients with IBD were at an increased risk of stroke, especially of ischemic events, irrespective of the IBD subtype. The excess risk persisted even 25 years after diagnosis. These findings highlight the need for clinical vigilance about the long-term excess risk of cerebrovascular events in patients with IBD.

OUTC-10. SELF-REPORTED RACE AND ETHNICITY AND GENETIC ANCESTRY GROUPS SHOW DISTINCT PREVALENCE AND OUTCOMES ACROSS PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS

Abstract BACKGROUND Race and ethnicity disparities have been identified in survival of pediatric central nervous system (CNS) tumors. No prior studies have investigated the comparative effects of self-identified race and ethnicity versus genetic ancestry on tumor prevalence and outcome. We examine these contributions in a retrospective analysis of pediatric patients with CNS tumors. METHODS Patients from Children’s Brain Tumor Network (CBTN; n=646) and Pacific Pediatric Neuro-Oncology Consortium (PNOC; n=35) with available clinical data and whole genome sequencing were included. Ancestry groups were predicted with somalier and genetic markers from reference individuals of known ancestry that participated in the 1000 Genomes Project: sub-Saharan African (AFR), admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS). Independence of predicted ancestry and self-reported race and ethnicity was assessed with chi-squared tests. Effects of predicted ancestry on survival were estimated using multivariate Cox models with molecular subtype and extent of tumor resection as covariates. RESULTS Predicted ancestry groups were highly concordant with self-reported race (χ2=897, p&amp;lt;0.001) and ethnicity (χ2=340, p&amp;lt;0.001). Patients from AFR ancestry were significantly enriched within ATRT (n=26; p=0.001) and neurofibroma plexiform (n=11; p=0.005) and patients with AMR ancestry were enriched within DMG (n=53; p&amp;lt;0.001). Patients diagnosed with H3 wildtype high-grade glioma (n=39) with non-EUR ancestry trended towards worse overall survival (OS; HR=2.0, p=0.07). Patients with ATRT (n=19) with AMR ancestry trended towards worse OS compared to AFRs (HR=4.1, p=0.09) and AFR patients with MB (n=78) trended toward worse OS compared to EUR patients (HR=3.7, p=0.07), including Group 4 MBs (n=39; HR=3.9, p=0.08). Patients with LGG (n=182) with non-EUR ancestry were more likely to have less than gross total/near total resection compared to patients with EUR ancestry (p=0.02). CONCLUSIONS Differences in ancestry are seen across pediatric CNS tumor entities and outcomes. Analyses are underway in an additional ~800 patients.