Reference Cohort Research Articles

Evaluating Genetic Modifiers of Duchenne Muscular Dystrophy Disease Progression Using Modeling and MRI.

Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder with a well-characterized disease phenotype but considerable interindividual heterogeneity that is not well understood. The aim of this study was to evaluate the effects of dystrophin variations and genetic modifiers of DMD on rate and age of muscle replacement by fat. One hundred seventy-five corticosteroid treated participants from the ImagingDMD natural history study underwent repeated magnetic resonance spectroscopy (MRS) of the vastus lateralis (VL) and soleus (SOL) to determine muscle fat fraction (FF). MRS was performed annually in most instances; however, some individuals had additional visits at 3 or 6 monthss intervals. FF changes over time were modeled using nonlinear mixed effects to estimate disease trajectories based on the age that the VL or SOL reached half-maximum change in FF (mu) and the time required for FF change (sigma). Computed mu and sigma values were evaluated for dystrophin variations that have demonstrated the ability to lead to a mild phenotype as well as compared between different genetic polymorphism groups. Participants with dystrophin gene deletions amenable to exon 8 skipping (n = 4) had minimal increases in SOL FF and had an increase in VL mu value by 4.4 years compared with a reference cohort (p = 0.039). Participants with nonsense variations within exons that may produce milder phenotypes (n = 11) also had minimal increases in SOL and VL FFs. No differences in estimated FF trajectories were seen for individuals amenable to exon 44 skipping (n = 10). Modeling of the SPP1, LTBP4, and thrombospondin-1 (THBS1) genetic modifiers did not result in significant differences in muscle FF trajectories between genotype groups (p > 0.05); however, trends were noted for the polymorphisms associated with long-range regulation of LTBP4 and THBS1 that deserve further follow-up. The results of this study link the historically mild phenotypes seen in individuals amenable to exon 8 skipping and with certain nonsense variations with alterations in trajectories of lower extremity muscle replacement by fat.

Overweight and obesity are not associated with worse clinical outcomes in COVID-19 patients treated with fixed-dose 6 mg dexamethasone.

ObjectiveA fixed 6 mg dexamethasone dose for 10 days is the standard treatment for all hospitalised COVID-19 patients who require supplemental oxygen. Yet, the pharmacokinetic properties of dexamethasone can lead to diminishing systemic dexamethasone exposure with increasing body mass index (BMI). The present study examines whether this translates to overweight and obesity being associated with worse clinical outcomes, defined as ICU admission or in hospital death, in COVID-19 patients treated with fixed-dose dexamethasone.MethodsWe conducted a single centre retrospective cohort study in COVID-19 patients who were admitted to a non-ICU ward and were treated with dexamethasone (6 mg once daily for a maximum of ten days) between June 2020 and January 2021. Univariable and multivariable logistic regression analyses were conducted to assess the association between BMI-categories and an unfavourable clinical course (ICU admission and/or in hospital death). Analyses were adjusted for age, comorbidities, inflammatory status, and oxygen requirement at admission. For reference, similar analyses were repeated in a cohort of patients hospitalised before dexamethasone was introduced (March 2020 through May 2020).ResultsIn patients treated with dexamethasone (n = 385) an unfavourable clinical course was most prevalent in patients with normal weight (BMI < 25) compared to patients with overweight (BMI 25–30) and patients with obesity (BMI ≥ 30) with percentages of 33, 26 and 21% respectively. In multivariable analyses, there was no association between BMI-category and an unfavourable clinical course (respectively with aORs of 0.81 (0.43–1.53) and 0.61 (0.30–1.27) with normal weight as reference). In the reference cohort (n = 249) the opposite was observed with an unfavourable clinical course being most prevalent in patients with overweight (39% vs 28%; aOR 2.17 (0.99–4.76)). In both cohorts, CRP level at admission was higher and lymphocyte count was lower in patients with normal weight compared to patients with obesity.ConclusionsOverweight and obesity are not associated with an unfavourable clinical course in COVID-19 patients admitted to a non-ICU ward and treated with 6 mg dexamethasone once daily.

Temporal changes in personal activity intelligence and the risk of incident dementia and dementia related mortality: A prospective cohort study (HUNT).

SummaryBackgroundThe Personal Activity Intelligence (PAI) translates heart rate during daily activity into a weekly score. Obtaining a weekly PAI score ≥100 is associated with reduced risk of premature morbidity and mortality from cardiovascular diseases. Here, we determined whether changes in PAI score are associated with changes in risk of incident dementia and dementia-related mortality.MethodsWe conducted a prospective cohort study of 29,826 healthy individuals. Using data from the Trøndelag Health-Study (HUNT), PAI was estimated 10 years apart (HUNT1 1984–86 and HUNT2 1995–97). Adjusted hazard-ratios (aHR) and 95%-confidence intervals (CI) for incidence of and death from dementia were related to changes in PAI using Cox regression analyses.FindingsDuring a median follow-up time of 24.5 years (interquartile range [IQR]: 24.1-25.0) for dementia incidence and 23.6 years (IQR: 20.8–24.2) for dementia-related mortality, there were 1998 incident cases and 1033 dementia-related deaths. Individuals who increased their PAI score over time or maintained a high PAI score at both assessments had reduced risk of dementia incidence and dementia-related mortality. Compared with persistently inactive individuals (0 weekly PAI) at both time points, the aHRs for those with a PAI score ≥100 at both occasions were 0.75 (95% CI: 0.58–0.97) for incident dementia, and 0.62 (95% CI: 0.43–0.91) for dementia-related mortality. Using PAI score <100 at both assessments as the reference cohort, those who increased from <100 at HUNT1 to ≥100 at HUNT2 had aHR of 0.83 (95% CI: 0.72–0.96) for incident dementia, and gained 2.8 (95% CI: 1.3–4.2, P<0.0001) dementia-free years. For dementia-related mortality, the corresponding aHR was 0.74 (95% CI: 0.59–0.92) and years of life gained were 2.4 (95% CI: 1.0–3.8, P=0.001).InterpretationMaintaining a high weekly PAI score and increases in PAI scores over time were associated with a reduced risk of incident dementia and dementia-related mortality. Our findings extend the scientific evidence regarding the protective role of PA for dementia prevention, and suggest that PAI may be a valuable tool in guiding research-based PA recommendations.FundingThe Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Gestational weight gain in triplet pregnancies in the United States

The Institute of Medicine has published national recommendations for optimal pregnancy weight gain ranges for singletons and twins but not for higher-order multiples. A common clinical resource suggests weight gain targets for triplet pregnancies, but they are based on a single, small study conducted over 20 years ago. We sought to describe contemporary maternal weight gain patterns in triplet gestations in the United States, the weight gain patterns associated with good neonatal outcomes, and how these patterns compare with those of healthy twin pregnancies. We used data from 7705 triplet pregnancies drawn from the United States live birth and fetal death files (2012‒2018). We calculated total pregnancy weight gain as weight at delivery minus the prepregnancy weight. A good neonatal outcome was defined as delivery at ≥32 weeks' gestation of 3 liveborn infants weighing ≥1500 g with 5-minute Apgar scores of ≥3. We described the weight gain patterns of triplet pregnancies with good neonatal outcomes by calculating week-specific percentiles of the total weight gain distribution for deliveries at 32 to 37 weeks' gestation. For comparative purposes, we plotted these values against the percentiles of a previously published weight gain chart for monitoring and evaluating twin pregnancies from a referent cohort. Most participants were over weight (26%) or obese (30%), and 42% were normal weight or underweight. The 50th percentile (25th-75th) of total weight gain in triplet pregnancies was 17 (11-23) kg. As the body mass index category increased, the total weight gain declined: underweight or normal weight, median 19 (14-25) kg; overweight, 17 (12-23) kg; obese, 14 (7.7-20) kg. Approximately 46% of triplet pregnancies had a good neonatal outcome (n=3562). For underweight or normal weight triplet pregnancies with good neonatal outcomes, the 50th percentiles of weight gain at 32 weeks' and 36 weeks' gestation were 12.3 kg and 22.7 kg, respectively. The 10th and 90th percentiles were 12.3 kg and 32.7 kg, respectively, at 32 weeks, and 15.0 kg and 34.1 kg, respectively, at 36 weeks. Triplet pregnancies with prepregnancy overweight or obesity and a good neonatal outcome had lower weight gains. Compared with the reference values for pregnancy weight gain from a twin-specific weight gain chart, the median total weight gain in triplet pregnancies with good neonatal outcomes was approximately 3 to 5 kg more than twins, regardless of body mass index. Our study fills an important gap in understanding how much weight gain can be expected among triplet pregnancies by body mass index category. These descriptive data are a necessary first step to inform science-based triplet gestational weight gain guidelines. Additional research is needed to determine whether monitoring triplet pregnancy weight gain is useful for promoting healthy outcomes for pregnant individuals and children and what targets should be used to optimize maternal and neonatal health.

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: APOLA network study.

Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described. We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (RT) (with or without chemotherapy [CT]), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n = 200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n = 543) based on progression-free survival before and after first progression. In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5months after RT. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted of the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2years after RT. The only factor associated with pseudoprogression occurrence was adjuvant PCV CT. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions. In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2years after RT, the possibility of a pseudoprogression should be carefully considered.

The effect of a tight control regime with monthly follow-up on remission rates and reported pain in early rheumatoid arthritis.

To determine whether a tight control (TC) regime with monthly consultations to the physician for the first 6months, could increase remission rate and improve reported pain of patients with early rheumatoid arthritis (RA). In this single-centre, TC study, with monthly visits to the physician, a cohort of 100 patients with early RA was consecutively included. They were compared with a reference cohort of 100 patients from the same clinic that had been conventionally managed. The patients were followed for 2years. The patients in the TC cohort had lower 28- joints disease activity score (DAS28) at three, six, 12 and 24months, compared with the conventionally managed cohort, p≤0.001. At 12months, 71% in the TC cohort versus 46% in the conventional cohort were in remission (DAS28<2.6) and at 24months 68% versus 49% respectively, p<0.05. The TC cohort reported less pain at three, six, 12 and 24months, p<0.001. Multiple logistical regression analyses adjusted for, respectively, age, disease duration, pharmacological treatment, DAS28 and visual analogue scale pain at inclusion, revealed that participation in the TC cohort had an independent positive association with remission at 12 and 24months and with acceptable pain at 24months. The intensive follow-up schedule for patients with early RA improved remission and led to improvement in reported pain and physical function. The positive effect of a TC regime in early disease may be due to increased empowerment, developed by meeting health professionals frequently.

Effectiveness of the Use of Standardized Vocabularies on Epilepsy Patient Cohort Generation.

ObjectivesThis study investigated the effectiveness of using standardized vocabularies to generate epilepsy patient cohorts with local medical codes, SNOMED Clinical Terms (SNOMED CT), and International Classification of Diseases tenth revision (ICD-10)/Korean Classification of Diseases-7 (KCD-7).MethodsWe compared the granularity between SNOMED CT and ICD-10 for epilepsy by counting the number of SNOMED CT concepts mapped to one ICD-10 code. Next, we created epilepsy patient cohorts by selecting all patients who had at least one code included in the concept sets defined using each vocabulary. We set patient cohorts generated by local codes as the reference to evaluate the patient cohorts generated using SNOMED CT and ICD-10/KCD-7. We compared the number of patients, the prevalence of epilepsy, and the age distribution between patient cohorts by year.ResultsIn terms of the cohort size, the match rate with the reference cohort was approximately 99.2% for SNOMED CT and 94.0% for ICD-10/KDC7. From 2010 to 2019, the mean prevalence of epilepsy defined using the local codes, SNOMED CT, and ICD-10/KCD-7 was 0.889%, 0.891% and 0.923%, respectively. The age distribution of epilepsy patients showed no significant difference between the cohorts defined using local codes or SNOMED CT, but the ICD-9/KCD-7-generated cohort showed a substantial gap in the age distribution of patients with epilepsy compared to the cohort generated using the local codes.ConclusionsThe number and age distribution of patients were substantially different from the reference when we used ICD-10/KCD-7 codes, but not when we used SNOMED CT concepts. Therefore, SNOMED CT is more suitable for representing clinical ideas and conducting clinical studies than ICD-10/KCD-7.

Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic

ObjectiveAntitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses...

Altered Lung Microbiome and Metabolome Profile in Children With Pulmonary Arterial Hypertension Associated With Congenital Heart Disease.

BackgroundsPulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular functional and structural changes, resulting in increased pulmonary vascular resistance and eventually right heart failure and death. Congenital Left-to-Right shunts (LTRS) is one type of congenital heart disease (CHD) and PAH associated with the congenital Left-to-Right shunt (PAH-LTRS) is a severe disease in children. However, changes in the lung microbiome and their potential impact on PAH-LTRS have not been not fully studied. We hypothesized that lung microbiota and their derived metabolites have been disturbed in children with PAH-LTRS, which might contribute to the progression and outcomes of PAH-LTRS.MethodsIn this study, 68 age- and sex-matched children of three different groups (patients with PAH-LTRS cohort, patients with LTRS but have no pathologic features of PAH cohort, and healthy reference cohort) were enrolled in the current study. Bronchoalveolar lavage fluid samples from these participants were conducted for multi-omics analysis, including 16S rRNA sequencing and metabolomic profiling. Data progressing and integration analysis were performed to identify pulmonary microbial and metabolic characteristics of PAH-LTRS in children.ResultsWe found that microbial community density was not significantly altered in PAH-LTRS based on α-diversity analysis. Microbial composition analysis indicated phylum of Bacteroidetes was that less abundant while Lactobacillus, Alicycliphilus, and Parapusillimonas were significantly altered and might contribute to PAH in children with LTRS. Moreover, metabolome profiling data showed that metabolites involved in Purine metabolism, Glycerophospholipid metabolism, Galactose metabolism, and Pyrimidine metabolism were also significantly disturbed in the PAH-LTRS cohort. Correlation analysis between microbes and metabolites indicated that alterations in the microbial composition from the lung microbiota could eventually result in the disturbance in certain metabolites, and might finally contribute to the pathology of PAH-LTRS.ConclusionLung microbial density was not significantly altered in patients with PAH-LTRS. Composition analysis results showed that the relative microbiome abundance was different between groups. Metabolome profiling and correlation analysis with microbiota showed that metabolome also altered in children with PAH-LTRS. This study indicated that pulmonary microbes and metabolites disturbed in PAH-LTRS could be potentially effective biomarkers and provides valuable perspectives on clinical diagnosis, treatment, and prognosis of pediatric PAH-LTRS.

Adopting the Pedagogy of Trust and its Impact on Learning

In this work, we present the results of our attempts to transit into a trust-based assessment environment for adult learners. The impact of utilizing an honour system of assessment throughout a course on data structures and algorithm design has been evaluated. The performance of the students has been compared with the performance of students from two previous cohorts that appeared for the same assessments in an invigilated environment. We found that with adult learners, who are more focused on learning the concepts to hone specific skills for applicability at their workplace, the performance variation between the test cohort and the reference cohorts was not significant. With further evidence of this promising initial step, we could evolve into a larger portfolio-based education framework in which students can showcase their competence and skills through a collection of projects and assessments (formative as well as summative), to help with their career growth. Establishment of such pedagogies will help our students step out of their comfort zone, undertake exploratory studies, be willing to unearth their vulnerabilities, and work to improve their shortcomings to help them advance their careers.

Cohort profile: The Growing Up Healthy Study (GUHS)-A prospective and observational cohort study investigating the long-term health outcomes of offspring conceived after assisted reproductive technologies.

Worldwide, over 8 million children and adults are conceived following assisted reproductive technologies (ART), and their long-term health is of consequential public health interest. The objective of this paper is to describe the Growing up Healthy Study (GUHS) cohort in detail, publicise it and invite collaboration. Combining the data collected in the GUHS with other cohorts or databases will improve the much-needed knowledge about the effects of ART, and allow for better understanding of the long-term health outcomes of offspring conceived after ART. The GUHS cohort is a prospective observational study of adolescents and young adults conceived after assisted reproductive technologies (ART). It was established to determine if the long-term health of offspring conceived by ART differs from that of the general population. This was investigated by comparing a substantial number of health parameters to those of a representative population of offspring conceived without ART. The n = 303 GUHS participants were born between 1991–2001 in the two fertility clinics operating at the time in Perth, Western Australia, and undertook assessments at ages 14, 17 and 20, replicating the pre-defined study protocols from the reference cohort—the Raine Study. Participants were comprehensively phenotyped through detailed questionnaires, anthropometry, biochemical analyses, as well as age-specific assessments (asthma, atopy, cardiometabolic health, body composition, mental health, thyroid function, epigenetics and vision). To date the GUHS cohort has been used to study the methylation, cardiometabolic, and thyroid profiles, as well as respiratory and mental health. To summarise, the GUHS cohort provides a valuable addition to the limited knowledge of the long-term health outcomes of ART-conceived offspring.

Ефекти віку, періоду та когорти у довгостроковій динаміці смертності в Україні

This study analyzes the effects of age, period, and birth cohorts on long-term mortality in Ukraine. For the first time, the APC model was used to analyze mortality in Ukraine for the 1850-2011 period and the cohorts born from 1850 to 1923. These estimations allow us to discriminate the impact of the historical and contemporary factors (at specific times) that could change the mortality rates. The following statistical methods are used: calculation of period and cohort death rates; age-period-birth cohort (APC) model that provides a method to assess the significance of the three interrelated factors (age, calendar period of death, and birth cohort) on mortality. As indicated by the results of APC analysis, the contribution of the period effect to the long-term mortality in Ukraine is likely to be larger than that of the cohort effect, and both effects are found to be more influential for men than for women. The analysis revealed intergenerational variations in death rates and inversion in cohort mortality when survival rates for the younger generations are worse than for the older generations. In particular, almost all generations born during the first half of the XX century had higher mortality rates than the reference cohort born in 1900, while lower mortality rates are found only for those born after 1945. At the same time, the overall decline in mortality among cohorts born after 1945 varied across different age groups: while death rates at the age 0 to 15 declined with each new generation, mortality in the 45 to 60 age group for younger generations tended to be higher than for older generations. The cohorts born in 1915—1925 and especially in 1917—1921 appeared to be the most disadvantaged and the hardest affected in terms of survival. A comparative analysis of the probability of dying in large age intervals for different generations showed that, first, among the cohorts of adult men who participated in World War II, those born in 1915—1925 were the most affected; second, during the First World War, the Ukrainian Revolution of 1917—1921 and the famine of 1921—1923 young and middle-aged men born in 1880—1890 suffered the greatest losses whereas the highest mortality due to Holodomor of 1932—1933 was observed among children and adolescents, as well as older persons born in the 1870s.

Socioeconomic Inequalities in All-Cause and Cause-Specific Mortality Among Patients With Osteoarthritis in the Skåne Region of Sweden.

To assess the association between education and all-cause and cause-specific mortality among patients with osteoarthritis (OA) in comparison to an OA-free reference cohort. Using data from the Skåne Healthcare Register, we identified all residents age ≥45 years in the region of Skåne in southern Sweden with doctor-diagnosed OA of peripheral joints between 1998 and 2013 (n=123,993). We created an age- and sex-matched reference cohort without OA diagnosis (n=121,318). Subjects were followed until death, relocation outside Skåne, or the end of 2014. The relative index of inequality (RII) and the slope index of inequality (SII) were estimated by the Cox model and Aalen's additive hazard model, respectively. We found an inverse association between education and mortality. The magnitude of relative inequalities in all-cause mortality were comparable in the OA, with an RII of 1.53 (95% confidence interval [95% CI] 1.46, 1.61), and reference cohorts (RII 1.54 [95% CI 1.47, 1.62]). The absolute inequalities were smaller in the OA cohort (all-cause deaths per 100,000 person-years, SII 937 [95% CI 811, 1,063]) compared with the reference cohort (SII 1,265 [95% CI 1,109, 1,421]). Cardiovascular mortality contributed more to the absolute inequalities in the OA cohort than in the reference cohort (60.1% versus 48.1%) while the opposite was observed for cancer mortality (8.5% versus 22.3%). We found higher all-cause and cause-specific mortality in OA patients with lower education. The observed inequalities in the OA cohort reflect the inequalities in the population at large. The greater burden of cardiovascular diseases in OA patients suggests that proper management of cardiovascular risk factors in OA patients is important.

A Cohort Study of the Age at Menopause in Female Patients With and Without Inflammatory Bowel Disease.

BackgroundMenopause, defined by the complete cessation of menstrual cycles for 12 consecutive months, may occur at a younger age in women who have concomitant immune dysregulation. Our aim was to determine whether women with inflammatory bowel disease (IBD) experience an earlier onset of menopause compared to women without IBD.MethodsThis was a retrospective cohort study using resources of the Rochester Epidemiology Project, a collaboration between clinics, hospitals, and medical facilities in Olmsted County, Minnesota. From these people, women who were diagnosed with IBD between 1970 and 2010 comprised the case cohort while the reference cohort included women with no diagnosis of IBD. Data including age, body mass index (BMI), ethnicity, smoking status, age at onset of menopause, and current use of hormone therapy were collected. Patients with history of hysterectomy or oophorectomy were excluded. Wilcoxon rank-sum test for numeric variables and Fisher’s exact test for categorical variables were used to analyze the data.ResultsA total of 171 women met criteria for inclusion (83 cases and 88 controls). Mean age of menopause in women with IBD was 50.0 years compared to 51.5 years in women with no IBD (P = .006). There was no difference in BMI of women with and without IBD (28.7 versus 28.2 kg m−2; P = .9), respectively. There were more former smokers (33.7%) and current (6%) smokers in the IBD group (P = .009) compared to the non-IBD group.ConclusionsIBD is associated with an earlier onset of menopause. Although it is unclear if this mean difference of 1.5 years is clinically relevant, it is known that early menopause is associated with an increased risk of osteoporosis and cardiovascular disease. Further research on the possible mechanisms is needed.

Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey)

Background Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. Research design and methods This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. Results At 3 years, Kaplan–Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%–2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%–3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79–1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28–0.78; P<0.05). Conclusions Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. Trial registration ClinicalTrials.gov, NCT02285166.

The Frequency of Primary Healthcare Contacts Preceding the Diagnosis of Lower-Extremity Arterial Disease: Do Women Consult General Practice Differently?

Background. Women with lower-extremity arterial disease (LEAD) are often underdiagnosed, present themselves with more advanced disease at diagnosis, and fare worse than men. Objective. To investigate to what extent potential gender differences exist in the frequency and reasons for general practitioner (GP) consultation six months prior to the diagnosis of LEAD, as potential indicators of diagnostic delay. Methods. Individuals older than 18 years diagnosed with LEAD, sampled from the Julius General Practitioner’s Network (JGPN), were included and compared with a reference population, matched (1:2.6 ratio) in terms of age, sex, and general practice. We applied a zero-inflated negative binomial (ZINB) regression model. Results. The study population comprised 4044 patients with LEAD (43.5% women) and 10,486 subjects in the reference population (46.3% women). In the LEAD cohort, the number of GP contacts was 2.70 (95% CI: 2.42, 3.02) in women and 2.54 (2.29, 2.82) in men. In the reference cohort, 1.77 (95% CI: 1.62, 1.94) in women and 1.63 (95% CI: 1.50, 1.78) in men. In the LEAD cohort, 21.9% of GP contacts occurred one month prior to diagnosis. In both cohorts and both sexes, the most common cause of consultation during the last month before the index date was cardiovascular problems. Conclusions. Six months preceding the initial diagnosis of LEAD, patients visit the GP more often than a similar population without LEAD, regardless of gender. Reported gender differences in the severity of LEAD at diagnosis do not seem to be explained by a delay in presentation to the GP.

Thyrotropin Receptor Antibodies in Early Pregnancy.

Thyrotropin (TSH) receptor antibodies (TRAb) are important when distinguishing between Graves' and gestational hyperthyroidism, but sparse evidence exists on the recommended cutoff during pregnancy. This work aimed to establish a method- and pregnancy-specific cutoff for TRAb, to describe the frequency of TRAb positivity in early pregnancy, and to follow up the women in the years after pregnancy. This cohort study used the North Denmark Region Pregnancy Cohort and Danish nationwide registers of women in the North Denmark Region who had a blood sample drawn in early pregnancy, 2011 to 2015, that was stored in a biobank for assessment of thyroid function and thyroid autoantibodies. A cutoff value for TRAb was established in a reference cohort (n = 524) and used to identify TRAb-positive and TRAb-negative hyperthyroidism in early pregnancy for evaluation of frequency and follow-up. The method- and cohort-specific cutoff for TRAb in early pregnancy was 0.98 IU/L (95% CI, 0.96-0.99 IU/L). Among women with low TSH in early pregnancy and no known thyroid disease (n = 414), 21 women (5.1%) were TRAb positive and 393 (94.9%) were TRAb negative. Follow-up in the years following the pregnancy (median 8.1 years) revealed that 52.4% of women with TRAb-positive hyperthyroidism and 8.4% of the women with TRAb-negative hyperthyroidism were diagnosed with hyperthyroidism. This is the first study to measure TRAb in a large group of women in early pregnancy and to establish a pregnancy-specific cutoff. Results reveal that TRAb-negative hyperthyroidism is predominant in early pregnancy and rarely associated with later development of hyperthyroidism.

Analytical Considerations in Deriving 99th Percentile Upper Reference Limits for High-Sensitivity Cardiac Troponin Assays: Educational Recommendations from the IFCC Committee on Clinical Application of Cardiac Bio-Markers.

The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers provides evidence-based educational documents to facilitate uniform interpretation and utilization of cardiac biomarkers in clinical laboratories and practice. The committee's goals are to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay in clinical practice. Measurement of high-sensitivity cardiac troponin (hs-cTn) assays is a cornerstone in the clinical evaluation of patients with symptoms and/or signs of acute cardiac ischemia. To define myocardial infarction, the Universal Definition of Myocardial Infarction requires patients who manifest with features suggestive of acute myocardial ischemia to have at least one cTn concentration above the sex-specific 99th percentile upper reference limit (URL) for hs-cTn assays and a dynamic pattern of cTn concentrations to fulfill the diagnostic criteria for MI. This special report provides an overview of how hs-cTn 99th percentile URLs should be established, including recommendations about prescreening and the number of individuals required in the reference cohort, how statistical analysis should be conducted, optimal preanalytical and analytical protocols, and analytical/biological interferences or confounds that can affect accurate determination of the 99th percentile URLs. This document also provides guidance and solutions to many of the issues posed.

The adrenal steroid profile in adolescent depression: a valuable bio-readout?

There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus–pituitary–adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.

Axial Length Distributions in Patients With Genetically Confirmed Inherited Retinal Diseases.

PurposeWe investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.MethodsAL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).ResultsMeasurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had >10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone–rod dystrophy (n = 5) than rod–cone dystrophy (P = 0.002).ConclusionsSeveral diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.