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Abstract Large-scale longitudinal biobank data can be leveraged to identify genetic variation contributing to human diseases progression and traits trajectories. While methods for genome-wide association studies (GWAS) of multiple correlated traits have been proposed, an efficient multiple-trait approach to model longitudinal phenotypes is not currently available. We developed GAMUT, a genome-wide association approach for multiple longitudinal traits. GAMUT employs a mixed-effects model to fit longitudinal outcomes where a fast algorithm for inversion by recursive partitioning of the random effects submatrix is introduced. To evaluate performance of the algorithms introduced and assess their statistical power and type I error, stochastic simulation was conducted. Consistent with our expectation, power was greater for cross-sectional (CS) than longitudinal (LT) effects, particularly with a diminishing LT/CS ratio. With a minimum minor allele count of 3 within genotype by time categories, observed type I error was roughly equal to theoretical genome-wide significance. Additionally, 28 blood-based biomarkers measured at 2 time points on participants of the UK Biobank were used to compare GAMUT against single-trait standard and longitudinal GWAS (including rate of change). Across all biomarkers, we observed 539 (CS) and 248 (LT) significant independent variants for the GAMUT method, and 513 (CS) and 30 (LT) for single-trait longitudinal GWAS, respectively. Only 37 variants were identified by modeling rates of change using standard GWAS.

Abstract Purpose Multigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined. Methods Clinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants (“pathogenic variants”) were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk. Results Of 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone. Conclusions A high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under‐recognized component of cancer predisposition syndromes.

Background: Adults born preterm (< 37 weeks’ gestation) exhibit altered cardiac growth and are susceptible to cardiac dysfunction. Sheep studies have shown that moderate preterm birth results in maladaptive structural remodelling of the cardiac ventricles. The aim of this study was to examine ventricular structure in lambs born at a greater severity of preterm birth and ventilated postnatally. Methods: Former-preterm lambs delivered at 128 days’ gestation, and mechanically ventilated for a week after birth, were compared with unventilated lambs born at term (150 days’ gestation), at 2 months (term: n = 10, former-preterm: n = 8), and 5 months (term: n = 9, former-preterm: n = 8) term-equivalent age. The right ventricle and left ventricle plus septum were analysed using immunohistochemistry, histology, and stereology. Results: Cardiomyocyte number, cross-sectional area, proliferation, and apoptosis were not affected by preterm birth or age. Left ventricle plus septum interstitial collagen levels increased with age (P = 0.0015) and were exacerbated by preterm birth (P = 0.0006; 2 months term: 0.57% ± 0.07%, former-preterm: 1.44% ± 0.18%; 5 months term: 1.37% ± 0.25%, former-preterm: 2.15% ± 0.31%). Right ventricle interstitial collagen levels increased with age (P = 0.012) but were not affected by preterm birth. Conclusion: This study is the first to explore the effect of preterm birth combined with modern neonatal interventions on the ventricular myocardium in lambs. There was no adverse impact on cardiomyocyte growth in early postnatal life. Of concern, however, there was increased collagen deposition in the preterm hearts, which has the potential to induce cardiac dysfunction, especially if it becomes exaggerated with ageing. Résumé: Introduction: Les adultes nés avant terme (< 37 semaines de grossesse) montrent une altération de la croissance cardiaque et sont exposés à une dysfonction cardiaque. Les études sur les moutons ont montré que la prématurité modérée entraîne un remodelage structurel inadapté des ventricules du cœur. L’objectif de la présente étude était d’examiner la structure ventriculaire des agneaux grands prématurés et oxygénés après la naissance. Méthodes: Les agneaux anciens prématurés nés après 128 jours de gestation et sous respirateur durant une semaine ont été comparés aux agneaux nés à terme qui n’avaient pas été sous respirateur (150 jours de gestation) à l’âge du terme, soit deux mois (à terme : n = 10, anciens prématurés : n = 8) et cinq mois (à terme : n = 9, anciens prématurés : n = 8). Le ventricule droit et le ventricule gauche plus le septum ont été analysés par immunohistochimie, histologie et stéréologie. Résultats: Le nombre de cardiomyocytes, la surface en coupe transversale, la prolifération et l’apoptose n’étaient pas affectés par la naissance prématurée ou l’âge. Les concentrations interstitielles en collagène du ventricule gauche plus le septum augmentaient avec l’âge (P = 0,0015) et étaient exacerbées par la naissance prématurée (P = 0,0006; âge du terme, deux mois : [à terme : 0,57 % ± 0,07 %, anciens prématurés : 1,44 % ± 0,18 % ]; âge du terme, cinq mois : [à terme : 1,37 % ± 0,25 %, anciens prématurés : 2,15 % ± 0,31 %]). Les concentrations interstitielles en collagène du ventricule droit augmentaient avec l’âge (P = 0,012), mais n’étaient pas affectées par la naissance avant terme. Conclusion: Il s’agit de la première étude qui porte sur la combinaison des effets de la naissance avant terme aux interventions néonatales modernes sur le myocarde ventriculaire des agneaux. Aucune conséquence sur la croissance des cardiomyocytes dans la phase précoce de la vie postnatale n’a été observée. Toutefois, le dépôt accru de collagène dans le cœur des prématurés est préoccupant puisqu’il a le potentiel d’induire une dysfonction cardiaque, particulièrement s’il s’exacerbe avec le vieillissement.

Abstract Background Atrial fibrillation (AF) patients are routinely prescribed medications to prevent and treat complications, including those from common co-occurring comorbidities. However, adherence to such medications may be suboptimal. Therefore, we sought to identify risk factors for general medication non-adherence in a population of patients with atrial fibrillation. Methods Data were collected from a large, ethnically-diverse cohort of Kaiser Permanente Northern and Southern California adult members with incident diagnosed AF between January 1, 2006 and June 30, 2009. Self-reported questionnaires were completed between May 1, 2010 and September 30, 2010, assessing patient socio-demographics, health behaviors, health status, medical history and medication adherence. Medication adherence was assessed using a previously validated 3-item questionnaire. Medication non-adherence was defined as either taking medication(s) as the doctor prescribed 75% of the time or less, or forgetting or choosing to skip one or more medication(s) once per week or more. Electronic health records were used to obtain additional data on medical history. Multivariable logistic regression analyses examined the associations between patient characteristics and self-reported general medication adherence among patients with complete questionnaire data. Results Among 12,159 patients with complete questionnaire data, 6.3% (n = 771) reported medication non-adherence. Minority race/ethnicity versus non-Hispanic white, not married/with partner versus married/with partner, physical inactivity versus physically active, alcohol use versus no alcohol use, any days of self-reported poor physical health, mental health and/or sleep quality in the past 30 days versus 0 days, memory decline versus no memory decline, inadequate versus adequate health literacy, low-dose aspirin use versus no low-dose aspirin use, and diabetes mellitus were associated with higher adjusted odds of non-adherence, whereas, ages 65–84 years versus

Abstract Background The association between Institute of Medicine (IOM) guidelines and pregnancy outcomes across ethnicities is uncertain. We evaluated the associations of gestational weight gain (GWG) outside 2009 IOM guidelines, with maternal and infant outcomes across the USA, western Europe and east Asia, with subgroup analyses in Asia. The aim was to explore ethnic differences in maternal prepregnancy body mass index (BMI), GWG and health outcomes across these regions. Methods Systematic review, meta-analysis and meta-regression of observational studies were used for the study. MEDLINE, MEDLINE In-Process, Embase and all Evidence-Based Medicine (EBM) Reviews were searched from 1999 to 2017. Studies were stratified by prepregnancy BMI category and total pregnancy GWG. Odds ratio (ORs) 95% confidence intervals (CI) applied recommended GWG within each BMI category as the reference. Primary outcomes were small for gestational age (SGA), preterm birth and large for gestational age (LGA). Secondary outcomes were macrosomia, caesarean section and gestational diabetes. Results Overall, 5874 studies were identified and 23 were included (n = 1,309,136). Prepregnancy overweight/obesity in the USA, Europe and Asia was measured at 42%, 30% and 10% respectively, with underweight 5%, 3% and 17%. GWG below guidelines in the USA, Europe and Asia was 21%, 18% and 31%, and above was 51%, 51% and 37% respectively. Applying regional BMI categories in Asia showed GWG above guidelines (51%) was similar to that in the USA and Europe. GWG below guidelines was associated with a higher risk of SGA (USA/Europe [OR 1.51; CI 1.39, 1.63]; Asia [1.63; 1.45, 1.82]) and preterm birth (USA/Europe [1.35; 1.17, 1.56]; Asia [1.06; 0.78, 1.44]) than GWG within guidelines. GWG above guidelines was associated with a higher risk of LGA (USA/Europe [1.93; 1.81, 2.06]; Asia [1.68; 1.51 , 1.87]), macrosomia (USA/Europe [1.87; 1.70, 2.06]; Asia [2.18; 1.91, 2.49]) and caesarean (USA/Europe [1.26; 1.21, 1.33]; Asia [1.37; 1.30, 1.45]). Risks remained elevated when regional BMI categories were applied for GWG recommendations. More women in Asia were categorised as having GWG below guidelines using World Health Organization (WHO) (60%) compared to regional BMI categories (16%), yet WHO BMI was not accompanied by increased risks of adverse outcomes. Conclusions Women in the USA and western Europe have higher prepregnancy BMI and higher rates of GWG above guidelines than women in east Asia. However, when using regional BMI categories in east Asia, rates of GWG above guidelines are similar across the three continents. GWG outside guidelines is associated with adverse outcomes across all regions. If regional BMI categories are used in east Asia, IOM guidelines are applicable in the USA, western Europe and east Asia.

Background: During normal human kidney development, nephrogenesis (the formation of nephrons) is complete by term birth, with the majority of nephrons formed late in gestation. The aim of this study was to morphologically examine nephrogenesis in fetal human kidneys from 20 to 41 weeks of gestation. Methods: Kidney samples were obtained at autopsy from 71 infants that died acutely in utero or within 24 h after birth. Using image analysis, nephrogenic zone width, the number of glomerular generations, renal corpuscle cross-sectional area and the cellular composition of glomeruli were examined. Kidneys from female and male infants were analysed separately. Findings: The number of glomerular generations formed within the fetal kidneys was directly proportional to gestational age, body weight and kidney weight, with variability between individuals in the ultimate number of generations (8 to 12) and in the timing of the cessation of nephrogenesis (still ongoing at 37 weeks gestation in one infant). There was a slight but significant (r2 = 0.30, P = 0.001) increase in renal corpuscle cross-sectional area from mid gestation to term in females, but this was not evident in males. The proportions of podocytes, endothelial and non-epithelial cells within mature glomeruli were stable throughout gestation. Interpretation: These findings highlight spatial and temporal variability in nephrogenesis in the developing human kidney, whereas the relative cellular composition of glomeruli does not appear to be influenced by gestational age.

Histoplasmosis is a common fungal infection, normally infecting people exposed to demolition sites or bat/bird droppings in the central and eastern states. When a child presents with a chest mass and eosinophilia in a non-endemic region the likelihood of an infectious process like pulmonary histoplasmosis is unknown. A seven year old immunocompetent child with a mediastinal mass and eosinophilia presented with acute cough, fever, non-bloody emesis, and four pound weight loss. A neoplastic work up was negative. Further evaluation showed a positive M band (chronic histoplasmosis infection) and negative H band (acute infection). Tissue obtained by thoracotomy demonstrated necrotizing granulomatous inflammation with calcification consistent with histoplasmosis. Patient recovered after completion of a twelve week course of itraconazole. A mediastinal mass in a symptomatic child has a 50% risk of cancer as the primary diagnosis. The Infectious Disease Society of America guidelines recommend treatment of histoplasmosis granulomatous disease with itraconazole if symptomatic and surgery only for obstruction. Thus our patient did not have a clear indication for surgery. In a child with a mediastinal mass, despite low risk factors should they be evaluated for a fungal infection prior to invasive surgery? This case demonstrates that histoplasmosis can cause a granuloma in a non-endemic region and that an infectious etiology ought to be considered when working up a symptomatic child with a chest mass as it may prevent unnecessary surgery. Keywords: Histoplasmosis, Fungal, Cough, Chest mass, Eosinophilia, Thoracotomy, Mediastinal

Abstract Aims The worldwide prevalence of gestational diabetes mellitus (GDM) is increasing. Studies in rodent models indicate that hyperglycaemia during pregnancy alters kidney development, yet few studies have examined if this is so in humans. The objective of this study was to evaluate the association of treated GDM with foetal kidney size. Materials and Methods Participants were recruited from an Australian tertiary hospital, and clinical data were collected from women without GDM and women diagnosed and treated for GDM and their offspring. Participants underwent an obstetric ultrasound at 32‐34 weeks gestation for foetal biometry and foetal kidney volume measurement. Results Sixty‐four non‐GDM and 64 GDM women participated in the study. Thirty percent of GDM women were diagnosed with fasting hyperglycaemia, while 89% had an elevated 2‐hour glucose level. Maternal age, weight and body mass index were similar in women with and without GDM. Estimated foetal weight, foetal kidney dimensions, total foetal kidney volume and birth weight were similar in offspring of women with and without GDM. Conclusions We conclude that a period of mild hyperglycaemia prior to diagnosis of GDM and treatment initiation, which coincides with a period of rapid nephron formation and kidney growth, does not alter kidney size at 32‐34 weeks gestation.