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To ascertain whether home-based care with community and primary healthcare workers' support improves adherence to antiseizure medications, seizure control, and quality of life over routine clinic-based care in community samples of people with epilepsy in a resource-poor country.Participants included consenting individuals with active epilepsy identified in a population survey in impoverished communities. The intervention included antiseizure medication provision, adherence reinforcement and epilepsy self- and stigma management guidance provided by a primary health care-equivalent worker. We compared the intervention group to a routine clinic-based care group in a cluster-randomized trial lasting 24 months. The primary outcome was antiseizure medication adherence, appraised from monthly pill counts. Seizure outcomes were assessed by monthly seizure aggregates and time to first seizure and impact by the Personal Impact of Epilepsy scale.Enrolment began on September 25, 2017 and was complete by July 24, 2018. Twenty-four clusters, each comprising ten people with epilepsy, were randomized to either home- or clinic-care. Home-care recipients were more likely to have used up their monthly-dispensed epilepsy medicine stock (regression coefficient: 0.585; 95% confidence intervals, 0.289-0.881; P = 0.001) and had fewer seizures (regression coefficient: -2.060; 95%CI, -3.335 to -0.785; P = 0.002). More people from clinic-care (n = 44; 37%) than home-care (n = 23; 19%) exited the trial (P = 0.003). The time to first seizure, adverse effects and the personal impact of epilepsy were similar in the two arms.Home care for epilepsy compared to clinic care in resource-limited communities improves medication adherence and seizure outcomes and reduces the secondary epilepsy treatment gap.

The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.

BACKGROUND: Parkinson’s disease (PD) is a common multi-system neurodegenerative disorder with possible vestibular system dysfunction, but prior vestibular function test findings are equivocal. OBJECTIVE: To report and compare vestibulo-ocular reflex (VOR) gain as measured by the video head impulse test (vHIT) in participants with PD, including tremor dominant and postural instability/gait dysfunction phenotypes, with healthy controls (HC). METHODS: Forty participants with PD and 40 age- and gender-matched HC had their vestibular function assessed. Lateral and vertical semicircular canal VOR gains were measured with vHIT. VOR canal gains between PD participants and HC were compared with independent samples t-tests. Two distinct PD phenotypes were compared to HC using Tukey’s ANOVA. The relationship of VOR gain with PD duration, phenotype, severity and age were investigated using logistic regression. RESULTS: There were no significant differences between groups in vHIT VOR gain for lateral or vertical canals. There was no evidence of an effect of PD severity, phenotype or age on VOR gains in the PD group. CONCLUSION: The impulsive angular VOR pathways are not significantly affected by the pathophysiological changes associated with mild to moderate PD.

To understand health-care burden from fall-related injury, we investigated patterns of health service use in participants of the Australian statewide Stepping On fall prevention program.Routinely collected ambulance, emergency, hospital and mortality data for 9163 participants across NSW Local Health Districts between 2009 and 2015 were analysed for patterns in fall-related health service use three years before and after the Stepping On program using negative binomial regression analyses.Overall fall-related health service use increased over the 6-year study period. There was a high period of usage prior to program participation, which decreased postprogram, then appeared to increase again after 12-15 months. Subgroup analysis showed strongest postprogram reductions for women.Patterns of service usage suggest initial program benefits that taper off over time. The results of this observational study need to be interpreted with caution. Investment in ongoing fall prevention programs may be needed for lasting impacts.

Background: Pituitary resistance to thyroid hormone (PRTH) is often seen in congenital hypothyroidism (CH), presenting as elevated thyrotropin (TSH) values despite (high-)normal thyroid hormone (TH) values achieved by levothyroxine treatment. In this study, we describe a girl with CH who was referred because of difficulties interpreting thyroid function tests. She was thought to have PRTH associated with CH, but genetic studies discovered a pathogenic variant in THRB, causing resistance to TH (RTH-β). Methods: Clinical, genetic, and biochemical data of the proband's family were collected. Results: The 3-year-old girl was diagnosed with CH due to a homozygous pathogenic c.470del p.(Asn157Thrfs*3) SLC5A5 variant in the neonatal period. She needed a notably high levothyroxine dose to normalize TSH, leading to high free thyroxine levels. There were no signs of hyperthyroidism. Sequencing identified a heterozygous pathogenic c.947G>A p.(Arg316His) THRB variant. Conclusions: To our knowledge, this is the first report of concomitant SLC5A5 and THRB variants causing CH and RTH-β.

Funder: RCUK | Science and Technology Facilities Council (STFC); doi: https://doi.org/10.13039/501100000271, Funder: Scottish Government Health and Social Care Directorate (SGHSC); doi: https://doi.org/10.13039/100011529, Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100010269, Funder: NHS Blood and Transplant; doi: https://doi.org/10.13039/100009033, Funder: Health Data Research UK Department of Health and Social Care (England) Health and Social Care Research and Development Division (Welsh Government) Public Health Agency (Northern Ireland), Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4,312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases., Participants in the INTERVAL trial were recruited with the active collaboration of NHS Blood and Transplant (www.nhsbt.nhs.uk), which has supported fieldwork and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health and Care Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (BRC) (no. BRC-1215-20014)*. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). Metabolon Metabolomics assays were funded by the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)*. The academic coordinating centre for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (no. NIHR BTRU-2014-10024), NIHR BTRU in Donor Health and Behaviour (NIHR203337), UK Medical Research Council (MRC) (no. MR/L003120/1), British Heart Foundation (nos SP/09/002, RG/13/13/30194 and RG/18/13/33946) and the NIHR Cambridge BRC (no. BRC-1215-20014)*. *The views expressed are those of the author(s) and not necessarily those of the NIHR, NHSBT or the Department of Health and Social Care. A complete list of the investigators and contributors to the INTERVAL trial is provided in ref. 36. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK MRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. The authors are grateful to UK Biobank for access to data to undertake this study (Projects #7439). This work was performed using resources provided by the Cambridge Service for Data Driven Discovery (CSD3) operated by the University of Cambridge Research Computing Service (www.csd3.cam.ac.uk), provided by Dell EMC and Intel using Tier-2 funding from the Engineering and Physical Sciences Research Council (capital grant EP/P020259/1), and DiRAC funding from the Science and Technology Facilities Council (www.dirac.ac.uk). S.R. is funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). S.L. is supported by a Canadian Institutes of Health Research postdoctoral fellowship (MFE-171279). E.P. was funded by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant 116074 and the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024) and is funded by the NIHR BTRU in Donor Health and Behaviour (NIHR203337). J.D. holds a British Heart Foundation Professorship and a NIHR Senior Investigator Award. M.I. is supported by the Munz Chair of Cardiovascular Prediction and Prevention and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). M.I. was also supported by the UK Economic and Social Research 878 Council (ES/T013192/1).

We performed collapsing analyses on 454,796 UK Biobank (UKB) exomes to detect gene-level associations with diabetes. Recessive carriers of nonsynonymous variants in

Funder: Wellcome Trust, Funder: Sydäntutkimussäätiö, Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW pFDR = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.

Objective Comparison of studies on remission rates in pediatric Graves’ disease is complicated by lack of uniformity in treatment protocols, remission definition, and follow-up duration. We performed a systematic review on remission rates in pediatric Graves’ disease and attempted to create uniformity by recalculating remission rates based on an intention-to-treat analysis. Methods PubMed and Embase were searched in August 2020 for studies on patients with Graves’ disease: (i) 2 to 18 years of age, (ii) initially treated with methimazole or carbimazole for at least 18 months, (iii) with a follow-up duration of at least 1 year after cessation of methimazole or carbimazole. All reported remission rates were recalculated using an intention-to-treat analysis. Results Of 1890 articles, 29 articles consisting of 24 patient cohorts were included with a total of 3057 patients (82.6% female). Methimazole or carbimazole was initially prescribed in 2864 patients (93.7%). Recalculation based on intention-to-treat analysis resulted in an overall remission rate of 28.8% (829/2880). Pooled remission rates based on treatment duration were 23.7, 31.0, 43.7, and 75% respectively after 1.5–2.5 years, 2.5–5 years, 5–6 years (two studies), and 9 years (single study) treatment duration. The occurrence of adverse events was 419 in 2377 patients (17.6%), with major side effects in 25 patients (1.1%). Conclusions Using a standardized calculation, the overall remission rate in methimazole-treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate. However, evidence is limited and further research is necessary to investigate the efficacy of longer treatment durations.

Screening for hypo- or hyperthyroidism in adults is generally done by measuring the serum thyrotropin (thyroid-stimulating hormone, TSH) concentration. This is an efficient approach in case of suspected acquired thyroid disease. However, in infants and children, congenital hypothalamus-pituitary-thyroid (HPT) axis disorders also need to be considered, including primary and central congenital hypothyroidism, and even rarer thyroid hormone receptor and transporter defects. In primary congenital hypothyroidism, TSH will be elevated, but in the other congenital HPT axis disorders, TSH is usually within the normal range. Free thyroxine (FT4) assessment is essential for the diagnosis in these conditions.Conclusion: Here we discuss a number of rare congenital HPT axis disorders in which TSH is normal, but FT4 is low, and provide a clinical algorithm to distinguish between these disorders. What is Known:• A single thyroid-stimulating hormone (TSH) measurement is an appropriate screening method for primary hypothyroidism.• For central hypothyroidism and rare thyroid hormone receptor and transporter defects a free thyroxine (FT4) measurement is essential for the diagnosis because TSH is usually normal. What is New:• Here we present a new problem-oriented clinical algorithm including a diagnostic flow-chart for low FT4 and normal TSH in infants and children.

We describe presenting clinical and imaging manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated Rhino-oculo-cerebral mucormycosis (ROCM) in a hospital setting during the second wave of SARS-CoV-2 pandemic in India. Data on the presenting manifestations were collected from 1 March to 31 May 2021. Associations between clinical and imaging findings were explored, specifically: (1) the presence or absence of orbital pain and infiltration of a superior orbital fissure on imaging; (2) the presence of unilateral facial nerve palsy and pterygopalatine fossa infiltration and geniculate ganglion signal on contrast magnetic resonance imaging, and (3) vision loss and optic nerve findings on imaging. Orbital pain was reported by 6/36 subjects. A fixed, frozen eye with proptosis and congestion was documented in 26 (72%), complete vision loss in 23 (64%), and a unilateral lower motor neuron facial nerve palsy in 18 (50%). No association was found between the presence of orbital pain and superior orbital fissure infiltration on imaging. The ipsilateral geniculate ganglion was found to enhance more profoundly in 7/11 subjects with facial palsy and available magnetic resonance (MR) imaging, and the ipsilateral pterygopalatine fossa was found infiltrated in 14. Among 23 subjects with complete loss of vision, 9 (39%) demonstrated long-segment bright signal in the posterior optic nerve on diffusion MR images. We conclude that orbital pain might be absent in SARS-CoV-2-associated ROCM. Facial nerve palsy is more common than previously appreciated and ischemic lesions of the posterior portion of the optic nerve underlie complete vision loss.Unique clinical and radiological manifestations identified in the outbreak of Rhino-oculo-cerebral mucormycosis (ROCM) during the second epidemic wave of coronavirus disease 2019 (COVID-19) infection included the common occurrence of facial paralysis, frequent absence of ocular pain, and long segments of optic nerve damage.

Informal carers play a vital role in the care and well-being of older people with dementia. This article examines the psychological and economic impacts caregiving has on carers of people with suspected dementia and the mechanisms by which they cope with challenges. A mixed-method design was adopted. A baseline survey of 123 older people was undertaken in a resource-poor setting in Kerala, India, using Addenbrooke's Cognitive Examination - Malayalam Version (ACE-m) to identify those with probable dementia. This was followed by in-depth interviews with ten carers of those identified as having cognitive impairment. The data were later transcribed and thematically analysed using N-Vivo to identify main concepts and themes. Analysis of the in-depth interviews with carers revealed that dementia was often interpreted as a 'second childhood', but that this conceptualisation aided carers to cope better. Anger and irritation were the commonly expressed psychological reactions which got accentuated by lack of reciprocation of emotion on the part of care recipient. Government support through social security measures and medical care, along with traditional social practises, helped carers to tide over care expenses. These support systems lessened the psychological and economic impacts of caring. Misconstruction of the disease nature, for example by considering it a normal part of ageing, also seem inadvertently to have helped in coping with care requirements, although this comes at a cost of lower than optimal healthcare access for older people with cognitive impairment.

Coagulation factor VIIa (FVIIa) consists of a γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor-like (EGF) domains and a protease domain. FVIIa binds three Mg2+ ions and four Ca2+ ions in the GLA domain, one Ca2+ ion in the EGF1 domain and one Ca2+ ion in the protease domain. Further, FVIIa contains an Na+ site in the protease domain. Since Na+ and water share the same number of electrons, Na+ sites in proteins are difficult to distinguish from waters in X-ray structures. Here, to verify the Na+ site in FVIIa, the structure of the FVIIa–soluble tissue factor (TF) complex was solved at 1.8 Å resolution containing Mg2+, Ca2+ and Rb+ ions. In this structure, Rb+ replaced two Ca2+ sites in the GLA domain and occupied three non-metal sites in the protease domain. However, Rb+ was not detected at the expected Na+ site. In kinetic experiments, Na+ increased the amidolytic activity of FVIIa towards the synthetic substrate S-2288 (H-D-Ile-Pro-Arg-p-nitroanilide) by ∼20-fold; however, in the presence of Ca2+, Na+ had a negligible effect. Ca2+ increased the hydrolytic activity of FVIIa towards S-2288 by ∼60-fold in the absence of Na+ and by ∼82-fold in the presence of Na+. In molecular-dynamics simulations, Na+ stabilized the two Na+-binding loops (the 184-loop and 220-loop) and the TF-binding region spanning residues 163–180. Ca2+ stabilized the Ca2+-binding loop (the 70-loop) and Na+-binding loops but not the TF-binding region. Na+ and Ca2+ together stabilized both the Na+-binding and Ca2+-binding loops and the TF-binding region. Previously, Rb+ has been used to define the Na+ site in thrombin; however, it was unsuccessful in detecting the Na+ site in FVIIa. A conceivable explanation for this observation is provided.

Objectives Linear enamel hypoplasia (LEH) is a common skeletal marker of physiological stress (e.g., malnutrition or illness) that is studied within and across populations, without reference to familial risk. We examine LEH prevalence in a population with known genealogical relationships to determine the potential influence of genetic heritability and shared environment. Methods LEH data of 239 individuals from a single population were recorded from the Ohio State University Menegaz-Bock collection dental casts. All individuals were of known age, sex, and genealogy. Narrow-sense heritability estimates were obtained for LEH presence and count data from all unworn, fully erupted teeth (excluding third molars) using SOLAR (v.8.1.1). Age, sex, and age-sex interaction were included as covariates. Models were re-run with a household effect variable. Results LEH persists across generations in this study population with moderate, significant heritability estimates for presence in four teeth, and count in four teeth (three teeth were significant for both). When a household effect variable was added, no residual heritability remained for LEH count on any tooth. There was no significant household effect for three of the four teeth that had significant heritability estimates for LEH presence. Age was a significant covariate. Further analyses with birth year data revealed a secular trend toward less LEH. Conclusions This study provides evidence for familial risk of LEH (genetic and environmental) that has consequences for the broad use of this skeletal marker of stress. These results have repercussions for archaeological assemblages, or population health studies, where genetic relatives and household groups might be heavily represented.

Background Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke. Methods A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18–70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up. Results A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 (p

IntroductionPediatric thyroid carcinoma is a rare malignancy and data on long-term oncological outcomes are sparse. The aim of this study was to describe the long-term oncological outcomes of pediatric papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) in a national cohort, and to identify risk factors for recurrence.MethodsWe conducted a nationwide, retrospective cohort study, in which we combined two national databases. Patients aged Results133 patients were included: 110 with PTC and 23 with FTC. Patients with PTC most often presented with pT2 tumors (24%) and pN1b (45%). During a median follow-up of 11.3 years, 21 patients with PTC developed a recurrence (19%). Nineteen recurrences were regional (91%) and 2 were pulmonary (9%). No risk factors for recurrence could be determined. One patient who developed pulmonary recurrence died two years later. Cause of death was not captured. Patients with FTC most often presented with pT2 tumors (57%). One patient presented with pN1b (4%). In 70%, no lymph nodes were collected. None of the patients with FTC developed a recurrence or died.ConclusionPediatric PTC and FTC are two distinct diseases. Recurrence in pediatric PTC is common, but in FTC it is not. Survival for both pediatric PTC and FTC is very good.

Leptin is an adipocytokine secreted by adipocytes which positively correlates with obesity. It is considered as a potential mediator for precipitating Gestational diabetes mellitus (GDM) which is more evident during 24-28 weeks of gestation. This study was conducted to see serum leptin level during 24-28 weeks of gestation in GDM at the Department of Endocrinology, BSMMU, Bangladesh from March 2019 to August 2020. Pregnant women (N=108) were challenged with 75gm oral glucose (OGTT) at 24-28 weeks of gestation and divided into GDM [n=45, age: 27.80±3.98 years, mean±SD; BMI: 27.88 (24.46-30.43) kg/m², median Interquartile range (IQR)] and normal glucose tolerance [NGT; n=62, age: 26.19±5.30 years, mean±SD; BMI: 25.80 (23.65-28.42) kg/m², median (IQR)] on basis of WHO-2013 diagnostic criteria. Fasting serum leptin and glucose were measured by ELISA and glucose oxidase method respectively. No statistically significant difference was found between GDM and NGT for leptin [26.05(16.92-50.55) vs. 23.50(14.95-38.30) median (IQR), p=0.360]. It was also not different statistically between GDM and NGT either for age groups (p=NS for all) or for Asian categories of BMI subgroups (p=NS for all). However, it was higher in subjects with BMI ≥23kg/m² than that with BMI ≤23kg/m² for both GDM [16.65 (6.39, 35.75) vs. 28.35 (19.60, 51.10) median (IQR), p=0.114] and NGT [14.65(9.19, 19.60) vs. 26.00 (17.30, 43.40) median (IQR), p=0.002]. It was also statistically similar in the GDM subgroups divided by Asian BMI cut-off (p=NS). BMI correlated with leptin in NGT (r=0.495, p0.001) but not in GDM (r=0.177, p=0.251) and regression analysis revealed BMI (kg/m²) as predictor for high leptin (p=0.008). ROC curve analysis for leptin showed AUC for GDM was 0.553 (p=0.360) suggesting it as a poor predictor. It is concluded that fasting leptin in 24-28 weeks of gestation better relates with BMI but does not differ between GDM and NGT anddoes not seem to be a good predictor for GDM. Further study is required to make a comment on its prediction over GDM.

Aims: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double‐blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin‐converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan. Methods: We performed genome‐wide association studies in 2727 patients of European ancestry from CHARM‐Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan‐treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome‐wide gene‐level collapsing analysis from whole‐exome sequencing data with the composite cardiovascular endpoint. Results: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM‐Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55–2.35; P = 1.7 × 10−9). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome‐wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene‐level collapsing analysis. Conclusions: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings.

Metaiodobenzylguanidine (MIBG) labeled with radioisotopes can be used for diagnosticsThyroid function and uptake ofAfter a median follow-up of 6.6 years, thyroid function was normal in 46 of 48 survivors (95.8%). Two survivors [prevalence 4.2% (95% CI 1.2-14.0)] had mild thyroid dysfunction. In 29.2% of the patients and 11.1% of imagesThe prevalence of thyroid dysfunction does not seem to be increased in patients with neuroblastic tumors who received

Purpose Many patients with lung cancer are inactive due to their disease and underlying comorbidities, and activity levels can decline further during cancer therapy. Here we explore dosimetric predictors of activity decline in a cohort of patients who underwent continuous activity monitoring during definitive concurrent chemoradiotherapy (CRT) for locally advanced lung cancer. Methods and Materials We identified patients who participated in prospective clinical trials involving the use of a commercial fitness tracker throughout the course of CRT. For each patient, we applied linear regression to log-transformed daily step counts to compute the weekly rate of activity change from 1 week before radiation therapy (RT) initiation to 2 weeks after RT completion. Clinical and dosimetric factors were tested as predictors of activity change using linear regressions. Results Forty-six patient met the eligibility criteria. Median age was 66 years (range, 38-90). Pretreatment Eastern Cooperative Oncology Group performance status was 0, 1, and 2 for 17%, 70%, and 13%, respectively. Mean lung dose ranged from 5.0 to 23.5 Gy, mean esophagus dose from 1.1 to 39.6 Gy, and mean heart dose from 0.6 to 31.5 Gy. Median daily step count average was 5861 (interquartile range, 3540-8282) before RT and 3422 (interquartile range, 2364-5395) 2 weeks after RT completion. Rate of activity change was not significantly associated with age, performance status, or mean RT dose received by lungs or esophagus. In multivariate analysis, mean heart dose was significantly associated with rate of activity decline, with a 3.1% reduction in step count per week for every 10 Gy increase in mean heart dose (95% confidence interval: 0.5-5.7, P = .023). Conclusions Extent of cardiac irradiation is associated with the rate of physical activity decline during CRT for lung cancer. Our novel finding contributes to the growing body of evidence that adverse effects of cardiac irradiation may be manifested at early time points.

Objective: Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C. Design and methods: In the present study, we evaluated 11 years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm. Results: Between 2007 and the end of 2017, 1 963 465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C cases by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%. Conclusion: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.

This study compared self-report logbooks of exercise performance to objective measures of performance to determine the accuracy of and patterns of misreporting in self-report logbooks in people with Parkinson's disease.Fifteen participants from the intervention arm of a randomized control trial were prescribed a minimally supervised, 12-week, home-based upper limb exergame program (ACTRN 12614001048673). The exergame system provided an objective electronic measure of adherence for comparison with self-report logbooks.Logbooks showed excellent to good accuracy of overall reported adherence to prescribed sessions (Intraclass correlation (ICC) = 0.83) and games (ICC 0.71). Logbooks were also a good to fair representation of weekly adherence across participants for both sessions (ICC 0.66) and games (ICC 0.56). Individual participant ICCs ranged from minimal to perfect agreement between logbooks and electronic records (ICC sessions range: -0.02 to 1; games range: -0.24 to 0.99). The pattern of logbook reporting suggested some participants were biasing entries to match prescribed exercise.Self-report logbooks may provide an accurate measure of overall adherence. However, the accuracy of individual logbooks was highly variable indicating caution is needed in using self-report measures to assess individual adherence in intervention studies and for clinical decision making.

While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.

OBJECTIVES This study generates a series of narrow-sense heritability estimates for crown morphology of the deciduous and permanent dentition with two overarching aims. The first is to test the hypothesis that deciduous teeth provide a more faithful reflection of genetic information than their permanent successors. The second is to use quantitative genetic methods to evaluate assumptions underlying common data collection and analysis practices in biodistance research. MATERIALS AND METHODS Dental morphology data were collected from longitudinal dental casts representing Australian twins and families using Arizona State Dental Anthropology System standards. Polygenic models and estimates of narrow-sense heritability were generated using SOLAR v.8.1.1. Each model considered age, sex, and age/sex interaction as covariates. RESULTS Heritability estimates significantly differed from zero for the majority of morphological crown characters. Most estimates fell within the 0.4-0.8 range typically observed for crown morphology. Mean heritability was stable across the dental complex, but for paired homologues, permanent traits often yielded higher estimates than their deciduous counterparts. Results indicate directional asymmetry in environmental influence for crown morphology and inform biodistance "best practices" related to data collection and treatment. CONCLUSIONS Overall, results for this sample support the use of crown morphology as a proxy for genetic variation in evolutionary research. This includes the deciduous dentition, which justifies the expansion of efforts to incorporate subadults into reconstructions of past microevolutionary processes. Results do not indicate that deciduous phenotypes more closely approximate underlying genotype, at least for deciduous/permanent homologues.

Highlights • Emotions comprise conscious, behavioural, physiological and cognitive elements. • Neural correlates of conscious emotion can be investigated in humans and animals. • Contemporary theories of consciousness have differing implications for animals., The componential view of human emotion recognises that affective states comprise conscious, behavioural, physiological, neural and cognitive elements. Although many animals display bodily and behavioural changes consistent with the occurrence of affective states similar to those seen in humans, the question of whether and in which species these are accompanied by conscious experiences remains controversial. Finding scientifically valid methods for investigating markers for the subjective component of affect in both humans and animals is central to developing a comparative understanding of the processes and mechanisms of affect and its evolution and distribution across taxonomic groups, to our understanding of animal welfare, and to the development of animal models of affective disorders. Here, contemporary evidence indicating potential markers of conscious processing in animals is reviewed, with a view to extending this search to include markers of conscious affective processing. We do this by combining animal-focused approaches with investigations of the components of conscious and non-conscious emotional processing in humans, and neuropsychological research into the structure and functions of conscious emotions.

Pathogenic variants in

Osteoarthritis (OA) is a chronic, progressive disease involving the degeneration of cartilage and joint tissue, resulting in pain and disability. Bilateral total knee arthroplasty (TKA) is is an effective intervention that improves quality of life, reduces pain and increases functional capability. This study was performed to compare the functional outcomes between staged and simultaneous total knee arthroplasty. This prospective interventional study was carried out in Arthroscopic and Arthroplasty unit of BSMMU, Dhaka from January 2017 to December 2018. A total of 60 OA patients underwent TKA were included in this study. Thirty patients underwent simultaneous TKA procedure and 30 patients underwent staged TKA procedures performed with 1-6 months between stages were included. Pre-operative and post operative data were collected. Data were analyzed using SPSS 12.0. Numerical data were analyzed using unpaired t test and categorical data were analyzed using Chi-Square test. A value of p0.05 was considered statistically significant. Mean age of the study subjects was 60.47±10.13 years in staged group and 59.30±9.90 years in simultaneous group. Male to female ratio was 1:1.5 in staged group and 1:2 in simultaneous group. Mean BMI of the study subjects was 30.70±4.91kg/m² in staged group and 30.06±4.79kg/m² in simultaneous group (p0.05). In both groups, maximum study subjects were housewife (33.3% vs. 33.3%). In staged group 13.3% and 16.7% in simultaneous group were heavy worker; 20.0% in staged group and 16.7% in simultaneous group were medium worker (p0.05). Pain, motion, stability and function were significantly changed after surgery comparing before surgery.Infection was observed in 10.0% cases in both groups. Stiffness was observed in 10.0% cases in staged group but in 6.7% cases in simultaneous group. Even final outcome showed better in simultaneous procedure, there was no significant difference between two procedures. The outcome of both simultaneous andstaged procedure of bilateral total knee replacement in Advanced Osteoarthritis is similar.

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation., Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women.

Background Multimorbidity is common in older adults and associated with high levels of illness burden and healthcare expenditure. The evidence base for how to manage older adults with multimorbidity is weak. Yoga might be a useful intervention because it has the potential to improve health-related quality of life, physical functioning, and several medical conditions. The British Wheel of Yoga’s Gentle Years Yoga© (GYY) programme was developed specifically for older adults, including those with chronic medical conditions. Data from a pilot trial suggested feasibility of using GYY in this population, but its effectiveness and cost-effectiveness remain uncertain. Methods This is a multi-site, individually randomised, superiority trial with an embedded process evaluation and an economic analysis of cost-effectiveness. The trial will compare an experimental strategy of offering a 12-week GYY programme against a control strategy of no offer in community-dwelling adults aged 65 or over who have multimorbidity, defined as having two or more chronic conditions from a predefined list. The primary outcome is health-related quality of life measured using the EQ-5D-5L, the primary endpoint being the overall difference over 12 months. Both groups will continue to be able to access their usual care from primary, secondary, community, and social services. Participants, care providers, and yoga teachers will not be blinded to the allocated intervention. Outcome measures are primarily self-reported. The analysis will follow intention-to-treat principles. Discussion This pragmatic randomised controlled trial will demonstrate if the GYY programme is an effective, cost-effective, and viable addition to the management of older adults with multimorbidity. Trial registration ISRCTN ISRCTN13567538. Registered on 18 March 2019

Context Central congenital hypothyroidism (CH) requires lifelong medical treatment. The majority of children with central CH have multiple pituitary hormone deficiencies (MPHD), but in some cases central CH is isolated. Most pituitary hormone deficiencies are associated with impaired health-related quality of life (HRQoL). However, studies on HRQoL in central CH are lacking. Objective To evaluate HRQoL and fatigue in children and young adults with central CH, as well as parent perspectives. Design Nationwide cross-sectional study comparing HRQoL between early-detected central CH patients and unaffected siblings with the Pediatric Quality of Life inventory (PedsQL™) and PedsQL Multidimensional Fatigue Scale. Participants ≥ 8 years old filled in self-reports; parents of participants aged 3 to 18 years filled in parent reports. Isolated central CH patients, MPHD patients, and siblings were compared using a linear mixed model and Tukey’s post hoc test. Results Eighty-eight patients and 52 siblings participated, yielding 98 self-reports and 115 parent reports. Isolated central CH patients (n = 35) and siblings showed similar scores on all subscales, both in the self-reports and parent reports. For MPHD patients (n = 53), self-reported scores were similar to those of siblings. Parent reported total HRQoL and fatigue scores were significantly poorer in MPHD patients compared with siblings (mean differences −10.2 and −9.4 points; P Conclusion Self-reported HRQoL scores in isolated central CH and MPHD patients were similar to siblings. However, parents reported significantly lower HRQoL and fatigue scores for MPHD patients, suggesting a difference in perceived limitations between MPHD patients and their parents.

BackgroundThyroidectomy is a treatment option in some benign thyroid disorders and the definitive treatment option for thyroid cancer. As postoperative mortality is extremely rare data on postoperative complications and long-term health consequences are important.ObjectiveTo evaluate the frequencies of short- and long-term complications, and their risk factors in pediatric patients (0-18 years) who underwent a thyroidectomy in a tertiary children’s hospital.MethodsA retrospective single center study was performed including all pediatric patients who underwent a thyroidectomy between January 2013 and February 2020.ResultsForty-eight patients were included in this study (mean age 14.6 years). Twenty-nine total thyroidectomies and 19 hemithyroidectomies were conducted. Thyroid carcinoma was the indication to perform a thyroidectomy in 12 patients, 36 patients underwent a thyroidectomy because of a benign thyroid disorder. Postoperative hypocalcemia was evaluated in patients who underwent a total thyroidectomy. Rapidly resolved hypocalcemia was observed in three patients (10.3%), transient hypocalcemia in 10 patients (34.5%) and permanent hypocalcemia in six patients (20.7%). Permanent hypocalcemia was only seen in patients who underwent a thyroidectomy combined with additional lymph node dissection because of thyroid carcinoma [thyroid carcinoma: OR 43.73, 95% CI (2.11-904.95); lymph node dissection: OR 76.14, 95% CI (3.49-458.98)]. Transient and permanent recurrent laryngeal nerve injury was reported in four (8.3%) and one (2.1%) of all patients, respectively.ConclusionPermanent postoperative complications after thyroidectomy are rare in pediatric patients undergoing a thyroidectomy without lymph node dissection. However, in this age group permanent hypocalcemia occurs more frequently after thyroidectomy with additional lymph node dissection because of thyroid cancer. With respect to quality of life, especially of pediatric thyroid cancer patients, reducing this complication is an important goal.

Background Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. Methods We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. Results We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Conclusions Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1,TBL1X,IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.

Good translatability of behavioral measures of affect (emotion) between human and nonhuman animals is core to comparative studies. The judgment bias (JB) task, which measures “optimistic” and “pessimistic” decision-making under ambiguity as indicators of positive and negative affective valence, has been used in both human and nonhuman animals. However, one key disparity between human and nonhuman studies is that the former typically use secondary reinforcers (e.g., money) whereas the latter typically use primary reinforcers (e.g., food). To address this deficiency and shed further light on JB as a measure of affect, we developed a novel version of a JB task for humans using primary reinforcers. Data on decision-making and reported affective state during the JB task were analyzed using computational modeling. Overall, participants grasped the task well, and as anticipated, their reported affective valence correlated with trial-by-trial variation in offered volume of juice. In addition, previous findings from monetary versions of the task were replicated: More positive prediction errors were associated with more positive affective valence, a higher lapse rate was associated with lower affective arousal, and affective arousal decreased as a function of number of trials completed. There was no evidence that more positive valence was associated with greater “optimism,” but instead, there was evidence that affective valence influenced the participants' decision stochasticity, whereas affective arousal tended to influence their propensity for errors. This novel version of the JB task provides a useful tool for investigation of the links between primary reward and punisher experience, affect, and decision-making, especially from a comparative perspective.

Brain arteriovenous malformations (AVMs) are characterized by a high-pressure, low-resistance vascular nidus created by direct shunting of blood from feeding arteries into arterialized veins, bypassing intervening capillaries. AVMs pose a risk of spontaneous rupture because the vessel walls are continuously exposed to increased shear stress and abnormal flow phenomena, which lead to vessel wall inflammation and distinct morphologic changes. The annual rupture rate is estimated at 2%, and once an AVM ruptures, the risk of rerupture increases 5-fold. The ability of AVMs to grow, regress, recur, and undergo remodeling shows their dynamic nature. Identifying the underlying cellular and molecular pathways of AVMs not only helps us understand their natural physiology but also allows us to directly block vital pathways, thus preventing AVM development and progression. Management of AVMs is challenging and often necessitates a multidisciplinary approach, including neurosurgical, endovascular, and radiosurgical expertise. Because many of these procedures are invasive, carry a risk of inciting hemorrhage, or are controversial, the demand for pharmacologic treatment options is increasing. In this review, we introduce novel findings of cellular and molecular AVM physiology and highlight key signaling mediators that are potential targets for AVM treatment. Furthermore, we give an overview of syndromes associated with hereditary and nonhereditary AVM formation and discuss causative genetic alterations.

Congenital hypothyroidism is the most frequent endocrine disorder in newborns, occurring in 1 per 3000-4000 newborns. In the Netherlands, the neonatal screening program is based primarily on heel prick thyroxine (T4). In contrast to thyroid-stimulating hormone-based programs, this approach allows for the detection of both primary and central congenital hypothyroidism. Over the past decade, the identification of families with isolated congenital central hypothyroidism enabled the identification of novel genetic causes of this condition, in addition to mutations in the TSHβ-subunit gene and thyrotropin-releasing hormone receptor gene reported earlier. In 2012, loss-of-function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene, were reported as a genetic cause of a syndrome including X-linked congenital central hypothyroidism and adult macroorchidism. IGSF1 encodes a hypothalamic plasma membrane glycoprotein. Mutations in IGSF1 represent the most prevalent genetic cause of isolated central hypothyroidism to date. In 2016, mutations in the transducin β-like 1X (TBL1X) gene were identified in patients with a combination of mild central hypothyroidism and sensorineural hearing loss. TBL1X is an essential subunit of the NCoR/SMRT corepressor complex and expressed in many tissues including the human hypothalamus and pituitary. In 2018, mutations in the insulin receptor substrate 4 (IRS4) gene were reported in cases of familial isolated central hypothyroidism. IRS4 encodes a hypothalamic protein that is part of the insulin and leptin signaling cascade. These recent developments will broaden our understanding of the role of the hypothalamus in hypothalamus-pituitary-thyroid axis regulation and will help to improve diagnosis and treatment of isolated central hypothyroidism.

Rib fractures are associated with increased mortality, particularly in the elderly. While opiate-based pain regimens remain the cornerstone of rib fracture management, issues related to opioids have driven research into alternative analgesics. Adjunctive ketamine use in lieu of opioids continues to increase but little evidence exists to support its efficacy or safety within the elderly trauma population.A prospective, randomized, double-blind placebo-controlled trial of elderly patients (age, ≥65 years) with three or more rib fractures admitted to a Level I trauma center was conducted. Exclusion criteria included Glasgow Coma Scale score less than 14, and chronic opiate use. Groups were randomized to either low-dose ketamine (LDK) at 2 μg·kg·min or an equivalent rate of 0.9% normal saline. The primary outcome was reduction in numeric pain scores (NPS). Secondary outcomes included oral morphine equivalent (OME) utilization, epidural rates, pulmonary complications, and adverse events.Thirty (50.8%) of 59 were randomized to the experimental arm. Groups were similar in makeup. Low-dose ketamine failed to reduce 24-hour NPS or OME totals. Subgroup analysis of 24 patients with Injury Severity Score greater than 15 demonstrated that LDK was associated with a reduction in OME utilization the first 24-hours (25.6 mg vs. 42.6 mg, p = 0.04) but at no other time points. No difference in other secondary outcomes or adverse events was noted.Low-dose ketamine failed to affect NPS or OME within the overall cohort, but a decrease in OME was observed in those with an Injury Severity Score greater than 15. Additional studies are necessary to confirm whether LDK benefits severely injured elderly patients.Therapeutic, level I.

Previous investigations of falls predictors in people with Parkinson’s disease (PD) have used various statistical methods and categorization of falls outcomes. The impact of methodological differences on falls predictors has not been investigated. To describe similarities and differences in predictors modelled for fall rates [negative binomial (NB), Poisson Inverse Gaussian (PIG) and quantile regression] and previously-reported predictors of time to second fall (Cox regression), i.e. past falls, motor fluctuations, disability, levodopa dose and balance impairment. To investigate whether predictors from quantile regression vary across subsets of fallers based on fall frequency. Participants with PD (n = 229) were followed-up for 12 months. NB and PIG regression were used to determine predictors of fall rates, with the best fitting model reported. Quantile regression was used to determine predictors at higher (62nd, 70th, 80th) percentiles of the falls distribution. Univariate and multivariate analyses were performed. Predictors of fall rates were the same in NB and PIG multivariate models, with the PIG model fitting our data better. Past falls, disability and levodopa dose were associated with fall rates from PIG and quantile regression. Freezing of gait was associated with fall rates from PIG regression. Disease severity predicted less (70th percentile, approximately 2–4) and more (80th percentile, approximately ≥ 5) frequent falls, and anteroposterior stability also predicted less frequent falls (p

Background People with Parkinson disease (PD) are twice as likely to develop flexed truncal posture as the general older population. Little is known about the mechanisms responsible beyond associations with age, axial motor impairments, and disease severity. Objective The objective was to explore: (1) the associations of the nonmotor impairments of PD with flexed posture, and (2) the relationships of flexed posture with activity limitations. Design This was a cross-sectional study. Methods Seventy people with PD participated. Posture was measured in standing as the distance between the seventh cervical vertebra and a wall. Nonmotor impairments (cognition, depression, pain, fatigue, and proprioception) and activity performance (upper limb activity, bed transfers, respiratory function, and speech volume) were variously assessed using objective measures and self-report questionnaires. Univariate and multivariate regression analyses were performed to ascertain relationships between nonmotor impairments and truncal posture, and between truncal posture and activities. Results Greater disease severity, greater axial impairment, poorer spinal proprioception, greater postural fatigue, and male sex were significantly associated with flexed truncal posture. The multivariate model containing these factors in addition to age explained 30% of the variability in flexed truncal posture, with male sex and axial motor impairment continuing to make independent contributions. A significant association was found between greater flexed truncal posture and poorer upper limb activity performance and respiratory function. Limitations A limitation to this study was that participants had mild-to-moderate disease severity. Conclusions Spinal proprioception and postural fatigue were the only nonmotor impairments to make significant contributions to flexed posture. Given the negative influence of flexed posture on upper limb activity and respiratory function, interventions targeting spinal proprioception and postural awareness should be considered for people with PD who might develop flexed posture.

Orthogonal confirmation of next-generation sequencing (NGS)-detected germline variants is standard practice, although published studies have suggested that confirmation of the highest-quality calls may not always be necessary. The key question is how laboratories can establish criteria that consistently identify those NGS calls that require confirmation. Most prior studies addressing this question have had limitations: they have been generally of small scale, omitted statistical justification, and explored limited aspects of underlying data. The rigorous definition of criteria that separate high-accuracy NGS calls from those that may or may not be true remains a crucial issue. We analyzed five reference samples and over 80.000 patient specimens from two laboratories. Quality metrics were examined for approximately 200.000 NGS calls with orthogonal data, including 1662 false positives. A classification algorithm used these data to identify a battery of criteria that flag 100% of false positives as requiring confirmation (CI lower bound, 98.5% to 99.8%, depending on variant type) while minimizing the number of flagged true positives. These criteria identify false positives that the previously published criteria miss. Sampling analysis showed that smaller data sets resulted in less effective criteria. Our methodology for determining test- and laboratory-specific criteria can be generalized into a practical approach that can be used by laboratories to reduce the cost and time burdens of confirmation without affecting clinical accuracy.

OBJECTIVES This article presents estimates of narrow-sense heritability and bivariate genetic correlation for 14 tooth crown morphological variants scored on permanent premolars, first molars, and second molars. The objective is to inform data collection and analytical practices in dental biodistance and to provide insights on the development of molar crowns as integrated structures. MATERIALS AND METHODS African American dental casts from the Menegaz-Bock collection were recorded for the Arizona State University Dental Anthropology System. Estimates of narrow-sense heritability and genetic correlation were generated using SOLAR v.8.1.1, which included assessment of age, sex, and birth year as covariates. Both continuous scale and dichotomized estimates are provided. RESULTS Heritability estimates were nonsignificant for the majority of variables; however, for variables yielding significant estimates, values were moderate to high in magnitude and comparable to previous studies. Comparing left and right-side heritability estimates suggests directional asymmetry in the expression of environmental variance, something not seen in anterior tooth traits. Genetic correlations were moderate among antimeres and metameres and low for different traits scored on the same tooth crown. Although several negative correlations were noted, few reached statistical significance. Results affirm some of the current data cleaning and analytical practices in dental biodistance, but others are called into question. These include the pooling of males and females and combining left and right-side data into a single dataset. CONCLUSIONS In comparison to anterior tooth crown traits, postcanine heritabilities were more often non-significant; however, those traits with significant heritability also tended to produce higher estimates. Genetic correlations were unremarkable, in part, because they were underpowered. However, M1 results may provide insight into the complex relationship between genes, environment, and development in determining ultimate crown form.

Approximately 15% of globally diagnosed breast cancers are designated as triple negative breast cancer (TNBC). In this study, we investigated the effect of the natural compound, Bis(2- ethyl hexyl) 1H-pyrrole-3,4-dicarboxylate (TCCP), purified from Tinospora cordifolia on MDA-MB-231, a TNBC cell line. The pro-apoptotic nature of TCCP on MDA-MB-231 was determined by assessing various apoptotic markers. ROS generation, intracellular calcium, mitochondrial membrane potential (ΔΨm), MPTP, cardiolipin peroxidation and caspase activity were determined fluorometrically. BAX, BCL-2, cytochrome c, caspases, and p53 protein expressions were determined by immunoblotting. Further, the effect of TCCP on DNA and cell death was determined by DNA fragmentation assay, annexin-V staining, and cell cycle analysis. TCCP treatment caused endogenous ROS generation, increase in intracellular calcium and phosphorylation of p53 in a concentration-dependent manner, which was reverted upon pre-treatment with pifithrin-μ. This led to the downstream altered expression of Bcl-2 and Bax proteins, mitochondrial membrane depolarization, MPTP, and cardiolipin peroxidation. TCCP induced cytochrome c release into the cytosol, caspase activation, ultimately resulting in DNA fragmentation. Further, induction of apoptosis and morphological alterations were evident from the phosphatidylserine externalization and increase in sub G1 population. The in vivo Ehrlich ascites tumor (EAT) mouse study revealed the effectiveness of TCCP in reducing the tumor burden and resulted in a ~2 fold increase in mice survival with minimal hepato-renal toxicity. Overall, TCCP was shown to be efficient in inducing ROS and mitochondrial-mediated apoptosis by restoring p53 activity in MDA-MB-231 cells and also induced EAT cell death in vivo thereby inhibiting tumor proliferation.

Purpose: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. Experimental Design: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function. Results: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. Conclusions: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. See related commentary by Grivas, p. 907