Distinct and shared genetic architectures of Gestational diabetes mellitus and Type 2 Diabetes Mellitus.

Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 diabetes (T2D). The diseases are hypothesized to share a genetic predisposition, but there are few GWAS studies of GDM and none of them is sufficiently powered to assess whether any variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen Study and identified 13 GDM-associated loci including 8 novel loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into two distinct categories - one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis, and placental expression. These results pave the way for an improved biological understanding of GDM pathophysiology and its role in the development and course of T2D.

Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs.

Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a canine monoclonal antibody (mAb), binds NGF and inhibits its interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. The objective of three integrated laboratory studies was to demonstrate the safety of bedinvetmab in adult laboratory Beagle dogs. Daily health, veterinary, clinical pathology, systemic exposure, and anti-drug antibody evaluations were performed. Study 1 additionally included electrocardiography, neurologic, and ophthalmic assessments, and radiographic monitoring of joints of the appendicular skeleton. Study 2 evaluated T-lymphocyte-dependent immune function. Study 3 evaluated the safety of short-term concurrent administration of carprofen, a nonsteroidal anti-inflammatory drug (NSAID), with bedinvetmab. Studies 1 and 3 included terminal pathology and histopathology evaluations. Study designs and procedures included directed complementary morphologic and functional evaluations of a literature- and in vitro-based list of potential safety issues related to the NGF signaling pathway and characteristics engineered into this mAb. Screening-level general procedures evaluated effects associated with mAbs that target and inhibit soluble agonist cytokines. There were no treatment-related adverse changes in clinical evaluations, clinical neurological and ophthalmic examinations, joints, immune morphology or function, and no effects of short-term concurrent NSAID usage. Treatment-emergent immunogenicity was not observed. Bedinvetmab (1 mg/kg SC monthly; 3× and 10× dose multiples) was well tolerated in normal laboratory Beagle dogs for 6 months and with 2 weeks' concurrent NSAID administration.

Physics-informed machine learning: case studies for weather and climate modelling.

Machine learning (ML) provides novel and powerful ways of accurately and efficiently recognizing complex patterns, emulating nonlinear dynamics, and predicting the spatio-temporal evolution of weather and climate processes. Off-the-shelf ML models, however, do not necessarily obey the fundamental governing laws of physical systems, nor do they generalize well to scenarios on which they have not been trained. We survey systematic approaches to incorporating physics and domain knowledge into ML models and distill these approaches into broad categories. Through 10 case studies, we show how these approaches have been used successfully for emulating, downscaling, and forecasting weather and climate processes. The accomplishments of these studies include greater physical consistency, reduced training time, improved data efficiency, and better generalization. Finally, we synthesize the lessons learned and identify scientific, diagnostic, computational, and resource challenges for developing truly robust and reliable physics-informed ML models for weather and climate processes. This article is part of the theme issue 'Machine learning for weather and climate modelling'.

Optimizing Opioid Pain Medication Use After Vasectomy-A Prospective Study.

OBJECTIVE: To act as good stewards, urologists need to balance patient's pain requirements against the risk of narcotic abuse. MATERIALS AND METHODS: We prospectively consented subjects who underwent vasectomies. Procedural technique was not standardized. All subjects received hydrooxycodone/acetaminophen 5-325 mg tablets and Ibuprofen 800 mg tablets. The subjects were then contacted by phone 1-3 weeks after their procedure with a follow-up questionnaire. Data collected included age, weight, number of pills used and pills remaining, number of days pain medication used, need for additional medication, pain treatment satisfaction, disposal knowledge, and complications. RESULTS: A total of 76 subjects completed the study. Overall, 88.3% rated excellent pain treatment satisfaction with score ⩾4 (scale 1-5). No opioid medication was used by 18.2% of subjects, 33.8% used 1-5 tablets, and 24.7% used all 15 tablets. At the end, 9 subjects (11.7%) reporting needing more pain medication. Using Pearson correlation, younger age was significantly related to number of pills used. (P <.001) In total, 648 additional narcotic tablets were prescribed. In terms of disposal, 20 (25.9%) subjects disposed of extra medication, 14 (24.7%) used all medication, and 50.6% did not dispose of medication. Proper disposal technique was known by 50 (64.9%) subjects. CONCLUSION: Opioid medication use after vasectomy is variable though correlated with age. Clinicians should weigh the need versus potential abuse to determine the amount of tablets they are comfortable prescribing. Counseling and documentation on proper use and disposal of opioid medication is strongly encouraged.

A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders.

Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic-rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS.

Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.

BACKGROUND: Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. METHODS: We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. RESULTS: Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. CONCLUSIONS: Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.

iPTF16geu: A multiply imaged, gravitationally lensed type Ia supernova.

We report the discovery of a multiply imaged, gravitationally lensed type Ia supernova, iPTF16geu (SN 2016geu), at redshift z = 0.409. This phenomenon was identified because the light from the stellar explosion was magnified more than 50 times by the curvature of space around matter in an intervening galaxy. We used high-spatial-resolution observations to resolve four images of the lensed supernova, approximately 0.3 arc seconds from the center of the foreground galaxy. The observations probe a physical scale of ~1 kiloparsec, smaller than is typical in other studies of extragalactic gravitational lensing. The large magnification and symmetric image configuration imply close alignment between the lines of sight to the supernova and to the lens. The relative magnifications of the four images provide evidence for substructures in the lensing galaxy.

Trends in the use of radiation therapy for stage IIA prostate cancer from 2004 to 2013: a retrospective analysis using the National Cancer Database.

BACKGROUND: Recent studies have shown a decrease in the overall use of radiation therapy in the treatment of prostate cancer over the past several decades, as well as a more conservative overall treatment approach. We aim to determine whether this trend continued from 2004 to 2013, and to determine whether there were changes in utilization for various types of radiation. METHODS: We conducted this retrospective study using the National Cancer Database. We identified 706 877 patients with sufficient treatment information diagnosed with stage IIA prostate cancer between 2004 and 2013. Logistic regression models were used to evaluate the yearly trend in radiation therapy utilization. RESULTS: There was a significant decline in the use of radiation therapy from 2004 to 2013, from 54.4% in 2004 to 34.5% in 2013 compared with all the other treatments. The use of external beam radiation therapy (EBRT) declined from 27.1% in 2004 to 25.0% in 2013, brachytherapy declined from 19.7% in 2004 to 6.1% in 2013, and combination therapy declined from 6.8% in 2004 to 2.6% in 2013. However, when considering only patients receiving radiation treatments, the use of EBRT steadily increased from 50.6% in 2004 to 74.0% in 2013, whereas the use of brachytherapy declined from 36.7% in 2004 to 18.2% in 2013. Finally, although the proportion of patients receiving combination radiation therapy initially declined from 2004 to 2009 (from 12.7 to 8.3%), there was little change in utilization from 2009 to 2013 (8.3 to 8.5%). CONCLUSIONS: There has been a significant decline in the use of overall radiation therapy, as well as for each radiotherapy modality, for the treatment of prostate cancer since 2004. For patients that are receiving radiation, the use of EBRT has increased while brachytherapy use has decreased. These data serve to encourage further analysis as to the causes of these trends and how they affect patient care.

Atom-scale compositional distribution in InAlAsSb-based triple junction solar cells by atom probe tomography.

The analysis by atom probe tomography (APT) of InAlAsSb layers with applications in triple junction solar cells (TJSCs) has shown the existence of In- and Sb-rich regions in the material. The composition variation found is not evident from the direct observation of the 3D atomic distribution and because of this a statistical analysis has been required. From previous analysis of these samples, it is shown that the small compositional fluctuations determined have a strong effect on the optical properties of the material and ultimately on the performance of TJSCs.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Contractures and muscle disease.

Contractures are one of a handful of signs in muscle disease, besides weakness and its distribution, whose presence can help guide us diagnostically, a welcome star on the horizon. Contractures are associated with several myopathies, some with important cardiac manifestations, and consequently are important to recognise; their presence may also provide us with a potential satisfying 'penny dropping' diagnostic moment.

Plastic and evolutionary responses to heat stress in a temperate dung fly: negative correlation between basal and induced heat tolerance?

Extreme weather events such as heat waves are becoming more frequent and intense. Populations can cope with elevated heat stress by evolving higher basal heat tolerance (evolutionary response) and/or stronger induced heat tolerance (plastic response). However, there is ongoing debate about whether basal and induced heat tolerance are negatively correlated and whether adaptive potential in heat tolerance is sufficient under ongoing climate warming. To evaluate the evolutionary potential of basal and induced heat tolerance, we performed experimental evolution on a temperate source population of the dung fly Sepsis punctum. Offspring of flies adapted to three thermal selection regimes (Hot, Cold and Reference) were subjected to acute heat stress after having been exposed to either a hot-acclimation or non-acclimation pretreatment. As different traits may respond differently to temperature stress, several physiological and life history traits were assessed. Condition dependence of the response was evaluated by exposing juveniles to different levels of developmental (food restriction/rearing density) stress. Heat knockdown times were highest, whereas acclimation effects were lowest in the Hot selection regime, indicating a negative association between basal and induced heat tolerance. However, survival, adult longevity, fecundity and fertility did not show such a pattern. Acclimation had positive effects in heat-shocked flies, but in the absence of heat stress hot-acclimated flies had reduced life spans relative to non-acclimated ones, thereby revealing a potential cost of acclimation. Moreover, body size positively affected heat tolerance and unstressed individuals were less prone to heat stress than stressed flies, offering support for energetic costs associated with heat tolerance. Overall, our results indicate that heat tolerance of temperate insects can evolve under rising temperatures, but this response could be limited by a negative relationship between basal and induced thermotolerance, and may involve some but not other fitness-related traits.

Effect of commercial cleansers on skin barrier permeability.

BACKGROUND: Addition of hydrophobically modified polymers (HMPs) to cleansers can reduce the negative impact of surfactant-based cleansers. In this study, the effects of a cleanser containing HMPs, a gentle lotion cleanser (GLC), water, and 1% sodium lauryl sulfate (SLS) on barrier permeability, were evaluated in vitro in pig skin and in vivo in humans. METHODS: Skin stratum corneum (SC) barrier function was quantitated by imaging fluorescence intensity of the sulforhodamine B (SRB) in a pig skin model system using 2-photon and conventional fluorescence confocal microscopy. Solutions containing SRB were applied to pig skin in Franz diffusion cells over a period of 2 h. Penetration of SRB into the skin was monitored from 2 µm to 38 µm. In vivo surfactant/cleanser penetration in human skin was determined using tape stripping. RESULTS: After 2 h, water, 1% SLS, and GLC, significantly increased SRB intensity at all depths measured. SRB intensity was reduced in the HMP-cleanser group compared with other groups at each depth. In vivo, the presence of HMP reduced SLS penetration as measured by tape stripping. CONCLUSION: The cleanser containing HMP prevented changes in SC permeability and surfactant penetration, indicating a protective effect on skin barrier properties.

Facial Onset Sensory and Motor Neuronopathy: Further Evidence for a TDP-43 Proteinopathy.

Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.

Experimental evolution for generalists and specialists reveals multivariate genetic constraints on thermal reaction norms.

Theory predicts the emergence of generalists in variable environments and antagonistic pleiotropy to favour specialists in constant environments, but empirical data seldom support such generalist-specialist trade-offs. We selected for generalists and specialists in the dung fly Sepsis punctum (Diptera: Sepsidae) under conditions that we predicted would reveal antagonistic pleiotropy and multivariate trade-offs underlying thermal reaction norms for juvenile development. We performed replicated laboratory evolution using four treatments: adaptation at a hot (31 °C) or a cold (15 °C) temperature, or under regimes fluctuating between these temperatures, either within or between generations. After 20 generations, we assessed parental effects and genetic responses of thermal reaction norms for three correlated life-history traits: size at maturity, juvenile growth rate and juvenile survival. We find evidence for antagonistic pleiotropy for performance at hot and cold temperatures, and a temperature-mediated trade-off between juvenile survival and size at maturity, suggesting that trade-offs associated with environmental tolerance can arise via intensified evolutionary compromises between genetically correlated traits. However, despite this antagonistic pleiotropy, we found no support for the evolution of increased thermal tolerance breadth at the expense of reduced maximal performance, suggesting low genetic variance in the generalist-specialist dimension.

Muscle diseases: mimics and chameleons.

Muscle diseases are not as common as headaches and funny turns in our general neurology clinics, but most of us will encounter them. We all pride ourselves on a methodical approach to clinical problems-discovering the where and what in neurological parlance-but any diagnostic process can unravel, particularly if one condition resembles another. Before we settle on a diagnosis, we need to ask ourselves, whether the 'ducks all line up' to avoid cases of mistaken identity.

Operating characteristics of follicle-stimulating hormone in azoospermic men.

OBJECTIVE: To validate factors predictive of nonobstructive azoospermia (NOA) and to determine the operating characteristics of FSH for predicting NOA. DESIGN: Retrospective cohort study. SETTING: Tertiary care military treatment facility. PATIENT(S): One hundred forty azoospermic males undergoing infertility evaluation. INTERVENTION(S): Standard evaluation included history and physical, hormonal workup, and genetic evaluation. Diagnostic testicular biopsy was offered to characterize patients as obstructive azoospermia (OA) or NOA. MAIN OUTCOME MEASURE(S): Semen volume, semen fructose, FSH, T, E2, PRL, testicular atrophy. RESULT(S): Seventy-eight of 140 azoospermic patients underwent a biopsy. The ability to predict NOA based on logistic regression was statistically significant for FSH and testicular atrophy. On multivariate analysis, only FSH remained predictive of NOA. The area under the FSH receiver operating characteristic curve was 0.847, which is significant. The cut point of FSH with the highest likelihood ratio of predicting NOA on biopsy was ≥12.3 mIU/mL. CONCLUSION(S): FSH remains the best predictor of NOA. With full knowledge of the operating characteristics of FSH in this population, a patient can be properly educated and treatment can be individualized, based on the specific risk associated with that subject's measured FSH.