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Aseptic meningitis, including culture negative and viral meningitis, contributes a significant health-care burden, including unnecessary antibiotic use and hospitalisation to treat possible bacterial meningitis. This study analysed aseptic meningitis hospitalisations in New Zealand (NZ) children over 29 years.In this population-based study, aseptic meningitis hospitalisations in NZ children15 years old were analysed from 1991 to 2020. Incident rate ratios were calculated using Poisson regression models. Variations in hospitalisations by age, year, sex, ethnicity, geographical region and socio-economic deprivation were analysed.There were 5142 paediatric aseptic meningitis hospitalisations from 1991 to 2020. Most were unspecified viral meningitis (64%), followed by enterovirus (29%). Hospitalisation rates varied annually with a median of 18.4/100 000 children including a peak in 2001 of 56.4/100 000 (51.7-61.6). From 2002 to 2019, rates increased by 8.4%/year (7.2-9.5%) in infants90 days old but decreased in all other age groups. In 2020, a reduction in hospitalisations to 9.6/100 000 (7.9-11.8) occurred, and in infants90 days old were 0.37 times expected. Hospitalisations were 1.50 times (1.49-1.68) higher in males than females; higher in children of Māori (P 0.001) and Pacific (P 0.001) versus European ethnicity; and higher for children living in the most (2.44 times, (2.16-2.75)) versus least deprived households; and in northern versus southern NZ.Aseptic meningitis hospitalisations increased in young infants during 29 years of surveillance, apart from 2020 when admissions reduced during the COVID-19 pandemic. In contrast, hospitalisations decreased in children aged1 year. Further investigation into reasons for higher admissions by ethnic group, geographical location and increased deprivation are required.

Purpose To assess ischemic adverse events following particle embolization when used as a second-line embolic to coil embolization for treatment of acute lower gastrointestinal bleeding(LGIB). Materials and Methods This single-institution retrospective study examined 154 procedures where embolization was attempted for LGIB. In 122 patients (64 males, mean age 69.9 years), embolization was successfully performed using microcoils in 73 procedures, particles in 34 procedures, and both microcoils and particles in 27 procedures. Particles were used as second-line only when coil embolization was infeasible or inadequate. Technical success was defined as angiographic cessation of active extravasation after embolization. Clinical success was defined as absence of recurrent bleeding within 30 days of embolization. Results Technical success for embolization of LGIB was achieved in 87.0% of cases (134/154), and clinical success was 76.1%(102/134) among technically successful cases. Clinical success was 82.2%(60/73) for coils alone and 68.9%(42/61) for particles +/- coils. Severe adverse events involving embolization-induced bowel ischemia occurred in 3 of 56 patients who underwent particle embolization +/- coils (5.3%) versus zero out of 66 patients when coils alone were used (P=0.09). In patients who had colonoscopy or bowel resection within 2 weeks of embolization, ischemic findings attributable to the embolization were found in 3 of 15 who underwent embolization with coils alone, versus 8 of 18 who underwent embolization with particles +/- coils (p=0.27). Conclusion Particle embolization for treatment of LGIB as second line to coil embolization was associated with a 68.9% clinical success rate and a 5.3% rate of ischemia-related adverse events.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Objective To report the 30-day outcomes of patients with perioperative SARS-CoV-2 infection undergoing surgery in the USA. Summary background data Uncertainty regarding the postoperative risks of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Methods As part of the COVIDSurg multicenter study, all patients aged ≥17 years undergoing surgery between January 1 and June 30, 2020 with perioperative SARS-CoV-2 infection in 70 hospitals across 27 states were included. The primary outcomes were 30-day mortality and pulmonary complications. Multivariable analyses (adjusting for demographics, comorbidities, and procedure characteristics) were performed to identify predictors of mortality. Results A total of 1,581 patients were included; more than half of them were males (n= 822, 52.0%) and older than 50 years (n=835, 52.8%). Most procedures (n=1,261, 79.8%) were emergent, and laparotomies (n= 538, 34.1%). The mortality and pulmonary complication rates were 11.0 and 39.5%, respectively. Independent predictors of mortality included age ≥70 years (OR 2.46, 95% CI [1.65-3.69]), male sex (2.26 [1.53-3.35]), ASA grades 3-5 (3.08 [1.60-5.95]), emergent surgery (2.44 [1.31-4.54]), malignancy (2.97 [1.58-5.57]), respiratory comorbidities (2.08 [1.30-3.32]), and higher Revised Cardiac Risk Index (1.20 [1.02-1.41]). While statewide elective cancelation orders were not associated with a lower mortality, a sub-analysis showed it to be associated with lower mortality in those who underwent elective surgery (0.14 [0.03-0.61]). Conclusions Patients with perioperative SARS-CoV-2 infection have a significantly high risk for postoperative complications, especially elderly males. Postponing elective surgery and adopting non-operative management, when reasonable, should be considered in the USA during the pandemic peaks.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = −0.05 educational years, 95% CI −0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers. CC BY 4.0Correspondence Address: Silventoinen, K.; University of Helsinki, P.O. Box 18, Finland; email: karri.silventoinen@helsinki.fi© 2021 The Authors

Purpose Proton pump inhibitor (PPI) use is a potential risk factor for hepatic encephalopathy (HE), but few studies have examined the effect on post-TIPS HE. The purpose of this study was to determine whether PPIs are associated with increased rates of post-TIPS HE in an independent patient cohort. Materials and methods This single-institution retrospective study analyzed 86 patients (54 male, mean age 58.2) following TIPS from 1/1/2017 to 12/31/2019. Dates of PPI usage and episodes of new or worsening HE were recorded. Poisson regression with generalized estimating equations was used to test for association between PPI use and post-TIPS HE and to test for dose dependence. Post-TIPS HE was also analyzed using the Andersen-Gill survival model for recurrent events. Results There were 1.88 episodes of new or worsening post-TIPS HE per person-year among 35 patients on uninterrupted PPIs therapy, 1.95 on PPIs and 0.94 off PPIs among 35 patients on intermittent therapy, and 0.47 among 16 patients never on PPIs. PPI use was significantly associated with post-TIPS HE in both univariable (incidence rate ratio (IRR) = 2.62; CI = 1.41–4.84; p = 0.002) and multivariable (IRR = 2.31; CI = 1.37–3.89; p = 0.002) regression. Analysis of only those patients on PPIs showed increased rates of HE with higher doses (IRR = 1.17 per 10 mg omeprazole equivalent; CI = 1.04–1.33; p = 0.011). Recurrent events survival analysis supported the association between PPI use and HE in univariable (hazard ratio (HR) = 2.17; CI = 1.19–3.95; p = 0.011) and multivariable (HR = 1.87; CI = 1.12–3.13; p = 0.017) analysis. Conclusion In an independent patient cohort PPI use was associated with increased rates of new or worsening post-TIPS HE.

Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere Z-disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. NEW & NOTEWORTHY Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.

De novo heterozygous variants in the brain-specific transcription factor Neuronal Differentiation Factor 2 (NEUROD2) have been recently associated with early-onset epileptic encephalopathy and developmental delay. Here, we report an adolescent with developmental delay without seizures who was found to have a novel de novo heterozygous NEUROD2 missense variant, p.(Leu163Pro). Functional testing using an in vivo assay of neuronal differentiation in Xenopus laevis tadpoles demonstrated that the patient variant of NEUROD2 displays minimal protein activity, strongly suggesting a loss of function effect. In contrast, a second rare NEUROD2 variant, p.(Ala235Thr), identified in an adolescent with developmental delay but lacking parental studies for inheritance, showed normal in vivo NEUROD2 activity. We thus provide clinical, genetic, and functional evidence that NEUROD2 variants can lead to developmental delay without accompanying early-onset seizures, and demonstrate how functional testing can complement genetic data when determining variant pathogenicity.

Background Glucose galactose malabsorption (GGM) is a congenital diarrheal disorder of intestinal Na+/glucose cotransport (SGLT1/SLC5A1). The required glucose and galactose-restricted diet has been well described in infancy, but long-term nutrition follow-up is limited. Aim To perform a comprehensive nutritional assessment on a cohort of patients with GGM to gain insights into the consumption patterns within the population. Methods A cross-sectional study examining dietary intake of a GGM cohort using prospective food records. The calories and nutrients of all foods, beverages, and condiments were analyzed with descriptive statistics and compared to intake patterns of age- and sex-matched NHANES groups. Results The six patients were 0.7–26 years old. Whole foods and vegetable fats were major parts of the diet, while dairy and added sweeteners were restricted. Compared to typical US intakes, mean macronutrient distribution was 88th percentile from fat, 18th percentile from carbohydrates, and 78th percentile from protein. Fructose consumption, as a proportion of total sugar intake, decreased with age, from 86.1 to 50.4%. Meanwhile, glucose consumption increased with age, from 13.8 to 48.6% of sugar intake. However, the actual amount of glucose consumed remained low, equivalent to 4th percentile of US consumption level. Galactose intake was marginal throughout life. Conclusions A GGM diet is a high-fat and high-protein/low-carbohydrate diet that is rich in fruits and vegetables but limited in dairy and added sugar. Relatively less fructose but more glucose is incorporated into the diet with age. Future studies should investigate the effects of the GGM diet on gut microbiome and long-term health. Supplementary Information The online version of this article (10.1007/s10620-020-06792-4) contains supplementary material, which is available to authorized users.

The ‘16Up’ study conducted at the QIMR Berghofer Medical Research Institute from January 2014 to December 2018 aimed to examine the physical and mental health of young Australian twins aged 16−18 years (N = 876; 371 twin pairs and 18 triplet sets). Measurements included online questionnaires covering physical and mental health as well as information and communication technology (ICT) use, actigraphy, sleep diaries and hair samples to determine cortisol concentrations. Study participants generally rated themselves as being in good physical (79%) and mental (73%) health and reported lower rates of psychological distress and exposure to alcohol, tobacco products or other substances than previously reported for this age group in the Australian population. Daily or near-daily online activity was almost universal among study participants, with no differences noted between males and females in terms of frequency or duration of internet access. Patterns of ICT use in this sample indicated that the respondents were more likely to use online information sources for researching physical health issues than for mental health or substance use issues, and that they generally reported partial levels of satisfaction with the mental health information they found online. This suggests that internet-based mental health resources can be readily accessed by adolescent Australians, and their computer literacy augurs well for future access to online health resources. In combination with other data collected as part of the ongoing Brisbane Longitudinal Twin Study, the 16Up project provides a valuable resource for the longitudinal investigation of genetic and environmental contributions to phenotypic variation in a variety of human traits.

Purpose: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody–drug conjugate (ADC). Experimental Design: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. Results: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. Conclusions: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.

Objective To evaluate predictors of stay-at-home order adoption among US states, as well as associations between order enactment and residents' mobility. Design We assess associations between state characteristics and adoption timing. We also assess associations between enactment and aggregate state-level measures of residents' mobility (Google COVID-19 Community Mobility Reports). Setting The United States. Participants Adoption population: 50 US states and District of Columbia. Mobility population: state residents using devices with GPS tracking accessible by Google. Intervention and exposures State characteristics: COVID-19 diagnoses per capita, 2016 Trump vote share, Republican governor, Medicaid expansion status, hospital beds per capita, public health funding per capita, state and local tax revenue per capita, median household income, population, percent residents 65 years or older, and percent urban residents. Mobility exposure: indicator of order enactment by March 29, 2020 (date of mobility data collection). Main outcome measures Order adoption timing: days since adoption of first order. Mobility: changes in mobility to 6 locations from February 6 to March 29, 2020. Results In bivariate models, order adoption was associated with COVID-19 diagnoses (hazard ratio [HR] = 1.01; 95% confidence interval [CI], 1.00 to 1.01), Republican governor (HR = 0.24; 95% CI, 0.13 to 0.44), Medicaid expansion (HR = 2.50; 95% CI, 1.40 to 4.48), and hospital capacity (HR = 0.43; 95% CI, 0.26 to 0.70), consistent with findings in the multivariate models. Order enactment was positively associated with time at home (beta (B) = 1.31; 95% CI, 0.35 to 2.28) and negatively associated with time at retail and recreation (B = -7.17; 95% CI, -10.89 to -3.46) and grocery and pharmacy (B = -8.28; 95% CI, -11.97 to -4.59) locations. Trump vote share was associated with increased mobility for 4 of 6 mobility measures. Conclusions and relevance While politics influenced order adoption, public health considerations were equally influential. While orders were associated with decreased mobility, political ideology was associated with increased mobility under social distancing policies.

PurposeParkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson’s Genetics Study seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression.ParticipantsIn the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA sample via traditional post.Findings to date65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions.Future plansWe plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.

To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date.Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment.A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%).The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies.Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.

The immune system during pregnancy teeters between maintaining fetal tolerance and providing protection against pathogens. Due to this delicate balance, pregnant women and their offspring often have increased susceptibilities to infection. During the first year of life, infant immunity against infection is mainly mediatedviapassively transferred maternal antibodies. However, our understanding of the route of transfer of the maternal antibodies for conferring protection to influenza A virus (IAV) infection in offspring is incomplete. Here we have demonstrated that offspring from IAV-infected mice were significantly protected against IAV infection. This remarkable increase in survival is mediatedviathe elevated maternal serum IgG1. By cross-fostering, we further showed that this enhanced host resistance was only achieved in mice born to and nursed by IAV-infected mothers. Collectively, our data suggest that the prolonged protection of offspring against IAV infection requires maternal IgG1 from both the placenta and breast milk.

Objective To describe a complex case involving the management of a dog with von Willebrand disease (vWD), active ehrlichiosis infection, nonregenerative anemia, and blood type incompatibility related to the Dal antigen. Case summary A 13-week-oldintact male Doberman Pinscher weighing 7.2 kg was presented to the emergency service for a previous hemorrhaging event and progressive nonregenerative anemia. The dog had received a fresh whole blood transfusion 8 days prior to presentation due to severe anemia. Upon presentation, the puppy was tachycardic, and his mucous membranes were pale. A CBC revealed a nonregenerative anemia with a PCV of 0.11 L/L (11%). von Willebrand factor deficiency was suspected and later confirmed. The dog's blood type was dog erythrocyte antigen (DEA) 1 positive, but cross-matching to 4 RBC units, both DEA 1 positive and negative, failed to yield any compatible units. Antibody against a possible Dal RBC antigen was suspected, and 11 blood donors (Dalmatians and Dobermans) were cross-matched to find 2 compatible donors. After an uneventful fresh whole blood transfusion, a bone marrow biopsy revealed a hypocellular bone marrow and erythroid hypoplasia. A SNAP4DxPlus test and subsequent polymerase chain reaction (PCR) testing were positive for Ehrlichia ewingii and E. canis. Treatment with doxycycline was started, and the PCV was 0.17 L/L (17%) at discharge. At the 1-week follow-up, the PCV was 0.24 L/L (24%), and the puppy was doing well. New or unique information provided This is a unique case of a dog presenting with several challenging disorders, including vWD resulting in hemorrhage, ehrlichiosis potentially contributing to a nonregenerative anemia, and a blood type incompatibility due to the Dal antigen. Doberman Pinschers have a high prevalence of vWD- and Dal-negative phenotype, which emphasizes the value of cross-matching and the recognition of antigen prevalence in specific breeds.

Marriage and parenthood are associated with alcohol use and use disorder (AUD), although they are confounded such that many studies struggle to identify their unique and/or causal effects. The present study utilized a genetically-informed discordant twin design that strengthens the putative causal role of marital and parental status in the presentation of AUD symptoms by using each individual’s co-twin as their own control while simultaneously modeling both predictors among men and women. Participants were 980 complete same-sex twin pairs from the Australian Twin Registry (M(age)=31.70 [SD=2.48]; 71% women). Marital status, parental status, and past year AUD symptoms were assessed via semi-structured interview. Three random-intercept generalized linear mixed models were fit in men and women including 1) marital status only, 2) parental status only, and 3) both marital and parental status; demographics, past year pregnancy, age of first drink, age of regular drinking, personality traits, and antisociality were included as covariates. Models tested for quasi-causal and familial effects. The sole-predictor marital status model (model 1) provided the best fit among men, while the simultaneous-predictor marital and parental status model (model 3) provided the best fit among women. Sole-predictor models showed familial effects of both predictors among men, and quasi-causal and familial effects of both predictors among women; the simultaneous-predictor model revealed familial effects of marital status only among men, and quasi-causal effects of parental status only among women. The present study elucidates important sex differences in the presentation of AUD among midlife adults in the context of notable developmental milestones.

BACKGROUND Long-term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. OBJECTIVE We investigated whether measures of asthma control and airway inflammation and remodelling differed by long-term FAO status in moderate-to-severe asthma. METHODS Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post-bronchodilator forced expired volume in one second (FEV1 )-to-forced vital capacity ratio below 0.70. RESULTS Sixty-two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow-up assessment (median interval 7.9 years; IQR: 5.4-8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long-term follow-up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long-term follow-up. Sputum eosinophils, ACQ and long-term FEV1 decline did not differ. Participants with incident FAO at long-term follow-up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1 , whereas baseline ASM was similar to those without FAO. CONCLUSION In moderate-to-severe asthma, long-term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long-term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline.

BackgroundDespite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG.MethodsParticipants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates.ResultsNeither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality.ConclusionsThese findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Objectives In 2014, the governor of New York announced the Ending the Epidemic (ETE) plan to reduce annual new HIV infections from 3000 to 750, achieve a first-ever decrease in HIV prevalence, and reduce AIDS progression by the end of 2020. The state health department undertook participatory simulation modeling to develop a baseline for comparing epidemic trends and feedback on ETE strategies. Methods A dynamic compartmental model projected the individual and combined effects of 3 ETE initiatives: enhanced linkage to and retention in HIV treatment, increased preexposure prophylaxis (PrEP) among men who have sex with men, and expanded housing assistance. Data inputs for model calibration and low-, medium-, and high-implementation scenarios (stakeholders’ rollout predictions, and lower and upper bounds) came from surveillance and program data through 2014, the literature, and expert judgment. Results Without ETE (baseline scenario), new HIV infections would decline but remain >750, and HIV prevalence would continue to increase by 2020. Concurrently implementing the 3 programs would lower annual new HIV infections by 16.0%, 28.1%, and 45.7% compared with baseline in the low-, medium-, and high-implementation scenarios, respectively. In all concurrent implementation scenarios, although annual new HIV infections would remain >750, there would be fewer new HIV infections than deaths, yielding the first-ever decrease in HIV prevalence. PrEP and enhanced linkage and retention would confer the largest population-level changes. Conclusions New York State will achieve 1 ETE benchmark under the most realistic (medium) implementation scenario. Findings facilitated framing of ETE goals and underscored the need to prioritize men who have sex with men and maintain ETE’s multipronged approach, including other programs not modeled here.

Scores on an optimistic-pessimistic personality scale have been associated with mortality, but optimism and pessimism scores are separable traits and it is unclear which has effects on health or longevity. The Life Orientation Test (LOT), containing items for optimism and pessimism, was included in a twin study on health of Australians aged over 50 in 1993–1995. After a mean of 20 years, participants were matched against death information from the Australian National Death Index. 1,068 out of 2,978 participants with useable LOT scores had died. Survival analysis tested for associations between separate optimism and pessimism scores and mortality from any cause, and from cancers, cardiovascular diseases or other known causes. Age-adjusted scores on the pessimism scale were associated with all-cause and cardiovascular mortality (Hazard Ratios per 1 standard deviation unit, 95% confidence intervals and p-values 1.134, 1.065–1.207, 8.85 × 10–5 and 1.196, 1.045–1.368, 0.0093, respectively) but not with cancer deaths. Optimism scores, which were only weakly correlated with pessimism scores (age-adjusted rank correlation = − 0.176), did not show significant associations with overall or cause-specific mortality. Reverse causation (disease causing pessimism) is unlikely because in that case both cardiovascular diseases and cancers would be expected to lead to pessimism.

The thioredoxin (Trx) system is an important enzyme family that regulates cellular redox homeostasis. Protein expression of Trx system family members has been assessed in various cancers and linked to various clinicopathological variables, disease progression, treatment response and survival outcomes but information is lacking in brain tumours. Expression of the system was therefore examined, by immunohistochemistry in different brain tumour types, adult and paediatric cases, to determine if expression was of importance to clinical outcome. Trx system proteins were expressed, to variable levels, across all brain tumour types with significant variations in expression between different tumour types/grades/regions. High Trx reductase (TrxR) expression was linked to worse prognosis across all cohorts. High cytoplasmic TrxR expression was significantly associated with adverse overall survival (OS) in adult glioblastoma (P = 0.027) and paediatric low-grade glioma (LGG) patients (P = 0.012). High expression of nuclear TrxR, cytoplasmic and nuclear Trx and Trx-interacting protein (TxNIP) was associated with improved OS in paediatric LGGs (P = 0.031, P P = 0.044 and P = 0.018, respectively). For patients with high-grade gliomas, both high cytoplasmic TrxR and Trx expression were associated with poor OS (P = 0.002 and P = 0.007, respectively). In medulloblastoma, high expression of cytoplasmic TrxR and Trx and nuclear Trx was associated with worse prognosis (P = 0.013, P = 0.033 and P = 0.007, respectively); with cytoplasmic TrxR and nuclear Trx remaining so in multivariate analysis (P = 0.009 and P = 0.013, respectively). The consistent finding that high levels of cytoplasmic TrxR are associated with a worse prognosis across all cohorts suggests that TrxR is an important therapeutic target in brain cancers.

Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids., Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.

ENIGMA-CNV Working Group: van der Meer, Dennis; Sonderby, Ida E; Kaufmann, Tobias; Walters, G Bragi; Abdellaoui, Abdel; Ames, David; Amunts, Katrin; Andersson, Micael; Armstrong, Nicola J; Bernard, Manon; Blackburn, Nicholas B; Blangero, John; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Bulow, Robin; Cahn, Wiepke; Calhoun, Vince D; Caspers, Svenja; Cavalleri, Gianpiero L; Ching, Christopher R K; Cichon, Sven; Ciufolini, Simone; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Dalvie, Shareefa; Dazzan, Paola; de Geus, Eco J C; de Zubicaray, Greig I; de Zwarte, Sonja M C; Delanty, Norman; den Braber, Anouk; Desrivieres, Sylvane; Di Forti, Marta; Doherty, Joanne L; Donohoe, Gary; Ehrlich, Stefan; Eising, Else; Espeseth, Thomas; Fisher, Simon E; Fladby, Tormod; Frei, Oleksandr; Frouin, Vincent; Fukunaga, Masaki; Gareau, Thomas; Glahn, David C; Grabe, Hans J; Groenewold, Nynke A; Gustafsson, Omar; Haavik, Jan; Haberg, Asta K; Hashimoto, Ryota; Hehir-Kwa, Jayne Y; Hibar, Derrek P; Hillegers, Manon H J; Hoffmann, Per; Holleran, Laurena; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jacquemont, Sebastien; Jahanshad, Neda; Jockwitz, Christiane; Johansson, Stefan; Jonsson, Erik G; Kikuchi, Masataka; Knowles, Emma E M; Kwok, John B; Le Hellard, Stephanie; Linden, David E J; Liu, Jingyu; Lundervold, Arvid; Lundervold, Astri J; Martin, Nicholas G; Mather, Karen A; Mathias, Samuel R; McMahon, Katie L; McRae, Allan F; Medland, Sarah E; Moberget, Torgeir; Moreau, Clara; Morris, Derek W; Muhleisen, Thomas W; Murray, Robin M; Nordvik, Jan E; Nyberg, Lars; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Michael J; Paus, Tomas; Pausova, Zdenka; Peralta, Juan M; Pike, Bruce; Prieto, Carlos; Quinlan, Erin Burke; Reinbold, Celine S; Reis Marques, Tiago; Rucker, James J H; Sachdev, Perminder S; Sando, Sigrid B; Schofield, Peter R; Schork, Andrew J; Schumann, Gunter; Shin, Jean; Shumskaya, Elena; Silva, Ana I; Sisodiya, Sanjay M; Steen, Vidar M; Stein, Dan J; Strike, Lachlan T; Tamnes, Christian K; Teumer, Alexander; Thalamuthu, Anbupalam; Tordesillas-Gutierrez, Diana; Uhlmann, Anne; Ulfarsson, Magnus O; van 't Ent, Dennis; van den Bree, Marianne B M; Vassos, Evangelos; Wen, Wei; Wittfeld, Katharina; Wright, Margaret J; Zayats, Tetyana; Dale, Anders M; Djurovic, Srdjan; Agartz, Ingrid; Westlye, Lars T; Stefansson, Hreinn; Stefansson, Kari; Thompson, Paul M; Andreassen, Ole A., [Importance] Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities., [Objective] To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance., [Design, Setting, and Participants] In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019., [Main Outcomes and Measures] The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort., [Results] Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks., [Conclusions and Relevance] These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders., This study is supported in part by grants U54 EB20403, R01MH116147, and R56AG058854 from the National Institutes of Health, grant 609020 from the European Union Seventh Framework Programme, and grants 223273 and 276082 from the Research Council Norway. Part of this work was performed using the Service for Sensitive Data (TSD), which is developed and operated by the TSD Service Groupand owned by the University of Oslo.

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.Genetic analyses of depression based on minimal phenotyping identify nonspecific genetic risk factors shared between major depressive disorder (MDD) and other psychiatric conditions, suggesting that this approach may have limited ability to identify pathways specific to MDD.

To compare early totally implantable central venous port catheter-related infection rates after inpatient vs outpatient placement and to determine whether the risk associated with inpatient placement is influenced by length of hospital stay.In this single-institution retrospective study, 5,301 patients (3,618 women; mean age 57 y) underwent port placement by interventional radiologists between October 2004 and January 2018. The 30-day infection rate was compared between inpatients and outpatients using survival analysis. Among inpatients, the effect of time from admission to port placement and from placement to discharge was analyzed using a survival regression tree.The 30-day infection rate was 3.6% (95% confidence interval [CI] = 1.9%-6.1%) among 386 inpatients and 1.0% (95% CI = 0.7%-1.3%) among 4,915 outpatients (hazard ratio [HR] = 3.6, 95% CI = 2.0-6.6, P.001). Inpatient placement was a significant risk factor after accounting for covariates in multivariate analysis (HR = 2.2, 95% CI = 1.0-4.7, P = .05) and controlling for demographic differences by propensity score matching (HR = 2.8, 95% CI = 1.0-7.8, P = .04). Infection rate was 11% (95% CI = 4.7%-22%) among 65 inpatients in whom time from admission to placement was ≥ 7 days, 5.1% (95% CI = 1.9%-11%) among 129 inpatients in whom admission to placement was7 days and time to discharge was3 days, and 0% (95% CI = 0%-2.1%) among 192 inpatients in whom admission to placement was7 days and time to discharge was ≤ 3 days (P.001).Inpatient port placement was associated with a higher risk of early infection. However, a clinical decision tree based on shorter length of stay before and after placement may identify a subset of hospitalized patients not at increased risk for infection.

Aim: Subthreshold syndromes (STS) frequently precede the onset of full-threshold syndromes (FTS) of the corresponding mental disorder (homotypic continuity). This study examines whether subthreshold conditions are comorbid and whether there is heterotypic continuity also between STS and FTS. Methods: Data were extracted from the Brisbane “19Up” cohort study of twins and siblings (N = 1838; 56% female) on individuals who (i) completed self-report ratings of depression-like (DLE), hypomanic-like (HMLE) and psychotic-like experiences (PLE) and (ii) were assessed for mood and psychotic FTS using the Composite International Diagnostic Interview (CIDI). Associations between STS and FTS were estimated using adjusted prevalence ratios (APR) and 95% confidence intervals (CI). Results: STS are prevalent, with 22% reporting DLE, 14% HMLE and 5% PLE; 7% reported >1 STS, with PLE most likely to demonstrate comorbidity. Individuals with DLE were likely to meet CIDI criteria for depression (APR: 3.71, 95% CI: 2.83, 4.89), hypo/mania (APR: 3.62, 95% CI: 2.21, 5.94) and psychotic disorders (APR: 1.74, 95% CI 1.08, 2.83). Individuals with HMLE were likely to meet CIDI criteria for depression (APR: 2.29, 95% CI: 1.58, 3.31) and hypo/mania (APR: 2.51, 95% CI: 1.29, 4.91); those with PLE were likely to meet criteria for hypo/mania (APR: 5.8, 95% CI: 1.90, 17.70) and psychotic disorders (APR: 17.27, 95% CI: 7.54, 39.65). Conclusions: The findings suggest that STS are common among young adults and show heterotypic as well as homotypic continuity with FTS and support the need for more trans-diagnostic research on the evolution of major mental disorders.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Publisher's version (útgefin grein), Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10− 9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes., 1000BRAINS: 1000BRAINS is a population-based cohort based on the Heinz-Nixdorf Recall Study and is supported in part by the German National Cohort. We thank the Heinz Nixdorf Foundation (Germany) for their generous support in terms of the Heinz Nixdorf Study. The HNR study is also supported by the German Ministry of Education and Science (FKZ 01EG940), and the German Research Council (DFG, ER 155/6-1). The authors are supported by the Initiative and Networking Fund of the Helmholtz Association (Svenja Caspers) and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 7202070 (Human Brain Project SGA1; Katrin Amunts, Sven Cichon). This work was further supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Program (grant 01ZX1314A to M.M.N. and S.C.), and by the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). 16p.11.2 European Consortium: B.D. is supported by the Swiss National Science Foundation (NCCR Synapsy, project grant Nr 32003B_159780) and Foundation Synapsis. LREN is very grateful to the Roger De Spoelberch and Partridge Foundations for their generous financial support. This work was supported by grants from the Simons Foundation (SFARI274424) and the Swiss National Science Foundation (31003A_160203) to A.R. and S.J. Betula: The relevant Betula data collection and analyses were supported by a grant from the Knut & Alice Wallenberg (KAW) to L. Nyberg. Brainscale: the Brainscale study was supported by the Netherlands Organization for Scientific Research MagW 480-04-004 (Dorret Boomsma), 51.02.060 (Hilleke Hulshoff Pol), 668.772 (Dorret Boomsma & Hilleke Hulshoff Pol); NWO/SPI 56-464-14192 (Dorret Boomsma), the European Research Council (ERC-230374) (Dorret Boomsma), High Potential Grant Utrecht University (Hilleke Hulshoff Pol), NWO Brain and Cognition 433-09-220 (Hilleke Hulshoff Pol). Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud university medical centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative has received supported from the participating departments and centres and from external grants, i.e., the Biobanking and Biomolecular Resources Research Infrastructure (the Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organisation for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant ‘Language in Interaction’, the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreements n° 602450 (IMAGEMEND), n°278948 (TACTICS), and n°602805 (Aggressotype) as well as from the European Community’s Horizon 2020 programme under grant agreement n° 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. COBRE: This work was supported by a NIH COBRE Phase I grant (1P20RR021938, Lauriello, PI and 2P20GM103472, Calhoun, PI) awarded to the Mind Research Network. We wish to express our gratitude to numerous investigators who were either external consultants to the Cores and projects, mentors on the projects, members of the external advisory committee and members of the internal advisory committee. Decode: The research leading to these results has received financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007–2013), EU-FP7 funded grant no. 602450 (IMAGEMEND) as well as support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no.115300 (EUAIMS). DemGene: Norwegian Health Association and Research Council of Norway. Dublin: Work was supported by Science Foundation Ireland (SFI grant 12/IP/1359 to Gary Donohoe and SFI08/IN.1/B1916-Corvin to Aidan C Corvin) and the European Research Council (ERC-StG-2015-677467). EPIGEN-UK (SMS, CL): The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health’s NIHR Biomedical Research Centres funding scheme. We are grateful to the Wolfson Trust and the Epilepsy Society for supporting the Epilepsy Society MRI scanner, and the Epilepsy Society for supporting CL. Haavik: The work at the K.G.Jebsen center for neuropsychiatric disorders at the University of Bergen, Norway, was supported by Stiftelsen K.G. Jebsen, European Community’s Seventh Framework Program under grant agreement no 602805 and the H2020 Research and Innovation Program under grant agreement numbers 643051 and 667302. HUNT: The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. HUNT-MRI was funded by the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, and the Norwegian National Advisory Unit for functional MRI. IMAGEN: The work received support from the European Union-funded FP6Integrated Project IMAGEN (Reinforcement-related behaviour in normal brain function and psychopathology) (LSHM-CT- 2007-037286), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network based stratification of reinforcement-related disorders) (695313), ERANID (Understanding the Interplay between Cultural, Biological and Subjective Factors in Drug Use Pathways) (PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (MR/N027558/1), the FP7 projects IMAGEMEND (602450; IMAging GEnetics for MENtal Disorders) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions) (MR/N000390/1), the Swedish Research Council FORMAS, the Medical Research Council, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc01ZX1311A; Forschungsnetz AERIAL), the Deutsche Forschungsgemeinschaft (DFG grants SM 80/7-1, SM 80/7-2, SFB 940/1). Further support was provided by grants from: ANR (project AF12-NEUR0008-01—WM2NA, and ANR-12-SAMA-0004), the Fondation de France, the Fondation pour la Recherche Médicale, the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA), the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Paris Sud University IDEX 2012; the National Institutes of Health, Science Foundation Ireland (16/ERCD/3797), USA (Axon, Testosterone and Mental Health during Adolescence; RO1 MH085772-01A1), and by NIH Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence. MCIC: This work was supported primarily by the Department of Energy DE-FG02-99ER62764 through its support of the Mind Research Network and the consortium as well as by the National Association for Research in Schizophrenia and Affective Disorders (NARSAD) Young Investigator Award (to SE) as well as through the Blowitz-Ridgeway and Essel Foundations, and through NWO ZonMw TOP 91211021, the DFG research fellowship (to SE), the Mind Research Network, National Institutes of Health through NCRR 5 month-RR001066 (MGH General Clinical Research Center), NIMH K08 MH068540, the Biomedical Informatics Research Network with NCRR Supplements to P41 RR14075 (MGH), M01 RR 01066 (MGH), NIBIB R01EB006841 (MRN), R01EB005846 (MRN), 2R01 EB000840 (MRN), 1RC1MH089257 (MRN), as well as grant U24 RR021992. NCNG: this sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr Einar Martens Fund, the K.G. Jebsen Foundation, the Research Council of Norway, to SLH, VMS and TE. The Bergen group was supported by grants from the Western Norway Regional Health Authority (Grant 911593 to AL, Grant 911397 and 911687 to AJL). NESDA: Funding for NESDA was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health.Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. NTR: The NTR study was supported by the Netherlands Organization for Scientific Research (NWO), MW904-61-193 (Eco de Geus & Dorret Boomsma), MaGW-nr: 400-07- 080 (Dennis van ‘t Ent), MagW 480-04-004 (Dorret Boomsma), NWO/SPI 56-464-14192 (Dorret Boomsma), the European Research Council, ERC-230374 (Dorret Boomsma), and Amsterdam Neuroscience. OATS: OATS (Older Australian Twins Study) was facilitated by access to Twins Research Australia, which is funded by a National Health and Medical Research Council (NHMRC) Enabling Grant 310667. OATS is also supported via a NHMRC/Australian Research Council Strategic Award (401162) and a NHMRC Project Grant (1045325). DNA extraction was performed by Genetic Repositories Australia, which was funded by a NHMRC Enabling Grant (401184). OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. PAFIP: PAFIP data were collected at the Hospital Universitario Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Carlos III Health Institute PIE14/00031 and SAF2013-46292-R and SAF2015-71526-REDT. We wish to acknowledge IDIVAL Neuroimaging Unit for imaging acquirement and analysis.We want to particularly acknowledge the patients and the BioBankValdecilla (PT13/0010/0024) integrated in the Spanish National Biobanks Network for its collaboration. QTIM: The QTIM study was supported by grants from the US National Institute of Child Health and Human Development (R01 HD050735) and the Australian National Health and Medical Research Council (NHMRC) (486682, 1009064). Genotyping was supported by NHMRC (389875). Lachlan Strike is supported by an Australian Postgraduate Award (APA). AFM is supported by NHMRC CDF 1083656. We thank the twins and siblings for their participation, the many research assistants, as well as the radiographers, for their contribution to data collection and processing of the samples. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, 01ZZ0403 and 01ZZ0701), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. Whole-body MR imaging was supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. StrokeMRI: StrokeMRI has been supported by the Research Council of Norway (249795), the South-Eastern Norway Regional Health Authority (2014097, 2015044, 2015073) and the Norwegian ExtraFoundation for Health and Rehabilitation. TOP: TOP is supported by the Research Council of Norway (223273, 213837, 249711), the South East Norway Health Authority (2017-112), the Kristian Gerhard Jebsen Stiftelsen (SKGJ‐MED‐008) and the European Community’s Seventh Framework Programme (FP7/2007–2013), grant agreement no. 602450 (IMAGEMEND). We acknowledge the technical support and service from the Genomics Core Facility at the Department of Clinical Science, the University of Bergen

OBJECTIVE. The purpose of this study was to assess the impact of relative sarcopenia with excess adiposity on mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS. In this single-institution retrospective study, patients underwent abdominal CT scans within 100 days before or 30 days after TIPS creation. Subcutaneous and visceral adipose tissue and muscle were segmented at the L3 vertebral level. Relative sarcopenia with excess adiposity was defined as the lowest sex-specific quartile of muscle area divided by muscle plus adipose. Dates of death, liver transplantation, TIPS occlusion, and hepatic encephalopathy (HE) after TIPS creation were identified. Mortality was evaluated using competing risks survival analysis. Number of HE episodes and time to first episode were analyzed using negative binomial regression and competing risks survival analysis, respectively. RESULTS. A total of 141 patients (91 men; mean age, 56 years) were included in this study. In univariate analyses, Model for End-Stage Liver Disease (MELD) score (hazard ratio [HR], 1.09 per point; CI, 1.05-1.13; p < 0.001) and relative sarcopenia with excess adiposity (HR, 2.70; CI, 1.55-4.69; p < 0.001) were significant risk factors for shorter survival after TIPS. In multivariate analysis, both MELD score (HR, 1.09; CI, 1.03-1.15; p = 0.003) and relative sarcopenia with excess adiposity (HR, 2.65; CI, 1.56-4.51; p < 0.001) were significant predictors of worse survival. The C-index at 30 days was 0.71 for MELD score, 0.72 for relative sarcopenia with excess adiposity, and 0.80 for a model including both. There was no association between relative sarcopenia with excess adiposity and number of HE episodes (incidence rate ratio, 1.08; CI, 0.49-2.40; p = 0.84) or time to first HE episode (HR, 0.89; CI, 0.51-1.54; p = 0.67). CONCLUSION. Relative sarcopenia with excess adiposity is a risk factor for mortality after TIPS and contributes additional prognostic information beyond MELD score.

Heat stress abatement strategies for pre-weaned dairy calves are seldom evaluated. An experiment was conducted to evaluate the effects of housing calves under a barn and provision of fans to calves housed under a barn on calfhood performance. The experiment was conducted in a dairy in southern Georgia, USA. Male Holstein calves (n = 60; 0 to 68 day of age) were assigned randomly at birth (day 0) to 1 of 3 treatments: hutch outdoors with 50% of its area covered with plywood (control = 20), hutch in a barn with no cooling (SH = 21), and hutch in a barn with ceiling fans (SHF = 19). Body weight (BW) was measured at birth, and total serum protein and wither-height were measured 24 to 48 h after birth. A sub-set of hutches was evaluated for air speed and temperature, and rectal temperature (RT) and respiratory frequency (RF) of calves housed in these hutches were measured at 0900 and 1500 h. Intakes of liquid feed (days 14 to 63) and starter (days 14 to 68) were recorded daily, BW and wither-height were measured weekly, and feed efficiency was calculated weekly. Blood was sampled on days 1, 14, 28, 42, 49, 52, 56, 58, 63, and 65 for the measurement of fatty acids, β-hydroxybutyrate, glucose, and insulin. The SHF treatment resulted in air velocity 0.56 to 0.83 m/s greater (P 0.01) than the control and SH treatments, respectively, whereas the control treatment resulted in air temperature 1.2 to 3.2 °C greater (P 0.01) than the SH and SHF treatments, respectively. The RT of calves in the control treatment was 0.1 to 1.1 °C greater (P ≤ 0.03) than the SH and SHF treatments, respectively, and the control treatment resulted in RF 39.4 to 60.2 mov/min greater (P 0.01) than the SH and SHF treatments, respectively. Treatment did not (P ≥ 0.27) affect feed efficiency and concentrations of metabolites and insulin, but calves in the control treatment were 2.6 cm shorter (P = 0.03) than calves in the SHF treatments at weaning. Provision of fans to calves housed under a barn reduced RT, RF, but only had a minute impact on wither-height.

Previous research has shown that self-reports of the amount of social support are heritable. Using the Kessler perceived social support (KPSS) measure, we explored sex differences in the genetic and environmental contributions to individual differences. We did this separately for subscales that captured the perceived support from different members of the network (spouse, twin, children, parents, relatives, friends and confidant). Our sample comprised 7059 male, female and opposite-sex twin pairs aged 18−95 years from the Australian Twin Registry. We found tentative support for different genetic mechanisms in males and females for support from friends and the average KPSS score of all subscales, but otherwise, there are no sex differences. For each subscale alone, the additive genetic (A) and unique environment (E) effects were significant. By contrast, the covariation among the subscales was explained — in roughly equal parts — by A, E and the common environment, with effects of different support constellations plausibly accounting for the latter. A single genetic and common environment factor accounted for between half and three-quarters of the variance across the subscales in both males and females, suggesting little heterogeneity in the genetic and environmental etiology of the different support sources.

Strategies to abate heat stress are seldom adopted for pre-weaned dairy calves and little is known about their effects on behavior and pain sensitivity of youngstock. Our objectives were to determine the effects of heat stress abatement on lying behavior and disbudding-related pain sensitivity, wound healing, and change in intake. Male Holstein calves (n = 60; 0 to 68 d of age) were assigned randomly at birth (d 0) to 1 of 3 treatments: hutch outdoors with 50% of its area covered with plywood (control = 20), hutch in a barn with no cooling (SH = 21), and hutch in a barn with ceiling fans (SHF = 19). Calves were fitted with lying-behavior loggers on the hind leg from d 1 to 68. On d 32 ± 8 (±SD), we disbudded calves using hot iron, 30 min after cornual nerves were blocked with lidocaine. Immediately before (0 h), and at 1, 2, and 3 h after disbudding, we evaluated calves for mechanical nociceptive threshold (MNT) and head (ear flick, head shake, head rubbing) and somatic (tail flicking, foot stamping, restlessness) behaviors. On d 1, 3, 7, and 14 after disbudding, we evaluated the MNT and, on d 7 and 14, we evaluated wound healing (1 = crust, 5 = exudate). We calculated the relative change in milk solids and starter intake from d 0 to 6 relative to disbudding compared with the average of the 72 h preceding the procedure. The lying time was 0.6 h/d greater for the SHF treatment compared with the SH treatment. The control treatment resulted in 3.2 and 4.1 more lying bouts per day than the SH and SHF treatments, respectively; consequently, the control treatment resulted in lying-bout duration 7.7 and 10.9 min/event shorter than the SH and SHF treatments, respectively. We did not detect an effect of treatment on the number of disbudding-related head and somatic behaviors and MNT. The odds of calves having abnormal wound was 3.5 and 3.2 times greater for the control treatment compared with the SH and SHF treatments, respectively. We did not detect an effect of treatment on the relative change in intake of milk solids and starter. Heat abatement improves the welfare of pre-weaned dairy calves and may hasten healing.

Steroid resistance in asthma has been associated with neutrophilic inflammation and severe manifestations of the disease. Macrolide add-on therapy can improve the quality of life and the exacerbation rate in refractory cases, possibly with greater effectiveness in neutrophilic phenotypes. The mechanisms leading to these beneficial effects are incompletely understood and whether macrolides potentiate the modulation of bronchial remodeling induced by inhaled corticosteroids (ICS) is unknown. The objective of this study was to determine if adding azithromycin to ICS leads to further improvement of lung function, airway inflammation and bronchial remodeling in severe asthma. The combination of azithromycin (10 mg/kg q48h PO) and inhaled fluticasone (2500 µg q12h) was compared to the sole administration of fluticasone for five months in a randomized blind trial where the lung function, airway inflammation and bronchial remodeling (histomorphometry of central and peripheral airways and endobronchial ultrasound) of horses with severe neutrophilic asthma were assessed. Although the proportional reduction of airway neutrophilia was significantly larger in the group receiving azithromycin, the lung function and the peripheral and central airway smooth muscle mass decreased similarly in both groups. Despite a better control of airway neutrophilia, azithromycin did not potentiate the other clinical effects of fluticasone.

Summary Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning., Graphical abstract, Highlights • GWAS identifies variants associated with fingerprint type across all digits • Fingerprint-associated genes are strongly enriched for limb development functions • Evi1 alters dermatoglyphs in mice by modulating limb rather than skin development • Fingerprint patterns are genetically correlated with hand and finger proportions, Genome-wide association scans in Han Chinese individuals and a trans-ethnic meta-analysis reveal genetic regions that are associated with specific fingerprint patterning; functional studies in mouse models confirm a role of EVI1 in early limb development and ridge patterning.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Background The Cox-Maze IV procedure is a proven surgical treatment for atrial fibrillation (AF). Previous studies on the procedure and its effect on left atrial mechanical function have yielded mixed results. Methods Sixty-four (64) patients underwent Cox-Maze IV at St Vincent’s Hospital, Melbourne between March 2010 and May 2016. Baseline characteristics were collected and outcomes assessed including rhythm analysis. Preoperative and postoperative transthoracic echocardiograms were reviewed. Results Fifty-seven (57) patients had complete follow-up with all clinical measures collected. The mean age was 71.1 ± 10.2 years, 63% being male. Fifty-eight per cent (58%) (33/57) of patients were in AF and 42% (24/57) in sinus rhythm (SR) at preoperative transthoracic echocardiography. Follow-up postoperative transthoracic echocardiography was performed at a mean of 2.3 ± 1.9 years. Nineteen (19) patients with a history of paroxysmal AF were in SR both preoperatively and postoperatively. In these patients, there was a significant decrease in Mitral A wave 0.63 ± 0.28 m/s (pre-op) vs 0.47 ± 0.29 m/s (post-op), p = 0.044. There was a significant decrease in left ventricular ejection fraction (LVEF) postoperatively 64.2 ± 9.7% vs 55.0 ± 12.9%, p = 0.005. At follow-up, 28% (16/57) were in AF, 61% (35/57) in SR, and 11% (6/57) in a paced rhythm. In a multivariate analysis, predictors of AF recurrence included higher LA volumes (p = 0.042) and younger age at surgery p = 0.030. Preoperative AF, sex and LVEF had no impact on AF recurrence. Conclusions The Cox-Maze IV procedure, while effective in converting patients to sinus rhythm, may reduce left atrial mechanical function in patients with paroxysmal AF.

Objective Lung shunt fraction studies using technetium-99 m macro aggregated albumin are routinely performed before yttrium-90 radioembolization regardless of underlying liver malignancy type. This study evaluates the role of lung shunt fraction studies in hepatocellular carcinoma compared to non-hepatocellular carcinoma liver tumors. Methods A single-institution retrospective analysis of all pre-yttrium-90 technetium-99 m macro aggregated albumin lung shunt fraction studies between November 2012 to March 2018 was performed. Patient variables including age, underlying malignancy, laboratory values, lung shunt fraction, and severity of liver disease were compared between hepatocellular carcinoma and non-hepatocellular carcinoma cases. Results A total of 734 technetium-99 m macro aggregated albumin studies were identified in 653 patients. Among these cases, the liver tumor was hepatocellular carcinoma in 368 (50.1%), colorectal cancer in 112 (15.3%), neuroendocrine tumor in 89 (12.1%), cholangiocarcinoma in 59 (8.0%), breast cancer in 27 (3.7%), and other metastatic malignancies in 79 (10.7%). The mean lung shunt fraction for non-hepatocellular carcinoma cases was 7.4%, which was significantly lower than the mean lung shunt fraction, 11.7%, for hepatocellular carcinoma cases (P = 0.0001). In only one non-hepatocellular carcinoma case was yttrium-90 radioembolization not pursued due to high lung shunt fraction (69.3%), wherein large scale shunting was grossly apparent on angiography in a patient with metastatic gastrointestinal stromal tumor. In comparison, the lung shunt fraction was too high to pursue radioembolization in 37 hepatocellular carcinoma cases (mean lung shunt fraction 35.1%). Conclusion Lung shunt fraction appears low among patients with non-hepatocellular carcinoma liver malignancies. Further analysis examining the necessity of pre-Y90 technetium-99 m macro aggregated albumin lung shunt fraction studies in patients with non-hepatocellular carcinoma malignancies is warranted, since a consolidated yttrium-90 radioembolization without prior lung shunt fraction evaluation could reduce resource consumption, improve workflows, and patient access.

Rationale and Objectives Requests for gastrostomy tube placement in patients on aspirin (ASA) 325 mg are common, particularly in patients following reconstructive surgery for head and neck cancer, but periprocedural guidelines and recommendations regarding management of high dose aspirin are inconsistent. The purpose of this study was to assess the bleeding risk of percutaneous gastrostomy tube placement in patients on ASA 325 mg. Materials and Methods This retrospective study of 213 patients who underwent image-guided “push” percutaneous gastrostomy tube placement compared rates of significant bleeding and other secondary outcomes (including all-cause mortality within 30 days, procedure-related mortality, bowel perforation, abdominal abscess, peritonitis, aspiration pneumonia, intraprocedural airway complications, and tube dislodgement) between patients maintained on ASA 325 mg and patients not on antiplatelet or anticoagulation therapy. Results No significant bleeding episodes occurred in patients on ASA 325 mg, compared to three episodes in patients not on ASA 325 mg (p = 0.37). A patient in each group had aspiration pneumonia possibly related to tube placement. There were no other notable secondary outcomes, including intraprocedural airway complications in this population with complex head and neck anatomy. Conclusion These findings suggest that holding ASA 325 mg in patients undergoing percutaneous gastrostomy tube placement is not necessary, especially in patients in whom holding ASA would pose considerable risk. Further multi-institutional longitudinal study is warranted to validate these results.

Men who have sex with men (MSM), regardless of HIV infection status, have an intestinal microbiome that is compositionally distinct from men who have sex with women (MSW) and women. We recently showed HIV-negative MSM have elevated levels of intestinal CD4+ T cells expressing CCR5, a critical co-receptor for HIV. Whether elevated expression of CCR5 is driven by the altered gut microbiome composition in MSM has not been explored. Here we used in vitro stimulation of gut Lamina Propria Mononuclear Cells (LPMCs) with whole intact microbial cells isolated from stool to demonstrate that fecal bacterial communities (FBCs) from HIV-positive/negative MSM induced higher frequencies of CCR5+ CD4+ T cells compared to FBCs from HIV-negative MSW and women. To identify potential microbial drivers, we related the frequency of CCR5+ CD4+ T cells to the abundance of individual microbial taxa in rectal biopsy of HIV-positive/negative MSM and controls, and Holdemanella biformis was strongly associated with increased frequency of CCR5+ CD4+ T cells. We used in vitro stimulation of gut LPMCs with the type strain of H. biformis, a second strain of H. biformis and an isolate of the closely related Holdemanella porci , cultured from either a HIV-positive or a HIV-negative MSM stool. H. porci elevated the frequency of both CCR5+ CD4+ T cells and the ratio of TNF-α/IL-10 Genomic comparisons of the 3 Holdemanella isolates revealed unique cell wall and capsular components, which may be responsible for their differences in immunogenicity. These findings describe a novel mechanism potentially linking intestinal dysbiosis in MSM to HIV transmission and mucosal pathogenesis.

Epistasis has rarely been shown among natural polymorphisms in human traits; this research using advanced computation and gene expression data reveals many instances of epistasis between common single nucleotide polymorphisms in humans, with epistasis and the direction of its effect replicating in independent cohorts. Although frequently demonstrated in model organisms and domesticated species, very few examples of epistasis — where the effect of one polymorphism on a trait depends on other polymorphisms present in the genome — have been demonstrated in humans. Using advanced computation and a gene expression study design, these authors reveal hundreds of instances of epistasis between common single nucleotide polymorphisms (SNPs) in humans. They show that epistasis and direction of its effect replicate in independent cohorts. Epistatic networks of three or more SNPs are shown to influence the expression levels of many genes, whereby one cis-acting SNP is modulated by several trans-acting SNPs. Epistasis is the phenomenon whereby one polymorphism’s effect on a trait depends on other polymorphisms present in the genome. The extent to which epistasis influences complex traits1 and contributes to their variation2,3 is a fundamental question in evolution and human genetics. Although often demonstrated in artificial gene manipulation studies in model organisms4,5, and some examples have been reported in other species6, few examples exist for epistasis among natural polymorphisms in human traits7,8. Its absence from empirical findings may simply be due to low incidence in the genetic control of complex traits2,3, but an alternative view is that it has previously been too technically challenging to detect owing to statistical and computational issues9. Here we show, using advanced computation10 and a gene expression study design, that many instances of epistasis are found between common single nucleotide polymorphisms (SNPs). In a cohort of 846 individuals with 7,339 gene expression levels measured in peripheral blood, we found 501 significant pairwise interactions between common SNPs influencing the expression of 238 genes (P

BackgroundThe heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample.MethodsData were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect.ResultsMDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66).ConclusionsNo meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

Objective Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. Methods Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9–16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery. Results Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7–74.9%) for TSH, 67.5% (59.8–75.3%) for fT4, 59.7% (54.4–65.0%) for fT3 and 48.8% (40.6–56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. Conclusion Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Objectives The heterogeneity and comorbidity of major mental disorders presenting in adolescents and young adults has fostered calls for trans-diagnostic research. This study examines early expressions of psychopathology and risk and trans-diagnostic caseness in a community cohort of twins and non-twin siblings. Methods Using data from the Brisbane Longitudinal Twin Study, we estimated median number of self-rated psychiatric symptoms, prevalence of subthreshold syndromes, family history of mood and/or psychotic disorders, and likelihood of subsequent trans-diagnostic caseness (individuals meeting diagnostic criteria for mood and/or psychotic syndromes). Next, we used cross-validated Chi-Square Automatic Interaction Detector (CHAID) analyses to identify the nature and relative importance of individual self-rated symptoms that predicted trans-diagnostic caseness. We examined the positive and negative predictive values (PPV; NPV) and accuracy of all classifications (Area under the Curve and 95% confidence intervals: AUC; 95% CI). Results Of 1815 participants (Female 1050, 58%; mean age 26.40), more than one in four met caseness criteria for a mood and/or psychotic disorder. Examination of individual factors indicated that the AUC was highest for subthreshold syndromes, followed by family history then self-rated psychiatric symptoms, and that NPV always exceeded PPV for caseness. In contrast, the CHAID analysis (adjusted for age, sex, twin status) generated a classification tree comprising six trans-diagnostic symptoms. Whilst the contribution of two symptoms (need for sleep; physical activity) to the model was more difficult to interpret, CHAID analysis indicated that four self-rated symptoms (sadness; feeling overwhelmed; impaired concentration; paranoia) offered the best discrimination between cases and non-cases. These four symptoms showed different associations with family history status. Conclusions The findings need replication in independent cohorts. However, the use of CHAID might provide a means of identifying specific subsets of trans-diagnostic symptoms representing clinical phenotypes that predict transition to caseness in individuals at risk of onset of major mental disorders.

The quantification of airway compliance ( Caw) is essential to the study of airway alterations in disease models. However, the required measurements of airway pressure and volume are difficult to acquire in mice. We hypothesized that the inflation limb of full-range pressure-volume (PV) curves could be used to quantify Caw, as it contains a segment where only the airway tree is distended. The study objective was to assess the feasibility of the approach by analysis of full-range PV curves previously collected in three mouse models: an elastase model of emphysema, a genetic model spontaneously developing emphysema (leukotriene C4 synthase knockout; LTC4S-KO), and a bleomycin model of lung fibrosis. Attempts to validate results included Caw change relative to respiratory system compliance (Δ Caw/Δ C), the minute work of breathing (mWOB), and the elastance at 20.5 Hz ( Ers_20.5) from prior respiratory mechanics measurements in the same subjects. Caw was estimated at 3% of total compliance in healthy mice or 2.3 ± 1 μL/cmH2O ( n = 17). The technique detected changes in models of respiratory obstructive and restrictive diseases relative to control mice as well as differences in the two emphysema models studied. The changes in Caw were consistent with those seen in Δ Caw/Δ C, mWOB, or Ers_20.5, with some variations according to the model, as well as with results reported in the literature in humans and mice. Direct Caw measurements in subjects as small as mice could prove useful to further characterize other respiratory disease models associated with airway remodeling or to assess treatment effects.

Biliary and urinary obstructions can be managed endoscopically or cystoscopically, surgically or by percutansous intervention or drainage. If the obtructed system is infected, emergent decompression is needed. Early recognition and treatment is paramount in both conditions. Acute cholangitis can present many different ways, from mild symptoms to fulminant sepsis. It is usually a result of ascending bacterial colonization and biliary obstruction resulting in bacterial overgrowth. Therefore, those patients with recent biliary instrumentation or previous biliary modification are at higher risk. Charcot's triad of fever, right upper quadrant abdominal pain, and jaundice is only seen in 50%-70% of patients. Fever is seen in over 90% of cases, pain is seen in 70% of cases, and jaundice is seen in 60% of cases. Altered mental status and hypotension are associated with severe cases. All 5 symptoms of fever, right upper quadrant abdominal pain, jaundice, altered mental status, and hypotension are referred to as Reynold's Pentad. Acute pyonephrosis can also present many different ways, from minimal symptoms to fulminant sepsis. Fever, chills, and flank pain are the classic symptoms, although some patients may be relatively asymptomatic. Pyonephrosis may present with a classic triad of fever, flank pain, and hydronephrosis, or simply hydronephrosis and sepsis. Pyonephrosis usually occurs as a result of urinary obstruction with either an ascending infection of the urinary tract or hematogenous spread of a bacterial pathogen as the culprit. Up to 75% of cases are related to urinary stone disease. Patients are at increased risk for pyonephrosis when they haven anatomic urinary tract obstruction, certain chronic diseases (diabetes meliitus and AIDS), or are immunosuppressed due to immunodeficiency or medications, (chronic steroid therapy).

ObjectiveNeuroticism is associated with poor health outcomes, but its contribution to the accumulation of health deficits in old age, i.e. frailty, is largely unknown. We aimed to explore associations between neuroticism and frailty cross-sectionally and over up to 29 years, and to investigate the contribution of shared genetic influences.MethodData were derived from the UK Biobank (UKB, n=502,631), the Australian Over 50’s Study (AO50, n=3,011) and the Swedish Twin Registry (SALT n=23,744, SATSA n=1,637). Associations between neuroticism and the Frailty Index were investigated using regression analysis cross-sectionally in UKB, AO50 and SATSA, and longitudinally in SALT (25-29y follow-up) and SATSA (6 and 23y follow-up). The co-twin control method was applied to explore the contribution of underlying shared familial factors (SALT, SATSA, AO50). Genome-wide polygenic risk scores for neuroticism in all samples were used to further assess whether common genetic variants associated with neuroticism predict frailty.ResultsHigh neuroticism was consistently associated with greater frailty cross-sectionally (adjusted β, 95% confidence intervals in UKB= 0.32, 0.32-0.33; AO50= 0.35, 0.31-0.39; SATSA= 0.33, 0.27-0.39) and longitudinally up to 29 years (SALT= 0.24; 0.22-0.25; SATSA 6y= 0.31, 0.24-0.38; SATSA 23y= 0.16, 0.07-0.25). When controlling for underlying shared genetic and environmental factors the neuroticism-frailty association remained significant, although decreased. Polygenic risk scores for neuroticism significantly predicted frailty in the two larger samples (meta-analyzed total β= 0.06, 0.05-0.06).ConclusionHigh neuroticism is associated with the development and course of frailty. Both environmental and genetic influences, including neuroticism-associated genetic variants, contribute to this relationship.