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Groin ultrasonography (US) has been used as an adjunct to inguinal hernia diagnosis, but there is limited evidence as to whether its use affects surgical decision-making. The primary aim of this study was to examine whether groin US affects surgical management of inguinal hernia; the secondary goal was to estimate the frequency of groin US ordered before surgical consultation.We performed a retrospective chart review of 400 consecutive patients aged older than 18 years referred to 1 of 4 general surgeons in Calgary, Alberta, for inguinal hernia between January 2014 and January 2015. Bilateral groin examinations were entered as separate entries into the database. Outcomes assessed included the frequency of groin US examinations performed within 1 year before the general surgery consultation, presence of inguinal hernia on clinical examination (CE), presence of inguinal hernia on groin US, and whether the hernia proceeded to herniorrhaphy.A total of 476 groins in the 400 patients (354 [88.5%] male; mean age 53.5 yr [standard deviation 15.2 yr]) were evaluated for a hernia during the study period. Groin US was performed before general surgery consultation in 336 cases (70.6%). Overall, 364 (76.5%) of the hernias were clinically palpable; of the 364, 220 (60.4%) had preconsultation US, even in the presence of a positive CE finding. Of the 112 groins that did not have a clinically palpable hernia, 103 (92.0%) underwent preconsultation US. Of the 476 groins, 315 (66.2%) underwent inguinal hernia repair: 310 (85.2%) of the 364 with clinically palpable hernias and 5 (4.8%) of the 103 with clinically negative findings but positive groin US findings. Surgical decision-making based on CE findings occurred in 390 cases (81.9%) overall, whereas surgery based on groin US findings alone occurred in 5 of 336 cases (1.5%).Routine groin US was frequently performed before general surgery consultation, whether a hernia was detectable on clinical examination or not. Positive groin US results alone infrequently affected whether the patient proceeded to surgery. Clinical examination findings played a larger role in surgical decision-making than groin US results. Eliminating the practice of routine groin US may provide considerable health care cost savings.

Neural oscillations may be sensitive to aspects of brain maturation such as myelination and synaptic density changes. Better characterization of developmental trajectories and reliability is necessary for understanding typical and atypical neurodevelopment. Here, we examined reliability in 110 typically developing children and adolescents (aged 9–17 years) across 2.25 years. From 10 min of magnetoencephalography resting-state data, normalized source spectral power and intraclass correlation coefficients were calculated. We found sex-specific differences in global normalized power, with males showing age-related decreases in delta and theta, along with age-related increases in beta and gamma. Females had fewer significant age-related changes. Structural magnetic resonance imaging revealed that males had more total gray, subcortical gray, and cortical white matter volume. There were significant age-related changes in total gray matter volume with sex-specific and frequency-specific correlations to normalized power. In males, increased total gray matter volume correlated with increased theta and alpha, along with decreased gamma. Split-half reliability was excellent in all frequency bands and source regions. Test–retest reliability ranged from good (alpha) to fair (theta) to poor (remaining bands). While resting-state neural oscillations can have fingerprint-like quality in adults, we show here that neural oscillations continue to evolve in children and adolescents due to brain maturation and neurodevelopmental change.

Background Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). Methods Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. Results Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. Conclusion Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.

Objective Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrum disorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex. Method This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and Western Australia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASD diagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex. Results During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases of childhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, there was an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling with CA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrence risk by sex. Conclusion The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in the context of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.

Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.

Season of birth has been hypothesized to be a risk factor for autism spectrum disorder (ASD). However, the evidence has been mixed and limited due to methodological challenges. We examine ASD birth trends for 5,464,628 births across 5 countries. ASD birth prevalence data were obtained from the International Collaboration for Autism Registry Epidemiology database, including children born in Denmark, Finland, Norway, Sweden, and Western Australia. Empirical mode decomposition and cosinor modeling were used to assess seasonality. We show seasonal variation in ASD births for the countries of Finland and Sweden. There was a modest increase in risk for children born in the fall and a modest decrease in risk for children born in the spring. Solar radiation levels around conception and the postnatal period were inversely correlated with seasonal trends in ASD risk. In the first multinational study of birth seasonality of ASD, there was evidence supporting the presence of seasonal trends in Finland and Sweden. The observations that risk was highest for fall births (i.e., conceived in the winter) and lowest for spring births (i.e., conceived in the summer), and sunlight levels during critical neurodevelopmental periods explained much of the seasonal trends, are consistent with the hypothesis that a seasonally fluctuating risk factor may influence risk of ASD. Electronic supplementary material The online version of this article (10.1007/s10654-019-00506-5) contains supplementary material, which is available to authorized users.

Recently approved vaccines have shown remarkable protection in limiting SARS-CoV-2 associated disease. However, immunologic mechanism(s) of protection, and how boosting alters immunity to wildtype and newly emerging strains, remains incompletely understood. Here we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike (S) glycoprotein (NVX-CoV2373) at two dose levels, administered as a one or two-dose regimen with a saponin-based adjuvant Matrix-M™. While antigen dose had minimal effects, boosting significantly altered the humoral response, driving unique vaccine-induced antibody fingerprints. Differences in antibody effector functions and neutralization were associated with protection in the upper and lower respiratory tract, pointing to compartment-specific determinants of protective immunity against infection. Moreover, NVX-CoV2373 elicited antibodies targeting emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease, but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. Funding: This work was funded by Operation Warp Speed. We thank Colin Mann and Kathryn Hastie for production of Spike antigens. We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for their support. We acknowledge support from the Ragon Institute of MGH, MIT and Harvard, the Massachusetts Consortium on Pathogen Readiness (Mass CPR), the NIH (3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, 1U01CA260476 – 01, CIVIC75N93019C00052), National Science Foundation Graduate Research Fellowship Grant No. #1745302, the Gates foundation Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV-001650), and the Musk Foundation. Conflict of Interest: NP, MGX, JHT, BZ, SM, AMG, MJM, ADP, GG, GS, and LE are current or past employees of Novavax, Inc. and have stock options in the company. GA is the founder of Serom Yx Systems, Inc. AZ is a current employee of Moderna, Inc. but conducted this work before employment.Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. YG, RC, MJG, CA, KMP, CL, DY, KB, MEM, JL, DM, CM, SS, FA, FK, EOS, DL, and MBF declare no competing interest. Ethical Approval: The work was conducted in accordance with a protocol approved by Texas Biomed’s Institutional Animal Care and Use Committee. All subjects signed informed consent and safety oversight was monitored by a data monitoring board.

Background Consumption of alcohol during pregnancy impacts fetal development and may lead to a variety of physical, cognitive, and behavioral abnormalities in childhood collectively known as fetal alcohol spectrum disorder (FASD). The FASD spectrum includes children with fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), and alcohol-related neurodevelopmental disorder (ARND). Children with a FASD or prenatal alcohol exposure (PAE) have impaired white matter, reduced structural volumes, impaired resting-state functional connectivity when measured with fMRI, and spectral hypersynchrony as infants. Magnetoencephalography (MEG) provides high temporal resolution and good spatial precision for examining spectral power and connectivity patterns unique from fMRI. The impact of PAE on MEG resting-state spectral power in children remains unknown. Methods We collected 2 minutes of eyes-open and eyes-closed resting-state data in 51 children (8 to 12 years of age) with 3 subgroups included: 10 ARND/PAE, 15 FAS/pFAS, and 26 controls (TDC). MEG data were collected on the Elekta Neuromag system. The following spectral metrics were compared between subgroups: power, normalized power, half power, 95% power, and Shannon spectral entropy (SSE). MEG spectral data were correlated with behavioral measures. Results Our results indicate children with FAS/pFAS had reduced spectral power and normalized power, particularly within the alpha frequency band in sensor parietal and source superior parietal and lateral occipital regions, along with elevated half power, 95% power, and SSE. We also found select hemisphere specific effects further indicating reduced corpus callosum connectivity in children with a FASD. Interestingly, while the ARND/PAE subgroup had significant differences from the FAS/pFAS subgroup, in many cases spectral data were not significantly different from TDC. Conclusions Our results were consistent with previous studies and provide new insight into resting-state oscillatory differences both between children with FAS and TDC, and within FASD subgroups. Further understanding of these resting-state variations and their impact on cognitive function may help provide early targets for intervention and enhance outcomes for individuals with a FASD.

Lack of food preparation knowledge, time to prepare meals and concerns about fruit and vegetable spoilage before consumption are the potential barriers to home cooking. These barriers may be addressed by meal kits (bundles of recipes and ingredients). We described home cooking barriers and evaluated acceptability of meal kits, using semi-structured focus groups with caregivers and adolescent patients of an outpatient paediatric weight management clinic. One meal kit per family, containing non-perishable food, a $20 gift card to a grocery store and recipes designed by clinic dietician for two meals, were given at clinic appointments. Two in-person semi-structured focus groups were conducted within 2 weeks of meal kit receipt. Four adolescent participants (75% female; 12.7 ± 0.9 years) and eight caregivers (88% female) participated in the focus groups. Four barriers to home cooking were identified: (a) healthy food cost, (b) preparation time, (c) food preparation knowledge and (d) picky eaters. Participants felt the meal kits addressed the time and lack of food preparation knowledge barriers to home cooking. A clinical meal kit programme was acceptable to a treatment-seeking adolescent population with obesity and their caregivers.

The present study aimed to explore clinical trends in the period 2000-2010, along with discriminating clinical factors for autism spectrum disorder (ASD), in young children suspected of ASD. The following trends were observed: (1) a rise in referrals including an increase in referrals among language-abled children, (2) an increase in children assigned an ASD diagnosis after assessment, and (3) a decrease in Autism Diagnostic Observation Schedule total score. The distribution of ASD subtypes and IQ level did not change. Results suggest that a higher proportion of children with less severe autism symptoms were referred and diagnosed. Further, restricted and repetitive behaviors seemed to be a key discriminating factor when distinguishing between ASD and no-ASD children with a discordant symptom profile.

Importance: Knowledge about the epidemiology of mental disorders in children and adolescents is essential for research and planning of health services. Surveys can provide prevalence rates, whereas population-based registers are instrumental to obtain precise estimates of incidence rates and risks.Objective: To estimate age- and sex-specific incidence rates and risks of being diagnosed with any mental disorder during childhood and adolescence.Design: This cohort study included all individuals born in Denmark from January 1, 1995, through December 31, 2016 (1.3 million), and followed up from birth until December 31, 2016, or the date of death, emigration, disappearance, or diagnosis of 1 of the mental disorders examined (14.4 million person-years of follow-up). Data were analyzed from September 14, 2018, through June 11, 2019.Exposures: Age and sex.Main Outcomes and Measures: Incidence rates and cumulative incidences of all mental disorders according to the ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, diagnosed before 18 years of age during the study period.Results: A total of 99 926 individuals (15.01%; 95% CI, 14.98%-15.17%), including 41 350 girls (14.63%; 95% CI, 14.48%-14.77%) and 58 576 boys (15.51%; 95% CI, 15.18%-15.84%), were diagnosed with a mental disorder before 18 years of age. Anxiety disorder was the most common diagnosis in girls (7.85%; 95% CI, 7.74%-7.97%); attention-deficit/hyperactivity disorder (ADHD) was the most common in boys (5.90%; 95% CI, 5.76%-6.03%). Girls had a higher risk than boys of schizophrenia (0.76% [95% CI, 0.72%-0.80%] vs 0.48% [95% CI, 0.39%-0.59%]), obsessive-compulsive disorder (0.96% [95% CI, 0.92%-1.00%] vs 0.63% [95% CI, 0.56%-0.72%]), and mood disorders (2.54% [95% CI, 2.47%-2.61%] vs 1.10% [95% CI, 0.84%-1.21%]). Incidence peaked earlier in boys than girls in ADHD (8 vs 17 years of age), intellectual disability (5 vs 14 years of age), and other developmental disorders (5 vs 16 years of age). The overall risk of being diagnosed with a mental disorder before 6 years of age was 2.13% (95% CI, 2.11%-2.16%) and was higher in boys (2.78% [95% CI, 2.44%-3.15%]) than in girls (1.45% [95% CI, 1.42%-1.49%]).Conclusions and Relevance: This nationwide population-based cohort study provides a first comprehensive assessment of the incidence and risks of mental disorders in childhood and adolescence. By 18 years of age, 15.01% of children and adolescents in this study were diagnosed with a mental disorder. The incidence of several neurodevelopmental disorders peaked in late adolescence in girls, suggesting possible delayed detection. The distinct signatures of the different mental disorders with respect to sex and age may have important implications for service planning and etiological research.

We estimated autism spectrum disorder (ASD) prevalence in 7-9 year-old children in 2015 using data from three nationwide health registry systems (Denmark, Finland, Iceland) and two French population-based regional registries. Prevalence ranged from 0.48% in South-East France to 3.13% in Iceland (South-West France: 0.73%, Finland: 0.77%, Denmark: 1.26%). Male/female ratios ranged from 3.3 in Finland to 5.4 in South-West France. Between 12% (Denmark) and 39% (South-West France) of cases were diagnosed with intellectual disability. The variations in population-based ASD prevalence across four European countries with universal health care practices likely reflect variation in detection, referral and diagnosis practices and autism awareness across these areas. Using established population-based data systems is an efficient approach to monitor ASD prevalence trends over time.

Early identification of children who experience developmental delays due to prenatal alcohol exposure (PAE) remains a challenge for individuals who do not exhibit facial dysmorphia. It is well-established that children with PAE may still exhibit the cognitive and behavioral difficulties, and individuals without facial dysmorphia make up the majority of individuals affected by PAE. This study employed a prospective cohort design to capture alcohol consumption patterns during pregnancy and then followed the infants to 6 months of age. Infants were assessed using magnetoencephalography to capture neurophysiological indicators of brain development and the Bayley Scales of Infant Development-III to measure behavioral development. To account for socioeconomic and family environmental factors, we employed a two-by-two design with pregnant women who were or were not using opioid maintenance therapy (OMT) and did or did not consume alcohol during pregnancy. Based on prior studies, we hypothesized that infants with PAE would exhibit broad increased spectral amplitude relative to non-PAE infants. We also hypothesized that the developmental shift from low to high frequency spectral amplitude would be delayed in infants with PAE relative to controls. Our results demonstrated broadband increased spectral amplitude, interpreted as hypersynchrony, in PAE infants with no significant interaction with OMT. Unlike prior EEG studies in neonates, our results indicate that this hypersynchrony was highly lateralized to left hemisphere and primarily focused in temporal/lateral frontal regions. Furthermore, there was a significant positive correlation between estimated number of drinks consumed during pregnancy and spectral amplitude revealing a dose-response effect of increased hypersynchrony corresponding to greater alcohol consumption. Contrary to our second hypothesis, we did not see a significant group difference in the contribution of low frequency to high frequency amplitude at 6 months of age. These results provide new evidence that hypersynchrony, previously observed in neonates prenatally exposed to high levels of alcohol, persists until 6 months of age and this measure is detectable with low to moderate exposure of alcohol with a dose-response effect. These results indicate that hypersynchrony may provide a sensitive early marker of prenatal alcohol exposure in infants up to 6 months of age., Highlights • 6 month old infants with prenatal alcohol exposure exhibit broadband hypersynchrony. • Hypersynchrony was positively correlated with number of drinks consumed prenatally. • Distribution of low frequency to high frequency amplitude did not differ by group. • Hypersynchrony may provide an early marker of prenatal alcohol exposure in infants.

Importance: Population-based data on educational and employment outcomes in adulthood among individuals diagnosed with autism spectrum disorder (ASD) in childhood are currently limited.Objective: To evaluate educational attainment and employment among individuals with and without a diagnosis of ASD before age 12 years in Denmark.Design, Setting, and Participants: This nationwide cross-sectional prevalence study was conducted using data from Danish registers. Individuals with a diagnosis of ASD recorded before age 12 years were identified among all individuals born in Denmark between January 1, 1989, and December 31, 1991, who were alive at age 25 years. Individuals with ASD were then matched on a 10:1 ratio by age, sex, and region of residence with a comparison population of individuals without a diagnosis of ASD at age 12 years. Data were analyzed from March 2019 to December 2020.Exposures: Autism spectrum disorder diagnosis and diagnostic subtype recorded before age 12 years.Main Outcomes and Measures: Adjusted prevalence ratios (aPRs) with 95% CIs for the completion of compulsory primary and lower secondary school (grade 9), upper secondary school (grades 10-12 or vocational), and tertiary school (university) and for employment by age 25 years were estimated using log-binomial regression analysis.Results: A total of 810 individuals with a diagnosis of ASD before age 12 years were matched with a comparison population of 8100 individuals without ASD. The prevalence of ninth-grade completion was similar among those with and without ASD (785 individuals [96.9%] and 7982 individuals [98.5%], respectively; aPR, 0.98; 95% CI, 0.97-1.00). Compared with those without ASD, persons with ASD had a lower prevalence of completing upper secondary school (6338 individuals [78.2%] vs 286 individuals [35.3%], respectively; aPR, 0.46; 95% CI, 0.42-0.50) and tertiary school (2185 individuals [27.0%] vs 70 individuals [8.6%]; aPR, 0.33; 95% CI, 0.26-0.41) and obtaining employment (4284 individuals [77.7%] vs 177 individuals [27.2%]; aPR, 0.35; 95% CI, 0.31-0.40) at age 25 years. A ninth-grade final examination score was available for 394 individuals (48.6%) with ASD and 7417 individuals (91.6%) without ASD. In an analysis stratified by ASD subtype, individuals diagnosed with childhood autism had lower educational attainment and employment than those diagnosed with Asperger syndrome or pervasive developmental disorder not otherwise specified. A total of 461 individuals (56.9%) with ASD were receiving public assistance or a pension (ie, disability benefits) at age 25 years compared with 1094 individuals (13.5%) without ASD in the comparison population.Conclusions and Relevance: In this population-based cross-sectional study, a diagnosis of ASD in childhood was not associated with the completion of compulsory primary and lower secondary education (ninth grade). An ASD diagnosis before age 12 years was associated with a lower prevalence of attaining education beyond ninth grade and obtaining employment by age 25 years, indicating a substantially higher risk of reliance on public assistance in young adulthood.

BACKGROUND: Exposure to air pollution in early life has been linked to cognitive deficits and adverse neurodevelopmental effects. However, studies examining associations between air pollutants and Attention-Deficit / Hyperactivity Disorder (ADHD) have had conflicting findings. METHODS: Individuals born in Denmark 1992-2007 (n=809,654) were followed for the development of ADHD from 1997 to 2013. Data on daily concentrations of nitrogen dioxide (NO(2)) and fine particulate matter (PM(2.5)) from air-modeling data at a 1 km x 1 km resolution at residences within the first five years of life, was linked with population-based data from the Danish national registers, including data on clinical diagnoses of ADHD. We estimated incidence rate ratios (IRRs) with 95% confidence intervals (CI) for ADHD, according to increases in exposures, adjusting for age, year, sex, and parental education and income. RESULTS: Exposure to NO(2) and PM(2.5) during early life was associated with a significantly increased risk of ADHD: IRR of 1.38 (Cl: 1.35 to 1.42) per 10 μg/m(3) increase in NO(2) and an IRR of 1.51 (Cl: 1.40 to 1.62) per 5 μg/m(3) increase in PM(2.5). In two-pollutant models, the association between NO(2) and ADHD did not change (IRR 1.35; 95% CI: 1.31 to 1.39), while the association with PM(2.5) was substantially attenuated (IRR 1.07; 95% CI: 0.98 to 1.16), although in stratified models an elevated association with PM(2.5) was found in the lowest quintile of NO(2) exposure. CONCLUSIONS: In this large nationwide prospective cohort study, residential air pollution exposure, specifically NO(2), during early childhood was associated with the development of ADHD, even when adjusted for parental level of income and education.

Background As Canada’s population ages, incidence of gastric cancer in elderly patients is increasing. There is little data on treatment and outcomes of gastric cancer in patients older than age 75. This study aimed to assess treatment patterns and outcomes of non-metastatic elderly gastric cancer patients in Alberta, Canada. Methods Records of elderly patients (age 75 or older) diagnosed with localized gastric or gastroesophageal junction cancer between 2007 and 2012 who received curative intent surgery were retrospectively collected from the Alberta Cancer Registry. A chart review was completed to gather demographics; treatment details of surgery, chemotherapy, and radiotherapy; and outcomes. Descriptive analyses were undertaken, and variables were compared with parametric and nonparametric tests where appropriate. Results 130 predominantly male (69%) patients, median age 80 (range 75–96) were included. 17 patients (13%) received multimodality therapy. 115 (88.5%) had negative margins on final pathology. Mean lymph nodes retrieved were 16 (range 0–43). 46 surgical patients (35.4%) had grade II or higher complications. 13 patients had a perioperative death (Clavien grade V). Four (3.1%) patients completed perioperative chemotherapy, and 13 (10%) patients had adjuvant chemo/radiotherapy. 50 (38.5%) recurred at median 13 months, while 80 (61.5%) did not have a recurrence of their cancer at any time during follow up. The 5 year DFS for the surgery only group was 67.3% and multimodality group was 52.9% (p = 0.25). The 5 year OS for the surgery only group was 38.9% and multimodality group was 47.1% (p = 0.52). Conclusions Our findings suggest that even with surgery alone, selected elderly patients with non-metastatic gastric cancer can obtain apparent prolonged survival, despite not receiving standard of care multimodality therapy. More studies are needed to optimise elderly patients’ treatment selection.

Correction: J Autism Dev Disord. 2019 Nov 28. doi: 10.1007/s10803-019-04303-7. Online ahead of print. The original version of this article unfortunately contained a mistake in one of the co-author's family name. The correct name should be María Victoria Martín-Cilleros instead of María Victoria Cilleros-Martín. https://link.springer.com/article/10.1007/s10803-019-04303-7 Early services for ASD need to canvas the opinions of both parents and professionals. These opinions are seldom compared in the same research study. This study aims to ascertain the views of families and professionals on early detection, diagnosis and intervention services for young children with ASD. An online survey compiled and analysed data from 2032 respondents across 14 European countries (60.9% were parents; 39.1% professionals). Using an ordinal scale from 1 to 7, parents' opinions were more negative (mean = 4.6; SD 2.2) compared to those of professionals (mean = 4.9; SD 1.5) when reporting satisfaction with services. The results suggest services should take into account child's age, delays in accessing services, and active stakeholders' participation when looking to improve services. This study was funded by the Spanish Ministry of Economy and Competitiveness [Grant PSI2016-80575-R], the European Union, DGSANCO, [Ref.: SANCO/2014/C2/035], and the Spanish Ministry of Education, Culture and Sport [Ref.: BOE-B-2017-2646]. info:eu-repo/semantics/publishedVersion

Background Despite increased reporting of resting-state magnetoencephalography (MEG), reliability of those measures remains scarce and predominately reported in healthy controls (HC). As such, there is limited knowledge on MEG resting-state reliability in schizophrenia (SZ). Methods To address test-retest reliability in psychosis, a reproducibility study of 26 participants (13-SZ, 13-HC) was performed. We collected eyes open and eyes closed resting-state data during 4 separate instances (2 Visits, 2 runs per visit) to estimate spectral power reliability (power, normalized power, alpha reactivity) across one hour and one week. Intraclass correlation coefficients (ICCs) were calculated. For source modeling, we applied an anatomically constrained linear estimation inverse model known as dynamic statistical parametric mapping (MNE dSPM) and source-based connectivity using the weighted phase lag index. Results Across one week there was excellent test-retest reliability in global spectral measures in theta-gamma bands (HC ICCAvg = 0.87, SZ ICCAvg = 0.87), regional spectral measures in all bands (HC ICCAvg = 0.86, SZ ICCAvg = 0.80), and parietal alpha measures (HC ICCAvg = 0.90, SZ ICCAvg = 0.84). Conversely, functional connectivity had poor reliability, as did source spectral power across one hour for SZ. Relative to HC, SZ also had reduced parietal alpha normalized power during eyes closed only, reduced alpha reactivity, and an association between higher PANSS positive scores and lower parietal alpha power. Conclusions There was excellent to good test-retest reliability in most MEG spectral measures with a few exceptions in the schizophrenia patient group. Overall, these findings encourage the use of resting-state MEG while emphasizing the importance of determining reliability in clinical populations.

Key Points Question Is family history of mental and neurological disorders associated with risk of autism spectrum disorders, and does this vary with vs without intellectual disability? Findings In this population-based cohort study of 567 436 Swedish participants, positive family history was associated with increased risk of autism spectrum disorders. Autism spectrum disorders with intellectual disability exhibited a weaker familial association with other mental disorder diagnoses but a stronger familial association with some neurological diagnoses as compared with autism spectrum disorders without intellectual disability. Meaning This study suggests that family history of mental and neurological disorders is associated with autism risk, and the familial component of autism etiology may differ by presence or absence of co-occurring intellectual disability., Importance Familial aggregation of mental and neurological disorders is often observed in autism spectrum disorders (ASD), but reports have generally focused on single disorders and are limited to first-degree relatives. Objectives To examine family history of mental and neurological disorders among first- to fourth-degree relatives and risk of ASD with and without intellectual disability (ID) in index persons. Design, Setting, and Participants In this population-based cohort study, 567 436 index persons were identified from the Stockholm Youth Cohort, an ongoing longitudinal register-linkage cohort study of the total population aged 0 to 17 years residing in Stockholm County, Sweden. Index persons were nonadopted singleton births born between 1984 and 2009 who were at least 2 years of age at the end of follow-up on December 31, 2011, had resided in Stockholm County for at least 2 years since birth, and could be linked to both biological parents. Data analysis was conducted from May 2017 to December 2018. Exposure Mental and neurological diagnoses of relatives of the index persons. Main Outcomes and Measures Diagnosis of ASD, with or without co-occurring ID, in the index persons. Results The cohort included 567 436 index persons (291 191 [51.3%] male; mean [SD] age at the end of follow-up, 14.3 [7.5] years). The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively. Positive family history of mental and neurological disorders was associated with higher odds of ASD in index persons; 6895 (63.1%) of index persons with ASD had a parent with history of mental and/or neurological disorders, compared with 252 454 (45.4%) of index persons without ASD. Family history of multiple disorders was associated with higher odds of ASD in index persons, including history of ASD (odds ratio among first-degree relatives for ASD with and without ID: 14.2, 9.0), intellectual disability (7.6, 2.3), attention-deficit/hyperactivity disorder (3.3, 4.7), obsessive compulsive disorder (1.9, 2.1), schizophrenia and other nonaffective psychotic disorders (2.1, 1.8), depression (1.4, 2.0), bipolar disorder (1.4, 2.2), personality disorder (2.1, 2.6), cerebral palsy (2.2, 1.5), and epilepsy (2.0, 1.3). The more closely related the affected family member was, the higher the odds was of ASD for the index person. ASD without intellectual disability was associated with more disorders compared to ASD with intellectual disability. ASD with intellectual disability exhibited a weaker familial association with other mental disorder diagnoses but a stronger familial association with some neurological diagnoses as compared to ASD without intellectual disability. Conclusions and Relevance This study suggests that family history of mental and neurological disorders is associated with increased risk of ASD. The familial component of ASD etiology may differ by presence or absence of co-occurring ID., This population-based cohort study examines family history of mental and neurological disorders among first- to fourth-degree relatives and risk of autism spectrum disorders with and without intellectual disability in index persons from the Stockholm Youth Cohort in Sweden.

Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days ("neonatal," from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Research 2019, 12: 136-146. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life.

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991-2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism - no ADHD, 2,205 autism + ID, and 11,342 autism - no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13-1.22]) but attenuated in the maternal cluster (0.98 [0.88-1.09]) and sibling (0.86 [0.64-1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2020, 13: 134-144. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Smoking during pregnancy has many harmful impacts, which may include harming the baby's developing brain. However, in a study of thousands of families in Denmark, it does not appear that smoking in pregnancy leads to autism or autism in combination with intellectual problems or attention deficits, once you account for the way smoking patterns and developmental disabilities run in families.

To evaluate the quantitative characteristics of the radial peripapillary capillary (RPC) network in glaucoma, glaucoma suspect, and normal eyes using speckle variance optical coherence tomography angiography (OCT-A). To determine correlations between RPC density, nerve fiber layer (NFL) thickness, and visual field indices.Cross-sectional study.OCT-A images of RPCs were acquired at a single institution using a custom-built 1060 nm system from 3 groups: unilateral glaucoma (10 eyes from 5 subjects), glaucoma suspects (6 eyes from 3 subjects), and normal control eyes (16 eyes from 9 normal subjects). Peripapillary NFL thickness measurements were determined using spectral-domain optical coherence tomography. Glaucoma and glaucoma suspects also underwent automated 30-2 Humphrey visual field analysis. Manual tracing techniques were used to quantify RPC density in the OCT-A images. Data were analyzed using a linear mixed model with 1 fixed-effect covariate. Correlations between main outcome measures (RPC density, NFL thickness, and visual field index) were determined.Mean age was not significantly different between the 3 groups (P = .25). The density of RPCs was significantly lower in glaucomatous eyes compared with matched-peripapillary regions in the fellow eye, glaucoma suspect group, and normal group (all P.001). RPC density was strongly correlated with NFL thickness (P.001) and visual field index (P.001).Significant reductions in RPC density were correlated with sites of NFL decrease and visual field loss in glaucoma. Speckle variance OCT-A allows visualization and quantification of RPCs and may therefore be a useful tool for indirectly quantifying and monitoring retinal ganglion cell axonal injury in glaucoma.

Maternal immune activity has been linked to children with autism spectrum disorder (ASD). We examined maternal occupational exposure to asthma-causing agents during pregnancy in relation to ASD risk. Our sample included 463 ASD cases and 710 general population controls from the Study to Explore Early Development whose mothers reported at least one job during pregnancy. Asthmagen exposure was estimated from a published job-exposure matrix. The adjusted odds ratio for ASD comparing asthmagen-exposed to unexposed was 1.39 (95 % CI 0.96–2.02). Maternal workplace asthmagen exposure was not associated with ASD risk in this study, but this result does not exclude some involvement of maternal exposure to asthma-causing agents in ASD. Electronic supplementary material The online version of this article (doi:10.1007/s10803-016-2882-6) contains supplementary material, which is available to authorized users.

Objectives: Imbalances in spatial attention are most often associated with right hemisphere brain injury. This report assessed 25 chronic left hemisphere stroke patients for attentional bias. Methods: Participants were evaluated with a computerized visual search task and a standardized neuropsychological assessment known as the Behavioral Inattention Test (BITC). Twenty age-matched controls were also tested. Results: Although little to no attentional impairment was observed on the BITC, the computerized visual search task revealed statistically significant contralesional attentional impairment in the left hemisphere stroke group. Specifically, these participants required 208 ms more viewing time, on average, to reliably detect visual targets on the right side of the display compared to detection on the left side, while controls showed a difference of only 8 ms between the two sides. Conclusions: The observation of significant leftward visuospatial bias in this chronic stroke group provides further evidence that the left hemisphere also plays a role in the balance of visual attention across space. These results have implications for left hemisphere patients who are often not screened for visuospatial problems, as well as for theories of visual attention which have primarily emphasized the role of the right hemisphere. (JINS, 2016, 22, 695–704)

During meiosis, a specialized chromosome structure is assembled to promote pairing/synapsis of homologous chromosomes and meiotic recombination, a process yielding chiasmata between homologs to ensure accurate segregation. Meiosis‐specific cohesin complexes mediating sister chromatid cohesion play pivotal roles in almost all these events, including synaptonemal complex (SC) formation. In this issue of EMBO Reports, Agostinho and colleagues have examined chromosome axes and SC structures by taking advantage of a hypomorphic Stag3 mutant in which the levels of the cohesin subunit REC8 are partly reduced 6. Using super‐resolution microscopy, the authors illuminate previously unforeseen chromosome axis structures, showing locally separated axes in regions where REC8 is absent, regardless of RAD21L or RAD21 cohesin localization. Furthermore, they assessed the relationship between sister chromatid cohesion and inter‐sister SC formation, demonstrating that “axial opening” in the REC8‐free region is accompanied by illegitimate SC formation between sister chromatids. This study highlights the physiological importance of REC8 in sister chromatid cohesion and proper SC formation during meiosis, suggesting a new model in which a high density of REC8 deposition along the chromosome prevents illegitimate inter‐sister SC formation.

This Research Letter examines cumulative incidence on autism spectrum disorder in Denmark using nationwide registered diagnosis data from 1980 to 2012 and assesses whether prevalence was stabilized.

Objective Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. A population-based cohort was used to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and Tourette's disorder/chronic tic disorder (TD/CT). Method The study cohort included all singleton births in Denmark from 1980 through 2007 with full information on parental ages (N = 1,490,745) and was followed through December 31, 2013. Cases of ASD, ADHD, OCD, and TD/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time. Results Younger parental age was significantly associated with increased estimates of risk for ADHD and TD/CT, whereas older parental age was associated with ASD and OCD. Except for OCD, no evidence for differential effects of parental ages on male versus female offspring was observed. Conclusion This study provides novel evidence for the association between age at parenthood and TD/CT and OCD and for the first time shows in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. These results are consistent with a model of shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes.

Background Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. Methods We quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. Results We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. Conclusions This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants. Electronic supplementary material The online version of this article (10.1186/s13073-018-0527-4) contains supplementary material, which is available to authorized users.

Background Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p

Background: The positive association between caesarean section (CS) and autism spectrum disorder (ASD) may be attributed to preterm delivery. However, due to lack of statistical power, no previous study thoroughly examined this association across gestational age. Moreover, most studies did not differentiate between emergency and planned CS.Methods: Using population-based registries of four Nordic countries and Western Australia, our study population included 4 987 390 singletons surviving their first year of life, which included 671 646 CS deliveries and 31 073 ASD children. We used logistic regression to estimate odds ratios (OR) and their 95% confidence intervals (CI) for CS, adjusted for gestational age, site, maternal age and birth year. Stratified analyses were conducted by both gestational age subgroups and by week of gestation. We compared emergency versus planned CS to investigate their potential difference in the risk of ASD.Results: Compared with vaginal delivery, the overall adjusted OR for ASD in CS delivery was 1.26 (95% CI 1.22–1.30). Stratified ORs were 1.25 (1.15–1.37), 1.16 (1.09–1.23), 1.34 (1.28–1.40) and 1.17 (1.04–1.30) for subgroups of gestational weeks 26–36, 37–38, 39–41 and 42–44, respectively. CS was significantly associated with risk of ASD for each week of gestation, from week 36 to 42, consistently across study sites (OR ranged 1.16–1.38). There was no statistically significant difference between emergency and planned CS in the risk of ASD.Conclusion: Across the five countries, emergency or planned CS is consistently associated with a modest increased risk of ASD from gestational weeks 36 to 42 when compared with vaginal delivery.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Objective:This study aimed to describe total volume and cross-sectional area measurement changes in obstructive sleep apnoea patients associated with a supine versus an upright position.Method:A retrospective chart review of patients who underwent cone beam computed tomography in upright and supine positions was performed, and the images were analysed.Results:Five obstructive sleep apnoea patients (all male) underwent both upright and supine cone beam computed tomography imaging. Mean age was 35.0 ± 9.3 years, mean body mass index was 28.1 ± 2.7 kg/m2 and mean apnoea–hypopnoea index was 39.3 ± 23.0 per hour. The airway was smaller when patients were in a supine compared with an upright position, as reflected by decreases in the following airway measurements: total volume; posterior nasal spine, uvula tip, retrolingual and tongue base (not significant) cross-sectional areas; and site of the minimum cross-sectional area (of the overall airway). Total airway volume decreased by 32.6 per cent and cross-sectional area measurements decreased between 32.3 and 75.9 per cent when patients were in a supine position.Conclusion:In this case series, the airway of obstructive sleep apnoea patients was significantly smaller when patients were in a supine compared with an upright position.

The objective of this study is to compare the time trend of reported diagnoses of autism spectrum disorder (ASD), hyperkinetic disorder, Tourette's syndrome, and obsessive-compulsive disorder across four countries after standardizing the study period, diagnostic codes used to define the conditions and statistical analyses across countries. We use a population-based cohort, including all live-born children in Denmark, Finland, Sweden and Western Australia, from January 1, 1990, through December 31, 2007 and followed through December 31, 2011. The main outcome measure is age-specific prevalence of diagnoses reported to population-based registry systems in each country. We observe an increase in age-specific prevalence for reported diagnoses of all four disorders across birth-year cohorts in Denmark, Finland, Sweden, and (for ASD) Western Australia. Our results highlight the increase in the last 20 years in the number of children and families in contact with health care systems for diagnosis and services for an array of childhood neuropsychiatric disorders, a phenomenon not limited to ASD. Also, the age of diagnosis of the studied disorders was often much higher than what is known of the typical age of onset of symptoms, and we observe limited leveling off in the incidence rate with increasing age.

Importance: The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries.Objective: To estimate the additive genetic, maternal, and environmental effects in ASD.Design, Setting, and Participants: Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018.Main Outcomes and Measures: Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects.Results: The analytic sample included 2 001 631 individuals, of whom 1 027 546 (51.3%) were male. Among the entire sample, 22 156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD.Conclusions and Relevance: Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries.

A B S T R A C T Objective: Describe anatomical and radiological findings in 742 patients evaluated for congenital aural atresia and microtia by a multidisciplinary team. Develop a new classification method to enhance multidisciplinary communication regarding patients with congenital aural atresia and microtia. Methods: Retrospective chart review with descriptive analysis of findings arising from the evaluation of patients with congenital atresia and microtia between January 2008 and January 2012 at a multidisciplinary tertiary referral center. Results: We developed a classification method based on the acronym HEAR MAPS (Hearing, Ear [microtia], Atresia grade, Remnant earlobe, Mandible development, Asymmetry of soft tissue, Paralysis of the facial nerve and Syndromes). We used this method to evaluate 742 consecutive congenital atresia and microtia patients between 2008 and January of 2012. Grade 3 microtia was the most common external ear malformation (76%). Pre-operative Jahrsdoerfer scale was 9 (19%), 8 (39%), 7 (19%), and 6 or less (22%). Twenty three percent of patients had varying degrees of hypoplasia of the mandible. Less than 10% of patients had an identified associated syndrome. Conclusion: Patients with congenital aural atresia and microtia often require the intervention of audiology, otology, plastic surgery, craniofacial surgery and speech and language professionals to achieve optimal functional and esthetic reconstruction. Good communication between these disciplines is essential for coordination of care. We describe our use of a new classification method that efficiently describes the physical and radiologic findings in microtia/atresia patients to improve communication amongst care providers.

While the cochlear implant has successfully restored hearing to many deaf patients, it cannot benefit those without a functional auditory nerve or an implantable cochlea. As an alternative, the auditory midbrain implant (AMI) has been developed and implanted into deaf patients. Consisting of a single-shank array, the AMI is designed for stimulation along the tonotopic gradient of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding because repeated stimulation of a single site causes strong suppressive and refractory effects. Applying the electrical stimulation to at least two sites within an isofrequency lamina can circumvent these refractory processes. Moreover, coactivation with short intersite delays (

The etiology of autism spectrum disorders (ASD) is for the majority of cases unknown and more studies of risk factors are needed. Geographic variation in ASD occurrence has been observed, and urban residence has been suggested to serve as a proxy for etiologic and identification factors in ASD. We examined the association between urbanicity level and ASD at birth and during childhood. The study used a Danish register-based cohort of more than 800,000 children of which nearly 4,000 children were diagnosed with ASD. We found a dose-response association with greater level of urbanicity and risk of ASD. This association was found for residence at birth as well as residence during childhood. Further, we found an increased risk of ASD in children who moved to a higher level of urbanicity after birth. Also, earlier age of ASD diagnosis in urban areas was observed. While we could not directly examine the specific reasons behind these associations, our results demonstrating particularly strong associations between ASD diagnosis and post-birth migration suggest the influence of identification-related factors such as access to services might have a substantive role on the ASD differentials we observed.

Objective The aim of this study is to summarize the clinical characteristics of patients with contact lens–associated focal limbal stem cell deficiency (FLSCD) from a tertiary corneal referral centre. Design Retrospective, observational case series in a tertiary care centre. Methods Patients with contact lens–associated FLCSD were identified in our database. Clinical data were retrieved by chart review. A questionnaire asking for contact lens brand, type, cleaning solution, and duration of contact lens wear was sent to the patients with telephone follow-up. Clinical features and recovery time were identified. Results Twenty-seven eyes of 17 patients were identified with superior corneal whorl-like patches of opaque epithelium, sometimes accompanied by neovascularization. Of the patients, 17/17 used soft contact lenses, with a mean wearing duration of 11.4 hours per day. Patients had been wearing lenses for an average of 18.1 years. Silicone hydrogel lenses were noted in 12/17 cases. LSCD was superior in all 27 eyes, and all of them improved with contact lens wear cessation, preservative-free topical steroids, and preservative-free artificial tears. Visual acuity improved from 20/28 to 20/22 ( p Conclusions Contact lens–associated FLSCD typically presents in the superior cornea with whorl-like epithelial opacities advancing from the limbus. Conservative medical treatment is available and shows a high success rate after a slow recovery.

OBJECTIVE: Epilepsy and autism spectrum disorder (ASD) often occur together in the same individual. However, it remains unknown whether siblings of children with ASD have an increased risk of epilepsy and vice versa. This study determines the risk of ASD and epilepsy among younger siblings of children with ASD and epilepsy.DESIGN: The study included all children born in Denmark between January 1, 1980 and 31 December 2006 who participated in follow-up until December 31, 2012 (1,663,302 children). We used Cox regression to calculate the adjusted hazard ratio (aHR) and the Kaplan-Meier method to calculate the cumulative incidence.RESULTS: The overall aHR of epilepsy in younger siblings increased by 70% (aHR 1.70, 95% confidence interval [CI] 1.34-2.16%) if the older sibling had ASD compared with siblings where the older sibling did not have ASD. The cumulative incidence of epilepsy at 20 years of age was 2.54% (95% CI 1.97-3.26%) if the older sibling had ASD, whereas the cumulative incidence of epilepsy at 20 years of age was 1.63% (95% CI 1.60-1.66%) if the older sibling did not have ASD. The overall aHR of ASD in younger siblings increased by 54% if the older sibling had epilepsy (aHR 1.54, 95% CI 1.32-1.80) compared with siblings where the older sibling did not have epilepsy. The cumulative incidence of ASD at 20 years of age was 2.06% (95% CI 1.84-2.32%) if the older sibling had epilepsy, whereas the cumulative incidence of ASD at 20 years of age was 1.27% (95% CI 1.25-1.29%) if the older sibling did not have epilepsy.SIGNIFICANCE: The cross-disorder sibling risk of epilepsy and ASD was increased for the two disorders, which suggests that genes or environmental factors shared by family members may play a causal role in the co-occurrence of ASD and epilepsy.

International audience; Evidence before this study We searched PubMed on June 30, 2016, for English-language cohort studies published since Jan 1, 1980, of patients with invasive listeriosis worldwide with the keywords " listeria " , " listeriosis " , " maternal " , and " neurolisteriosis ". Studies had to include epidemiological or clinical data on listeriosis. All clinical forms of infection were included (bacteraemia, neurolisteriosis, and maternal–neonatal infection). Host risk factors for listeriosis have been well identified, but the clinical features and prognostic factors of the disease are based on retrospective studies compiling heterogeneous data or random collected cases. Furthermore, no clinical trial has ever been done and medical management is not evidence based. Added value of the study Our study is the first prospective clinical study focusing on all forms of invasive listeriosis. The study is based on a national mandatory system that allowed the nearly complete capture of microbiologically proven cases. The study shows a higher burden of listeriosis than reported before: more than 80% of infected mothers experienced major fetal or neonatal complications (fetal loss, very high prematurity, early or late onset disease); only 39% of patients with neurolisteriosis survived and fully recovered. The study provides important new data to improve management and predict outcome in listeriosis, such as determination of the time window for fetal losses (

Effective drug selection is the current challenge in rheumatoid arthritis (RA). Treatment failure may follow different pathomechanisms and therefore require investigation of molecularly defined subgroups. In this exploratory study, whole blood transcriptomes of 68 treatment-naive early RA patients were analyzed before initiating MTX. Subgroups were defined by serologic and genetic markers. Response related signatures were interpreted using reference transcriptomes of various cell types, cytokine stimulated conditions and bone marrow precursors. HLA-DRB4-negative patients exhibited most distinctive transcriptional differences. Preponderance of transcripts associated with phagocytes and bone marrow activation indicated response and transcripts of T- and B-lymphocytes non-response. HLA-DRB4-positive patients were more heterogeneous, but also linked failure to increased adaptive immune response. RT-qPCR confirmed reliable candidate selection and independent samples of responders and non-responders the functional patterning. In summary, genomic stratification identified different molecular pathomechanisms in early RA and preponderance of innate but not adaptive immune activation suggested response to MTX therapy.

Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth.

Motivation Cross-reactivity (CR) or invocation of autoimmune side effects in various tissues has important safety implications in adoptive immunotherapy directed against selected antigens. The ability to predict CR (on-target and off-target toxicities) may help in the early selection of safer therapeutically relevant target antigens. Results We developed a methodology for the calculation of quantitative CR for any defined peptide epitope. Using this approach, we performed assessment of 4 groups of 283 currently known human MHC-class-I epitopes including differentiation antigens, overexpressed proteins, cancer-testis antigens and mutations displayed by tumor cells. In addition, 89 epitopes originating from viral sources were investigated. The natural occurrence of these epitopes in human tissues was assessed based on proteomics abundance data, while the probability of their presentation by MHC-class-I molecules was modelled by the method of Keşmir et al. which combines proteasomal cleavage, TAP affinity and MHC-binding predictions. The results of these analyses for many previously defined peptides are presented as CR indices and tissue profiles. The methodology thus allows for quantitative comparisons of epitopes and is suggested to be suited for the assessment of epitopes of candidate antigens in an early stage of development of adoptive immunotherapy. Availability and Implementation Our method is implemented as a Java program, with curated datasets stored in a MySQL database. It predicts all naturally possible self-antigens for a given sequence of a therapeutic antigen (or epitope) and after filtering for predicted immunogenicity outputs results as an index and profile of CR to the self-antigens in 22 human tissues. The program is implemented as part of the iCrossR webserver, which is publicly available at http://webclu.bio.wzw.tum.de/icrossr/. Supplementary information Supplementary data are available at Bioinformatics online.