Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Sleep problems in children and adolescents in an attention deficit hyperactivity disorder service.

OBJECTIVES: Sleep problems are common amongst children and adolescents with attention deficit hyperactivity disorder (ADHD). The purpose of this study was to investigate sleep problems in children and adolescents attending a specialist ADHD service. METHODS: This was a cross-sectional online survey combined with a retrospective chart review, conducted in the ADHD Assessment, Diagnosis, Management, initiation, Research and Education (ADMiRE) service, the first public specialist ADHD service for young people in Ireland. Participants were caregivers of children and adolescents with ADHD attending ADMiRE. Sleep was assessed using The Children's Sleep Habits Questionnaire (CSHQ) and ADHD symptoms were assessed using an abbreviated version of the Swanson, Nolan and Pelham Teacher and Parent Rating Scale (SNAP-IV). Details regarding patient demographics, co-morbidities and medication were collected from patient records. RESULTS: Eighty-four percent of young people scored above the clinical cut-off for a sleep disorder. The most frequently reported sleep problems were related to sleep onset and sleep duration, and 64% of respondents met the criteria for two or more sleep problems. ADHD severity was associated with greater sleep problems. Co-morbid physical, neurodevelopmental, and mental health disorders as well as stimulant use were not associated with greater sleep problems. CONCLUSION: Sleep problems are very common amongst children and adolescents with ADHD. This study has demonstrated an association between more sleep problems and ADHD severity. These findings highlight the need for both effective ADHD treatment to ensure optional sleep in young people as well as effective interventions for sleep problems to prevent worsening of ADHD symptoms.

A contiguous de novo genome assembly of sugar beet EL10 (Beta vulgaris L.).

A contiguous assembly of the inbred 'EL10' sugar beet (Beta vulgaris ssp. vulgaris) genome was constructed using PacBio long-read sequencing, BioNano optical mapping, Hi-C scaffolding, and Illumina short-read error correction. The EL10.1 assembly was 540 Mb, of which 96.2% was contained in nine chromosome-sized pseudomolecules with lengths from 52 to 65 Mb, and 31 contigs with a median size of 282 kb that remained unassembled. Gene annotation incorporating RNA-seq data and curated sequences via the MAKER annotation pipeline generated 24,255 gene models. Results indicated that the EL10.1 genome assembly is a contiguous genome assembly highly congruent with the published sugar beet reference genome. Gross duplicate gene analyses of EL10.1 revealed little large-scale intra-genome duplication. Reduced gene copy number for well-annotated gene families relative to other core eudicots was observed, especially for transcription factors. Variation in genome size in B. vulgaris was investigated by flow cytometry among 50 individuals producing estimates from 633 to 875 Mb/1C. Read-depth mapping with short-read whole-genome sequences from other sugar beet germplasm suggested that relatively few regions of the sugar beet genome appeared associated with high-copy number variation.

Antipsychotic prescribing in GMS paediatric and young adult population in Ireland 2005-2015: repeated cross-sectional study.

OBJECTIVES: To examine the rates of antipsychotic prescribing in the Irish paediatric and young adult population enrolled in the Irish General Medical Services Scheme pharmacy claims database from the Health Service Executive Primary Care Reimbursement Services database, with a focus on age and sex differences. To examine concomitant prescribing of certain other related medicines in this population. METHODS: Data were obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive (HSE) - Primary Care Reimbursement Services (PCRS). Participants included children aged <16 years and youth aged 16-24 years availing of medicines under the HSE-PCRS GMS scheme between January 2005 and December 2015. Outcome measures included prescribing rates of antipsychotics from 2005 to 2015, differences in prescribing rates between different ages and sexes, and percentage of concomitant prescriptions for antidepressants, psychostimulants, anxiolytics and hypnosedatives. RESULTS: Overall the trend in prescribing rates of antipsychotic medications was stable at 3.94/1000 in 2005 compared with 3.97/1000 in 2015 for children <16 years, and 48.37/1000 eligible population in 2005 compared to 39.64/1000 in 2015 for those aged 16-24. There was a significant decrease in prescribing rates for males in the 16-24 age group. CONCLUSIONS: While rates of antipsychotic prescribing have decreased or remained stable over the timeframe of the study, we did find a significant proportion of this population were prescribed antipsychotics. This study also shows that co-prescribing of antidepressants increased and highlights the need for guidelines for antipsychotic prescribing in children and youth in terms of clinical indication, monitoring, co-prescribing and treatment duration.

Risk factors for SARS-CoV-2 infection in healthcare workers following an identified nosocomial COVID-19 exposure during waves 1-3 of the pandemic in Ireland.

Healthcare workers (HCWs) have increased exposure and subsequent risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This case-control study was conducted to investigate the contemporaneous risks associated with confirmed SARS-CoV-2 infection amongst HCWs following in-work exposure to a confirmed coronavirus disease-2019 (COVID-19) case. We assessed the influence of demographic (age, sex, nationality, high risk co-morbidities and vaccination status) and work-related factors (job role, exposure location, contact type, personal protective equipment (PPE) use) on infection risk following nosocomial SARS-CoV-2 exposure. All contact tracing records within the hospital site during waves 1-3 of the COVID-19 pandemic in Ireland were screened to identify exposure events, cases and controls. In total, 285 cases and 1526 controls were enrolled, as a result of 1811 in-work exposure events with 745 index cases. We demonstrate that male sex, Eastern European nationality, exposure location, PPE use and vaccination status all impact the likelihood of SARS-CoV-2 infection following nosocomial SARS-CoV-2 exposure. The findings draw attention to the need for continuing emphasis on PPE use and its persisting benefit in the era of COVID-19 vaccinations. We suggest that non-work-related factors may influence infection risk seen in certain ethnic groups and that infection risk in high-risk HCW roles (e.g. nursing) may be the result of repeated exposures rather than risks inherent to a single event.

Autism spectrum disorders: current issues and future directions.

This edition of Irish Journal of Psychological Medicine is a Special Themed Issue on Autism Spectrum Disorders (ASD). Mental health services are not currently meeting the needs of autistic people across the lifespan. We have limited evidence based treatments for core symptoms and comorbidities and there is lack of awareness and under-recognition of ASD, particularly in adults and certain groups of individuals. The key themes in this edition focus on challenges with recognition and diagnosis and address these from both clinical and research perspectives. Co-occurring conditions also feature, which are also under-recognised and can contribute to less optimal outcomes. New and existing research developments in stratification for clinical trials and neuroimaging are also discussed. We hope this Issue highlights relevant current issues in ASD, and provides insights which can help address the challenges in providing evidence based pathways to better meet the needs of autistic people into the future.

Genomic distances reveal relationships of wild and cultivated beets.

Cultivated beets (Beta vulgaris ssp. vulgaris), including sugar beet, rank among the most important crops. The wild ancestor of beet crops is the sea beet Beta vulgaris ssp. maritima. Species and subspecies of wild beets are readily crossable with cultivated beets and are thus available for crop improvement. To study genomic relationships in the genus Beta, we sequence and analyse 606 beet genomes, encompassing sugar beet, sea beet, B. v. adanensis, B. macrocarpa, and B. patula. We observe two genetically distinct groups of sea beets, one from the Atlantic coast and the other from the Mediterranean area. Genomic comparisons based on k-mers identify sea beets from Greece as the closest wild relatives of sugar beet, suggesting that domestication of the ancestors of sugar beet may be traced to this area. Our work provides comprehensive insight into the phylogeny of wild and cultivated beets and establishes a framework for classification of further accessions of unknown (sub-)species assignment.

The potential of gene therapy for recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal-epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.

Weather Conditions Conducive for the Early-Season Production and Dispersal of Cercospora beticola Spores in the Great Lakes Region of North America.

In many parts of the world including the Great Lakes region of North America, Cercospora leaf spot (CLS), caused by the fungal pathogen Cercospora beticola, is a major foliar disease of sugar beet (Beta vulgaris). Management of CLS involves an integrated approach which includes the application of fungicides. To guide fungicide application timings, disease prediction models are widely used by sugar beet growers in North America. While these models have generally worked well, they have not included information about pathogen presence. Thus, incorporating spore production and dispersal could make them more effective. The current study used sentinel beets to assess the presence of C. beticola spores in the environment early in the 2017 and 2018 growing seasons. Weather variables including air temperature, relative humidity, rainfall, leaf wetness, wind speed, and solar radiation were collected. These data were used to identify environmental variables that correlated with spore levels during a time when CLS is not generally observed in commercial fields. C. beticola spores were detected during mid-April both years, which is much earlier than previously reported. A correlation was found between spore data and all the weather variables examined during at least one of the two years, except for air temperature. In both years, spore presence was significantly correlated with rainfall (P < 0.0001) as well as relative humidity (P < 0.0090). Rainfall was particularly intriguing, with an adjusted R2 of 0.3135 in 2017 and 0.1652 in 2018. Efforts are ongoing to investigate information on spore presence to improve prediction models and CLS management.

WNT10A, dermatology and dentistry.

WNTs (Wingless-related integration sites) are secreted glycoproteins that are involved in signalling pathways critical to organ development and tissue regeneration. Of the 19 known WNT ligands, one member of this family, WNT10A, appears to have specific relevance to skin, its appendages and teeth. This review focuses on how variants in the WNT10A gene have been associated with various ectodermal disorders and how such changes may have clinical relevance to dermatologists and dentists. Germline mutations in WNT10A underlie several forms of autosomal recessive ectodermal dysplasia in which heterozygous carriers may also display some lesser ectodermal anomalies. Within the general population, multiple heterozygous variants in WNT10A can cause skin, hair, sweat gland or dental alterations, also known as ectodermal derivative impairments. WNT10A variants have also been implicated in hair thickness, male androgenetic alopecia, hair curl, acne vulgaris, lipodystrophy, keloids, wound healing, tooth size, tooth agenesis, hypodontia, taurodontism and oral clefting. Beyond dermatology and dentistry, WNT10A abnormalities have also been identified in kidney fibrosis, keratoconus, certain malignancies (particularly gastrointestinal) and neuropathic pain pathways. In this review, we detail how WNT10A is implicated as a key physiological and pathological contributor to syndromic and nonsyndromic disorders, as well as population variants, affecting the skin and teeth, and document all reported mutations in WNT10A with genotype-phenotype correlation.

A multidisciplinary evaluation of suspected, non-confirmed cases of COVID-19 including chest CT, as compared to World Health Organization recommendations.

AIM: To report an audit of the evaluation of suspected, unconfirmed cases of COVID-19 including chest computed tomography (CT), as compared to World Health Organization recommendations. METHODS: A clinical audit was undertaken examining the evaluation of patients with suspected COVID-19 with negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) results, with comparison to WHO recommendations. A retrospective chart review was undertaken for 90 patients examining investigations, in particular CT, used to clarify the diagnosis. RESULTS: Ninety patients underwent additional investigation. Seventy-five per cent adherence to WHO recommendations was observed. Fifty-two men (57.78%) and 38 (42.22%) women were investigated, with a median age of 69 years (range 20-96 years). Seventy-nine chest CT examinations demonstrated positive, indeterminate, and negative rates for COVID-19 of 3.79%, 24.1%, and 72.15% respectively. Three patients had discordant swab results with initially negative and subsequently positive results for SARS-CoV-2, resulting in false-negative rates of 5.1% for those retested. Combining discordant RT-PCR swab results, positive radiology, and patients treated as COVID-19-positive due to indeterminate radiology and highly consistent symptoms, resulted in a false-negative rate for initial SARS-CoV-2 RT-PCR swabs of 16.67%. CONCLUSION: Seventy-five per cent compliance with relevant WHO guidance and a false-negative rate for initial swabs of 16.67% was demonstrated. Further evidence is needed to fully determine the utility of chest CT in the diagnosis of COVID-19 in the context of initial false-negative RT-PCR results.

Effect of 25-hydroxyvitamin D3 during prepartum transition and lactation on production, reproduction, and health of lactating dairy cows.

We hypothesized that feeding 25-hydroxyvitamin D3 [25-(OH)D3] during lactation and prepartum in conjunction with negative dietary cation-anion difference diets would improve milk production, increase the probability of pregnancy, and reduce the incidence of postcalving diseases. Cows from 4 dairies with prepartum transition diets negative in dietary cation-anion difference were used in 2 randomized cohort experiments. In Experiment 1 (Exp. 1), cows were assigned to control [CON; n = 645; no 25-(OH)D3] or treatment [TRT; n = 537; 2 mg/d of 25-(OH)D3 from ∼21 d prepartum to parturition and 1 mg/d in lactation] groups at ∼21 d prepartum. Cows were monitored for weekly milk yield, milk composition every 60 d, and health and reproductive measures. In Experiment 2 (Exp. 2), cows (n = 2,064; median 147 d in milk) were assigned to 4 groups and monitored for the same measures as in Exp. 1 to the end of that lactation (L1), the subsequent transition (∼21 d prepartum to parturition), and the next lactation (L2). Groups were as follows, with the amount of 25-(OH)D3 fed (mg/d) indicated in parentheses for L1, transition, and L2, respectively: (A) control-control (CON-CON; 0-0-0), (B) treatment-treatment (TRT-TRT; 1-2-1), (C) control-treatment (CON-TRT; 0-2-1), and (D) treatment-control (TRT-CON; 1-0-0). For L1, a total of 1,032 cows entered the control groups A or C and a total of 1,032 cows in groups B or D. The number of cows in groups A to D that entered L2 was 521, 523, 273, and 248, respectively. Blood calcium, phosphorus, and 25-(OH)D3 concentrations were measured from 17 cows/group at 5 times. In Exp. 1, TRT cows had 0.2 lower log somatic cell count than CON cows (4.21 ± 0.045 vs. 4.01 ± 0.050, respectively) and multiparous TRT cows had 41 ± 23% higher probability of pregnancy/day than multiparous CON cows, resulting in a 22-d median decrease in time to pregnancy. Primiparous TRT cows had 1.67 ± 0.40 times greater odds of mastitis/day than primiparous CON cows. In Exp. 2 TRT-TRT cows had between 16 and 29% lower probability to be bred/day than other groups. Multiparous CON-CON and TRT-CON cows had 20 ± 8% and 30 ± 17% greater probability of pregnancy, respectively, than multiparous TRT-TRT cows. Serum calcium concentrations were not affected by group, but phosphorus and 25-(OH)D3 concentrations were highest in the TRT-TRT cows. The study provides further insights into the use of 25(OH)D3 in transition and lactation.

The provision of a time-critical elective surgical service during the COVID-19 Crisis: a UK experience.

INTRODUCTION: With the emergence of the COVID-19 pandemic, all elective surgery was temporarily suspended in the UK, allowing for diversion of resource to manage the anticipated surge of critically unwell patients. Continuing to deliver time-critical surgical care is important to avoid excess morbidity and mortality from pathologies unrelated to COVID-19. We describe the implementation and short-term surgical outcomes from a system to deliver time-critical elective surgical care to patients during the COVID-19 pandemic. MATERIALS AND METHODS: A protocol for the prioritisation and safe delivery of time-critical surgery at a COVID-19 'clean' site was implemented at the Nuffield Health Exeter Hospital, an independent sector hospital in the southwest of England. Outcomes to 30 days postoperatively were recorded, including unplanned admissions after daycase surgery, readmissions and complications, as well as the incidence of perioperative COVID-19 infection in patients and staff. RESULTS: A total of 128 surgical procedures were performed during a 31-day period by a range of specialties including breast, plastics, urology, gynaecology, vascular and cardiology. There was one unplanned admission and and two readmissions. Six complications were identified, and all were Clavien-Dindo grade 1 or 2. All 128 patients had preoperative COVID-19 swabs, one of which was positive and the patient had their surgery delayed. Ten patients were tested for COVID-19 postoperatively, with none testing positive. CONCLUSION: This study has demonstrated the implementation of a safe system for delivery of time-critical elective surgical care at a COVID-19 clean site. Other healthcare providers may benefit from implementation of similar methodology as hospitals plan to restart elective surgery.

A decade of next-generation sequencing in genodermatoses: the impact on gene discovery and clinical diagnostics.

BACKGROUND: Discovering the genetic basis of inherited skin diseases is fundamental to improving diagnostic accuracy and genetic counselling. In the 1990s and 2000s, genetic linkage and candidate gene approaches led to the molecular characterization of several dozen genodermatoses, but over the past decade the advent of next-generation sequencing (NGS) technologies has accelerated diagnostic discovery and precision. OBJECTIVES: This review examines the application of NGS technologies from 2009 to 2019 that have (i) led to the initial discovery of gene mutations in known or new genodermatoses and (ii) identified involvement of more than one contributing pathogenic gene in individuals with complex Mendelian skin disorder phenotypes. METHODS: A comprehensive review of the PubMed database and dermatology conference abstracts was undertaken between January 2009 and December 2019. The results were collated and cross-referenced with OMIM. RESULTS: We identified 166 new disease-gene associations in inherited skin diseases discovered by NGS. Of these, 131 were previously recognized, while 35 were brand new disorders. Eighty-five were autosomal dominant (with 43 of 85 mutations occurring de novo), 78 were autosomal recessive and three were X-linked. We also identified 63 cases harbouring multiple pathogenic mutations, either involving two coexisting genodermatoses (n = 13) or an inherited skin disorder in conjunction with other organ system phenotypes (n = 50). CONCLUSIONS: NGS technologies have accelerated disease-gene discoveries in dermatology over the last decade. Moreover, the era of NGS has enabled clinicians to split complex Mendelian phenotypes into separate diseases. These genetic data improve diagnostic precision and make feasible accurate prenatal testing and better-targeted translational research.