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Data sharing: The PHOSP-COVID study protocol, consent form, definition, and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online. UK Biobank information can be released once necessary approvals have been obtained. Other data (eg, the R code and protocol) will be made available on reasonable request to the corresponding author. Copyright © 2023 The Author(s). Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council. UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.

Data sharing statement: PHOSP-COVID: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, requests for data access and other relevant study materials are available online at https://www.phosp.org. COVIDENCE UK: De-identified participant data will be made available upon reasonable request to the corresponding author. Supplementary data is available online at: https://www.sciencedirect.com/science/article/pii/S2666776223000546?via%3Dihub#appsec1 . Copyright © 2023 The Author(s). Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders. PHOSP-COVID: This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma + Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. COVIDENCE UK: We thank all participants of COVIDENCE UK, and the following organisations who supported study recruitment: Asthma UK/British Lung Foundation, the British Heart Foundation, the British Obesity Society, Cancer Research UK, Diabetes UK, Future Publishing, Kidney Care UK, Kidney Wales, Mumsnet, the National Kidney Federation, the National Rheumatoid Arthritis Society, the North West London Health Research Register (DISCOVER), Primary Immunodeficiency UK, the Race Equality Foundation, SWM Health, the Terence Higgins Trust, and Vasculitis UK.

Adult form and function are dependent upon the activity of specialized signaling centers that act early in development at the embryonic midline. These centers instruct the surrounding cells to adopt a positional fate and to form the patterned structures of the phylotypic embryo. Abnormalities in these processes have devastating consequences for the individual, as exemplified by holoprosencephaly in which anterior midline development fails, leading to structural defects of the brain and/or face. In the 25 years since the first association between human holoprosencephaly and the sonic hedgehog gene, a combination of human and animal genetic studies have enhanced our understanding of the genetic and embryonic causation of this congenital defect. Comparative biology has extended the holoprosencephaly network via the inclusion of gene mutations from multiple signaling pathways known to be required for anterior midline formation. It has also clarified aspects of holoprosencephaly causation, showing that it arises when a deleterious variant is present within a permissive genome, and that environmental factors, as well as embryonic stochasticity, influence the phenotypic outcome of the variant. More than two decades of research can now be distilled into a framework of embryonic and genetic causation. This framework means we are poised to move beyond our current understanding of variants in signaling pathway molecules. The challenges now at the forefront of holoprosencephaly research include deciphering how the mutation of genes involved in basic cell processes can also cause holoprosencephaly, determining the important constituents of the holoprosencephaly permissive genome, and identifying environmental compounds that promote holoprosencephaly. This article is categorized under: Congenital DiseasesStem Cells and Development Congenital DiseasesGenetics/Genomics/Epigenetics Congenital DiseasesMolecular and Cellular Physiology Congenital DiseasesEnvironmental Factors.

Zinc finger of the cerebellum (Zic) proteins act as classic transcription factors to promote transcription of the Foxd3 gene during neural crest cell specification. Additionally, they can act as co-factors that bind proteins from the T-cell factor/lymphoid enhancing factor (TCF/LEF) family (TCFs) to repress WNT–β-catenin-dependent transcription without contacting DNA. Here, we show that ZIC activity at the neural plate border is influenced by WNT-dependent SUMOylation. In the presence of high canonical WNT activity, a lysine residue within the highly conserved zinc finger N-terminally conserved (ZF-NC) domain of ZIC5 is SUMOylated, which reduces formation of the ZIC–TCF co-repressor complex and shifts the balance towards transcription factor function. The modification is crucial in vivo, as a ZIC5 SUMO-incompetent mouse strain exhibits neural crest specification defects. This work reveals the function of the ZF-NC domain within ZIC, provides in vivo validation of target protein SUMOylation and demonstrates that WNT–β-catenin signalling directs transcription at non-TCF DNA-binding sites. Furthermore, it can explain how WNT signals convert a broad region of Zic ectodermal expression into a restricted region of neural crest cell specification.

Most juvenile detention facilities do not screen for Trichomonas Vaginalis (TV) despite being the most common parasitic STI. We aimed to assess TV prevalence and risk factors among young women in a large urban juvenile detention center. We evaluated a retrospective cohort from April to December 2016. Youth submitted an intake urine sample for gonorrhea and chlamydia testing; we tested remnant urine for TV. Outcomes included prevalence of TV and risk factors for infection. A total of 1009 samples were collected, 374 from young women ages 13 - 17 years old. Among females, 8% tested positive for TV with co-infection of either gonorrhea, chlamydia or both occurring in 12/29 (41%) patients. Compared to youth without TV females with TV were more likely to be African American (76%) and report symptoms (41%) (p0.05). In our study population, prevalence of TV was 8%. As nearly half of those with TV were asymptomatic, we recommend routine screening among this population.

Liver fluke infection (fascioliasis) is a parasitic disease which affects the health and welfare of ruminants. It is a concern for the livestock industry and is considered as a growing threat to the industry because changing climatic conditions are projected to be more favorable to increased frequency and intensity of liver fluke outbreaks. Recent reports highlighted that the incidence and geographic range of liver fluke has increased in the UK over the last decade and estimated to increase the average risk of liver fluke in the UK due to increasing temperature and rainfall. This paper explores financial impacts of the disease with and without climate change effects on Scottish livestock farms using a farm-level economic model. The model is based on farming system analysis and uses linear programming technique to maximize farm net profit within farm resources. Farm level data from a sample of 160 Scottish livestock farms is used under a no disease baseline scenario and two disease scenarios (with and without climate change). These two disease scenarios are compared with the baseline scenario to estimate the financial impact of the disease at farm levels. The results suggest a 12% reduction in net profit on an average dairy farm compared to 6% reduction on an average beef farm under standard disease conditions. The losses increase by 2-fold on a dairy farm and 6-fold on a beef farm when climate change effects are included with disease conditions on farms. There is a large variability within farm groups with profitable farms incurring relatively lesser economic losses than non-profitable farms. There is a substantial increase in number of vulnerable farms both in dairy (+20%) and beef farms (+27%) under the disease alongside climate change conditions.

Zinc finger of the cerebellum (Zic) proteins act as classical transcription factors to promote transcription of the Foxd3 gene during neural crest cell specification. Additionally, they can act as co-factors that bind TCF molecules to repress WNT/β-catenin dependent transcription without contacting DNA. Here, we show ZIC activity at the neural plate border is influenced by WNT-dependent SUMOylation. In a high WNT environment, a lysine within the highly conserved ZF-NC domain of ZIC5 is SUMOylated, which decreases formation of the TCF/ZIC co-repressor complex and shifts the balance towards transcription factor function. The modification is critical in vivo, as a ZIC5 SUMO-incompetent mouse strain exhibits neural crest specification defects. This work reveals the function of the ZIC ZF-NC domain, provides in vivo validation of target protein SUMOylation, and demonstrates that WNT/β-catenin signalling directs transcription at non-TCF DNA binding sites. Furthermore, it can explain how WNT signals convert a broad domain of Zic ectodermal expression into a restricted domain of neural crest cell specification.

Understanding RNA expression in space and time is a key initial step in dissecting gene function. The ability to visualize gene expression in whole-tissue or whole-specimen preparations, called in situ hybridization (ISH), was first developed 50 years ago. Two decades later, these protocols were adapted to establish robust methods for whole-mount ISH to murine embryos. The precise protocols vary somewhat between early-gestation and mid-gestation mouse embryos; the protocol presented here is optimal for use with post-implantation stage mouse embryos (stages 5.5-9.5 dpc). Routine uses of whole-mount ISH include documenting the wild-type expression pattern of individual genes and comparison of the expression pattern of signature genes (i.e., those that identify particular cells and tissues within an embryo) between wild-type and mutant embryos as part of a phenotyping experiment. This technique remains a mainstay of developmental biology studies and complements the massively parallel assessment of gene expression from dissociated tissues and cells via RNA-sequencing techniques. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Dissection of post-implantation (5.5-9.5 dpc) murine embryos Basic Protocol 2: Whole-mount in situ hybridization in post-implantation embryos Basic Protocol 3: Visualization of post-WMISH embryos Support Protocol 1: Creation of siliconized glass pipettes Support Protocol 2: Creation of embryo powder.

Experiments that visualize gene expression in intact tissues or organisms are fundamental to studies of gene function. These experiments, called in situ hybridization, require the production of a riboprobe, which is a labeled antisense RNA corresponding to a particular gene. The most commonly used system for visualizing gene expression via in situ hybridization is the incorporation of a digoxigenin label into an in vitro-transcribed RNA probe. After hybridization of the riboprobe to a target mRNA, its location can be detected via a high-affinity α-digoxigenin antibody conjugated to an alkaline-phosphatase enzyme. The article describes the design and production of digoxigenin-labeled riboprobes transcribed in vitro from template DNA (either plasmid or PCR amplicon). These riboprobes are suitable for use in tissue and whole-mount in situ hybridization protocols. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Plasmid-derived riboprobes Alternate Protocol: PCR-derived riboprobes Basic Protocol 2: Riboprobe synthesis with DIG label.

The knowledge of epidemiology of a disease is paramount in identifying preventive measures. Currently there is a paucity of literature on the epidemiologic determinants of childhood onset essential hypertension (EH). We evaluated children with EH, ascertained in a rigorous manner, in a large multiethnic population in a tertiary pediatric hypertension clinic. We enrolled children with and without EH and obtained data by in-person interview of their parents and by direct anthropometric measurements including blood pressures. A total of 148 children (76 hypertension probands, 72 control probands, and males 53%, mean age 12.2 ± 4.3 years) were enrolled. Of these 148 children, 51 pairs were matched 1:1 on ethnicity, gender and age (± 2.5 years). In this study we evaluated the demographics, genetic predisposition and a variety of exposures including, socioeconomic, perinatal, lifestyle and environmental, between cases and controls. All measures were similar between cases and controls other than a significantly higher BMI (p = 0.01) and rates of obesity (p = 0.03), and a difference of near-significance in any family history of EH (p = 0.05) higher in cases compared to controls. The odds of obesity was 3.5 times higher among cases than controls. In this study we evaluated a variety of prenatal and postnatal exposures that could potentially contributed to the EH phenotype in childhood. The findings of the study elucidate the epidemiology of EH in children and two important associated risk factors, any family history of hypertension and a higher body weight.

The mechanisms of neural crest cell induction and specification are highly conserved among vertebrate model organisms, but how similar these mechanisms are in mammalian neural crest cell formation remains open to question. The zinc finger of the cerebellum 1 (ZIC1) transcription factor is considered a core component of the vertebrate gene regulatory network that specifies neural crest fate at the neural plate border. In mouse embryos, however, Zic1 mutation does not cause neural crest defects. Instead, we and others have shown that murine Zic2 and Zic5 mutate to give a neural crest phenotype. Here, we extend this knowledge by demonstrating that murine Zic3 is also required for, and co-operates with, Zic2 and Zic5 during mammalian neural crest specification. At the murine neural plate border (a region of high canonical WNT activity) ZIC2, ZIC3, and ZIC5 function as transcription factors to jointly activate the Foxd3 specifier gene. This function is promoted by SUMOylation of the ZIC proteins at a conserved lysine immediately N-terminal of the ZIC zinc finger domain. In contrast, in the lateral regions of the neurectoderm (a region of low canonical WNT activity) basal ZIC proteins act as co-repressors of WNT/TCF-mediated transcription. Our work provides a mechanism by which mammalian neural crest specification is restricted to the neural plate border. Furthermore, given that WNT signaling and SUMOylation are also features of non-mammalian neural crest specification, it suggests that mammalian neural crest induction shares broad conservation, but altered molecular detail, with chicken, zebrafish, and Xenopus neural crest induction.

The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE.

Johne's disease is an endemic contagious bacterial infection of ruminants which is prevalent in the United Kingdom and elsewhere. It can lower financial returns on infected farms by reducing farm productivity through output losses and control expenditures. A farm-level analysis of the economics of the disease was conducted taking account of farm variability and different disease prevalence levels. The aim was to assess the financial impacts of a livestock disease on farms and determine their financial vulnerability if farm support payments were to be removed under future policy reforms. A farm-level optimization model, ScotFarm, was used on 50 Scottish dairy farms taken from the Farm Business Survey to determine the impacts of the disease. A counterfactual comparison of five alternative "disease" scenarios with a "no-disease" scenario was carried out to evaluate economic impact of the disease. The extent of a farm's reliance on direct support payments was considered to be an indicator of their financial vulnerability. Under this definition, farms were grouped into three financial vulnerability risk categories; "low risk," "medium risk," and "high risk" farms. Results show that farms are estimated to incur a loss of 32% on average of their net profit under a standard disease prevalence level. Farms in the "low risk" and "medium risk" categories were estimated to have a lower financial impact of the disease (22 and 28% reduction on farm net profit, respectively) which, along with their lower reliance on farm direct support payments, indicate they would be more resilient to the disease under future changes in farm payment support. On the contrary, farms in the "high risk" category were estimated to have a reduction of 50% on their farm net profit. A majority of these farms (61%) in the "high risk" category move from being profitable to loss making under the standard disease scenario when farm support payments are removed. Of these, 15% do so because of the impact of the disease. These farms will be more vulnerable if changes were to be made in farm support payments under future agricultural policy reforms.

Objective: This study aimed to assess fluoride intake in infants from formula reconstituted with water, with fluorosis risk in mind. Study Design: Data on water source, formula brand/type, volume of formula consumption and infant weight were collected for infants at two-, four-, six-, nine- and twelve-month pediatrician well child visits. Identified formula brands and water types were reconstituted and analyzed for fluoride concentration. Patient body mass and volume consumed/day were used to estimate fluoride intake from reconstituted formula. Descriptive statistics, one-way analysis of variance and chi-square tests were utilized. Results: All infants consumed formula reconstituted with minimally fluoridated water (0.0– 0.3 ppm). 4.4% of infants exceeded the recommended upper limit (UL) of 0.1mg/kg/day. Although mean daily fluoride consumption significantly differed among all groups, the proportion of infants at each visit milestone that exceeded daily fluoride intake of 0.1mg/kg/day was not statistically significantly different (p>0.05) for any age group. Predicted values calculated with optimally fluoridated water (0.7ppm) resulted in 36.8% of infants exceeding the UL. Conclusions: Optimally fluoridated water may increase fluorosis risk for patients younger than six months. Future investigation should include multiple sites and multi-year follow-up to assess actual fluorosis incidence.

Quantitative reverse transcriptase PCR (RT-qPCR), a powerful and efficient means of rapidly comparing gene expression between experimental conditions, is routinely used as a phenotyping tool in developmental biology. The accurate comparison of gene expression across multiple embryonic stages requires normalisation to reference genes that have stable expression across the time points to be examined. As the embryo and its constituent tissues undergo rapid growth and differentiation during development, reference genes known to be stable across some time points cannot be assumed to be stable across all developmental stages. The immediate post-implantation events of gastrulation and patterning are characterised by a rapid expansion in cell number and increasing specialisation of cells. The optimal reference genes for comparative gene expression studies at these specific stages have not been experimentally identified. In this study, the expression of five commonly used reference genes (H2afz, Ubc, Actb, Tbp and Gapdh) was measured across murine gastrulation and patterning (6.5–9.5 dpc) and analysed with the normalisation tools geNorm, Bestkeeper and Normfinder. The results, validated by RT-qPCR analysis of two genes with well-documented expression patterns across these stages, indicated the best strategy for RT-qPCR studies spanning murine gastrulation and patterning utilises the concurrent reference genes H2afz and Ubc.

PURPOSE: Determining familial aggregation is an important first step in narrowing the search for disease-causing genes and hence we determined the familial aggregation of EH among first degree relatives of children with EH. MATERIALS AND METHODS: We prospectively enrolled children with EH along with their first degree relatives from a tertiary pediatric hypertension clinic in a large ambulatory care center. We utilized rigorous methodology for blood pressure (BP) measurements and diagnoses of EH to reduce the heterogeneity in the phenotype. For those enrolled, parental BP status was confirmed by in-clinic direct BP measurements. We also enrolled control children without EH along with their first degree relatives from the same pediatric ambulatory center. RESULTS: In our case-control study of 153 families, the odds of having familial EH was more than 3 times higher among the cases than in controls (OR: 3.63, 95% CI: 1.85 – 7.12) with 71% of the cases and 41% of the controls reporting familial EH. One parent with EH was seen in 88% of the cases and 52% of the controls (OR: 6.92, 95% CI: 2.68 – 17.84). The odds of at least one parent (compared to neither) with EH was almost 7-fold higher, and odds of having two parents with EH was 14-fold higher among cases versus controls. The risk of EH did not go back from the first degree relative to the second degree relatives. CONCLUSIONS: We identified familial aggregation with an increased liability of childhood onset EH with parental EH. The risk of childhood onset EH is more than doubled in the presence of EH in both parents versus in a single parent. Prediction for childhood-onset EH is improved by obtaining a family history of EH in the first degree relatives.

The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.

The five murine Zic genes encode multifunctional transcriptional regulator proteins important for a large number of processes during embryonic development. The genes and proteins are highly conserved with respect to the orthologous human genes, an attribute evidently mirrored by functional conservation, since the murine and human genes mutate to give the same phenotypes. Each ZIC protein contains a zinc finger domain that participates in both protein-DNA and protein-protein interactions. The ZIC proteins are capable of interacting with the key transcriptional mediators of the SHH, WNT and NODAL signalling pathways as well as with components of the transcriptional machinery and chromatin-modifying complexes. It is possible that this diverse range of protein partners underlies characteristics uncovered by mutagenesis and phenotyping of the murine Zic genes. These features include redundant and unique roles for ZIC proteins, regulatory interdependencies amongst family members and pleiotropic Zic gene function. Future investigations into the complex nature of the Zic gene family activity should be facilitated by recent advances in genome engineering and functional genomics.

The prevalence and effect of single-parent families in childhood-onset essential hypertension (EH) is unknown. Children with EH and age-, sex-, and ethnicity-matched controls were enrolled. Family structure data were obtained by in-person interview. A total of 148 families (76 hypertension probands, 72 control probands; median 14 years) were prospective-ly enrolled in the study. Single-parent status was seen in 42% of the families--with and without EH (38% vs 46%, P=.41; odds ratio, 0.7; 95% confidence interval, 0.4-1.4). After multivariable analysis, a statistically significant sociofamilial contributor to the development of childhood-onset EH was not identified. A significant number of single-parent families (42%), the majority with single mothers, were found in our pedigree study. Sociofamilial factors are known to contribute to the expression of adult-onset EH, but findings in our study suggest that they appear to contribute less in the expression of childhood-onset EH.

[This corrects the article DOI: 10.1371/journal.pone.0198436.].

The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.

The five murine Zic genes encode multifunctional transcriptional regulator proteins important for a large number of processes during embryonic development. The genes and proteins are highly conserved with respect to the orthologous human genes, an attribute evidently mirrored by functional conservation, since the murine and human genes mutate to give the same phenotypes. Each ZIC protein contains a zinc finger domain that participates in both protein-DNA and protein-protein interactions. The ZIC proteins are capable of interacting with the key transcriptional mediators of the SHH, WNT and NODAL signalling pathways as well as with components of the transcriptional machinery and chromatin-modifying complexes. It is possible that this diverse range of protein partners underlies characteristics uncovered by mutagenesis and phenotyping of the murine Zic genes. These features include redundant and unique roles for ZIC proteins, regulatory interdependencies amongst family members and pleiotropic Zic gene function. Future investigations into the complex nature of the Zic gene family activity should be facilitated by recent advances in genome engineering and functional genomics.

Objective In 2013, the Association of American Medical Colleges created the “Core Entrustable Professional Activities (EPAs) for Entering Residency” to more clearly define the set of activities that entering residents should be able to perform on day 1 of residency without direct supervision. EPA #11 is obtaining informed consent for tests and/or procedures. This EPA acknowledges that an entrustable learner should be able to document a complete consent among other components. The aim of this study is to explore whether incoming pediatric interns demonstrated the behaviors of an “entrustable learner” in the domain of documenting informed consent for a common pediatric procedure. Methods All incoming interns in our program (2007–2017) completed a 6-station Objective Structured Clinical Examination during residency orientation. One of the scenarios involves obtaining parental consent for a lumbar puncture (LP). The researchers determined and agreed what components would be important for a complete and accurately documented consent. A retrospective review of the resident's written informed consents occurred looking for accuracy of documented components. Results Of the 258 consents reviewed, 8 were complete and accurate. Incoming interns appear to be skilled when completing the basics of the informed consent form such as documenting names, obtaining signatures, and correctly identifying the procedure. However, detailing all the risks of the LP were areas for which they did not demonstrate proficiency. Conclusions Documenting informed consent is not adequately demonstrated by our learners prior to the beginning of internship. We would recommend specific training before entrusting pediatric interns to obtain LP consent independently.

Animal diseases are global issues affecting the productivity and financial profitability of affected farms. Johne’s disease is distributed on farms worldwide and is an endemic contagious bacterial infection in ruminants caused by Mycobacterium avium subspecies paratuberculosis. In cattle, the clinical disease manifests itself as chronic enteritis resulting in reduced production, weight loss, and eventually death. Johne’s disease is prevalent in the UK, including Scotland. Direct costs and losses associated with Johne’s disease have been estimated in previous research, confirming an important economic impact of the disease in UK herds. Despite this, the distributional impact of Johne’s disease among milk consumers and producers in Scotland has not been estimated. In this paper, we evaluate the change in society’s economic welfare, namely to dairy producers (i.e. infected and uninfected herds) and milk consumers in Scotland induced by the introduction of Johne’s disease in the national Scottish dairy herd. At the national-level, we conclude that the economic burden falls mainly on producers of infected herds and, to a lesser extent, milk consumers, while producers of uninfected herds benefit from the presence of Johne’s. An infected producer’s loss per cow is approximately two times larger in magnitude than that of an uninfected producer’s gain. Such economic welfare estimates are an important comparison of the relative costs of national herd prevalence and the wider economic welfare implications for both producers and consumers. This is particularly important from a policy, public good, cost sharing, and human health perspective. The economic welfare framework presented in this paper can be applied to other diseases to examine the relative burden of society’s economic welfare of alternative livestock disease scenarios. In addition, the sensitivity analysis evaluates uncertainty in economic welfare given limited data and uncertainty in the national herd prevalence, and other input parameters, associated with Johne’s disease in Scotland. Therefore, until the prevalence of Johne’s is better understood, the full economic cost to Scottish dairy herds remains uncertain but in the meantime the sensitivity analysis evaluates the robustness of economic welfare to such uncertainties.

Objective. To determine the variability of the institutional review board (IRB) process for a minimal risk multicenter study. Methods. Participants included 24 Continuity Research Network (CORNET) sites of the Academic Pediatric Association that participated in a cross-sectional study. Each site obtained individual institutional IRB approval. An anonymous questionnaire went to site investigators about the IRB process at their institution. Results Twenty-two of 24 sites (92%) responded. Preparation time ranged from 1 to 20 hours, mean of 7.1 hours. Individuals submitting ≤3 IRB applications/year required more time for completion than those submitting >3/year ( P < .05). Thirteen of 22 (59%) study sites received approval with “exempt” status, and 6 (27%) approved as “expedited” studies. Conclusions. IRB experiences were highly variable across study sites. These findings indicate that multicenter research projects should anticipate barriers to timely study implementation. Improved IRB standardization or centralization for multicenter clinical studies would facilitate this type of practice-based clinical research.

Summary The first molecular herald of organ asymmetry during murine embryogenesis is found at the periphery of the node in early-somite stage embryos. Asymmetric gene expression and calcium accumulation at the node occurs in response to a left-ward flow of extracellular fluid across the node, generated by motile cilia within the pit of the node and likely sensed by immotile cilia in the periphery of the node. The ciliation of node cells is controlled by a cascade of node-restricted transcription factor activity during mid-late gastrulation. Mutation of the murine Zic2 transcription factor is associated with random cardiac situs and a loss of asymmetric gene expression at the early-somite node and in the lateral plate. Zic2 is not expressed in these regions but is transiently expressed in the mid-late gastrula node at the time of ciliogenesis. The cilia of the node are overtly abnormal in Zic2 mutant embryos being dysmorphic and short relative to wild-type littermates. The expression of the Noto, Rfx3, and Foxj1 transcription factors known to regulate ciliogenesis is greatly depleted in the mid-gastrula node of mutants, as is the expression of the Pkd1l1 gene required for cilia function. Zic2 appears to be a component of the gene regulatory network that drives ciliation of node cells during gastrulation. genesis 52:626–635, 2014. © 2014 Wiley Periodicals, Inc.

Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

Background: Exposure to high levels of maternal stress and ineffective maternal–child engagement (MC-E) may adversely affect child health-related outcomes. Objective: The aim of this study was to examine the impact of maternal stress and MC-E on maternal and child biological responses (salivary cortisol and testosterone) and child health outcome in mother–child dyads of preschool children (3–5.9 years) in a low socioeconomic setting. Methods: Observational and biobehavioral data were collected from 50 mother–child dyads in a preschool setting. Assessments included maternal stress with the Perceived Stress Scale, child health outcomes with the Pediatric Quality of Life Inventory, and MC-E with videotaped mother–child interactions and scored with the Keys to Interactive Parenting Scale. Morning and evening saliva samples were collected from mother and child for biological assays. Results: Maternal stress was negatively correlated with MC-E (r = −.32, p < .05) and child health outcome (r = −.33, p < .05). Lower levels of MC-E predicted higher morning cortisol (p = .02) and higher morning and bedtime testosterone levels in children (p = .03 and p = .04, respectively). Child biological responses did not predict child health outcome. Discussion: Maternal stress and MC-E during mother–child interactions play a significant role in the regulation of child stress physiology and child health outcome. Elevated cortisol and testosterone related to high maternal stress and low MC-E may increase the child's vulnerability to negative health outcomes—if sustained. More biobehavioral research is needed to understand how parent–child interactions affect child development and health outcomes in early childhood.

Purpose Telephone interpretation and recent technology advances assist patients with more timely access to rare languages, but no one has examined the role of this technology in the medical setting and how medical students can be prepared for their use. We sought to determine if structured curriculum on interpretation would promote learners self-reported competency in these encounters and if proficiency would be demonstrated in actual patient encounters. Methods Training on the principles of interpreter use with a focus on communication technology was added to medical student education. The students later voluntarily completed a retrospective pre/post training competency self-assessment. A cohort of students rotating at a clinical site had a blinded review of their telephone interpretation encounters scored on a modified validated scale and compared to scored encounters with preintervention learners. Nested ANOVA models were used for audio file analysis. Results A total of 176 students who completed the training reported a statistically significant improvement in all 4 interpretation competency domains. Eighty-three audio files were analyzed from students before and after intervention. These scored encounters showed no statistical difference between the scores of the 2 groups. However, plotting the mean scores over time from each encounter suggests that those who received the curriculum started their rotation with higher scores and maintained those scores. Conclusions In an evaluation of learners' ability to use interpreters in actual patient encounters, focused education led to earlier proficiency of using interpreters compared to peers who received no training.

A constant challenge for industrialists in cold cathode technologies is the selection of a cathode material which exhibits suitable properties in order to improve performance. One particularly important aspect of performance is the sputter erosion of the cathode, which can lead to lamp failures. Traditionally, refractory metals have been favored for their high densities and energies of sublimation, which result in low sputter yields according to the theory due to Sigmund, and in experiment. However, this paper presents a simple theory which shows that the primary sputter yield is only one step in the liberation of sputtered material from the electrode. The energy of sublimation in fact plays an important role in the energy distribution of the sputtered material. Also, collisions in the bulk gas and the voltage characteristics of the cathode dark space should be taken into consideration for calculating the flux of liberated material. The paper presents a heuristic model of cold cathode sputtering in glow discharges with a view to elucidating the underlying physics in the process. The theory results in a reappraisal of electrode material properties that differs from the traditional view.

Various efforts within the cold cathode fluorescent lamp (CCFL) industry are underway to decrease costs and increase electrode performance. In order to understand the impact that the choice of gas mixtures and pressures, cathode shape and material might have on the lamp's operation requires a knowledge of the underlying principles governing the glow discharge. We present a review of the literature on the hollow cathode effect and glow discharges, which has particular relevance to the design of CCFL lamp electrodes used in liquid crystal displays. We show that industry-wide standard gas pressures and electrode designs cannot operate in the hollow cathode regime.

Tobacco use and secondhand tobacco-smoke (SHS) exposure are major national and international health concerns. Pediatricians and other clinicians who care for children are uniquely positioned to assist patients and families with tobacco-use prevention and treatment. Understanding the nature and extent of tobacco use and SHS exposure is an essential first step toward the goal of eliminating tobacco use and its consequences in the pediatric population. The next steps include counseling patients and family members to avoid SHS exposures or cease tobacco use; advocacy for policies that protect children from SHS exposure; and elimination of tobacco use in the media, public places, and homes. Three overarching principles of this policy can be identified: (1) there is no safe way to use tobacco; (2) there is no safe level or duration of exposure to SHS; and (3) the financial and political power of individuals, organizations, and government should be used to support tobacco control. Pediatricians are advised not to smoke or use tobacco; to make their homes, cars, and workplaces tobacco free; to consider tobacco control when making personal and professional decisions; to support and advocate for comprehensive tobacco control; and to advise parents and patients not to start using tobacco or to quit if they are already using tobacco. Prohibiting both tobacco advertising and the use of tobacco products in the media is recommended. Recommendations for eliminating SHS exposure and reducing tobacco use include attaining universal (1) smoke-free home, car, school, work, and play environments, both inside and outside, (2) treatment of tobacco use and dependence through employer, insurance, state, and federal supports, (3) implementation and enforcement of evidence-based tobacco-control measures in local, state, national, and international jurisdictions, and (4) financial and systems support for training in and research of effective ways to prevent and treat tobacco use and SHS exposure. Pediatricians, their staff and colleagues, and the American Academy of Pediatrics have key responsibilities in tobacco control to promote the health of children, adolescents, and young adults.

Measurements of impulsive and premeditated aggression, developed recently, have been applied to prison and outpatient populations without severe mental disorders. Comparable measures of impulsive and premeditated aggression have not been developed for populations with a severe mental disorder. A practical difficulty is that seriously disturbed, thought-disordered patients are incapable of providing reliable historical information. The investigators adapted the Barratt-Stanford instrument for differentiating impulsive from premeditated aggression so that instead of serving as an interview schedule, it could be used to assess aggression from previously documented written descriptions. The study found that the majority of ratable patients showed predominantly impulsive aggression, and after omitting four weak items, the inter-rater reliability for the determination of impulsive aggression was good (k = 0.53). Far fewer of the patients were determined to have shown predominantly premeditated aggression (from 14.2% to 15.5%) and the inter-rater reliability for premeditated aggression was deemed fair (k = 0.33).

Polycystic ovary syndrome (PCOS) was first described in 1935 by Stein and Levanthal (1935) in the American Journal of Obstetrics and Gynecology. Yet, it remains a syndrome that is confusing to many patients and practitioners in terms of its presentation, work-up, and management. There is a spectrum of presenting complaints and physical findings as well as overlap with other disorders, such as the metabolic syndrome. PCOS affects about 5% to 10% of women in their reproductive years (Asuncion et al., 2000; Diamanti-Kandarakis, 2008; Knochenhauer et al., 1998), and can be associated with infertility, uterine changes, and endocrinopathies. Furthermore, as we are seeing an increase in obesity among our younger patients, particularly in the United States (Molnar, 2004; Ogden et al., 2006), we are likely to be identifying more adolescent patients with this syndrome. Recognizing the presenting signs and symptoms and knowing the proper diagnostic tests and treatment options for PCOS is therefore important. DIAGNOSTIC CRITERIA Adolescents with hirsutism, acne, obesity, and/or irregular menses may raise concern of PCOS. Because the clinical presentations vary, it is important to have specific diagnostic criteria. The Androgen Excess and PCOS Society recently convened to review available data and provide a revised definition of PCOS based on current knowledge. The most current proposed criteria from the Society include the presence of all of the following (Azziz et al., 2009): 1. Hyperandrogenism: Hirsutism and/or hyperandrogenemia 2. Ovarian dysfunction: Oligoanovulation and/or polycystic ovaries 3. Exclusion of other androgen excess or related disorders

The purpose of this policy statement is to address the serious underinsurance (ie, insurance that exists but is inadequate) problems affecting insured adolescents' access to needed preventive, reproductive, and behavioral health care. In addition, the statement addresses provider payment problems that disproportionately affect clinicians who care for adolescents.Among adolescents with insurance, particularly private health insurance, coverage of needed services is often inadequate. Benefits are typically limited in scope and amount; certain diagnoses are often excluded; and cost-sharing requirements are often too high. As a result, underinsurance represents a substantial problem among adolescents and adversely affects their health and well-being.In addition to underinsurance problems, payment problems in the form of inadequate payment, uncompensated care for confidential reproductive services, and the failure of insurers to recognize and pay for certain billing and diagnostic codes are widespread among both private and public insurers. Payment problems negatively affect clinicians' ability to offer needed services to adolescents, especially publicly insured adolescents.

Background: Impulsivity is a key component of the manic behavior of bipolar disorder and is reported to occur in bipolar patients as a stable characteristic, i.e. a trait. Nevertheless, impulsivity has not been widely studied in depressed bipolar patients. We assessed impulsivity in depressed and euthymic bipolar and unipolar patients and healthy controls. We hypothesized that bipolar subjects would have higher levels of trait impulsivity than the comparison groups. Methods: Twenty-four depressed bipolar, 24 depressed unipolar, 12 euthymic bipolar, and 10 euthymic unipolar patients, as well as 51 healthy subjects were evaluated with the Barratt Impulsiveness Scale (BIS). Analysis of covariance with age and sex as covariates was used to compare mean group differences. Results: Depressed bipolar, euthymic bipolar, and depressed unipolar patients did not differ, and showed greater impulsivity than healthy controls on all of the BIS scales. Euthymic unipolar patients scored higher than healthy controls only on motor impulsivity. Limitations: Higher number of past substance abusers in the bipolar groups, and no control for anxiety and personality disorders, as well as small sample sizes, limit the reach of this study. Conclusions: This study replicates prior findings of stable trait impulsivity in bipolar disorder patients, and extends them, confirming that this trait can be demonstrated in depressed patients, as well as manic and euthymic ones. Trait impulsivity may be the result of repeated mood episodes or be present prior to their onset, either way it would influence the clinical presentation of bipolar disorder.

The oxide cathode is probably the most widely used electron emitter in vacuum electronic devices and is still in use today. This paper reviews the evolution of the theories and technology of the oxide cathode from its origins in 1904 up to the present day. The paper illustrates how the theories have changed with advances in analytical techniques and how the performance of oxide cathodes has developed in response to the demands of the cathode ray tube (CRT) industry. By manipulation of the interface between the oxide coating and the cathode cap and by varying the composition of the coating itself, the oxide cathode has continued to evolve for over 100 years and remains the predominant technology in the cathode ray tube industry.