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Background: Video-based interventions (VBIs) are an approach that can be used to promote social behavioural skills for autistic children and young people. Despite an abundance of literature in this area, previous evidence syntheses are limited by their exclusive search strategies and eligibility criteria. Therefore, there is a lack of comprehensive evidence syntheses to provide insight on whether these interventions work, for whom, and in what circumstances. Evidence and Gap Maps (EGMs) are used to collate vast literature on a broad topic area such as this, highlighting areas for synthesis, and identifying gaps for future research., Objectives: To identify, map and synthesise existing primary research on VBIs promoting social behavioural skills for autistic children and young people, creating a live, searchable and publicly available EGM., Search Methods: Searches were conducted in electronic databases ( n  = 8), web search engines, and other repositories including published papers and grey literature. The search strategy was developed around two concepts including (1) terms related to autism, and (2) terms related to VBIs. Searches were conducted in May 2021., Selection Criteria: All primary studies evaluating the effectiveness of VBIs in promoting social behaviours for autistic children and young people aged 3-18 were included in the EGM., Data Collection and Analysis: Search results were imported into Eppi-Reviewer where duplicates of identical studies were removed. Titles and abstracts were then screened by two independent reviewers. Potentially eligible full texts were located and also screened by two reviewers. Data were then extracted on study design, participant characteristics, type of intervention, type of outcome, and country of study, by one of three reviewers. EPPI-Mapper was used to create the interactive EGM., Main Results: The current EGM contains 438 studies reporting on 394 single subject research designs, 25 randomised controlled trials, 15 non-randomised group designs, and 8 pretest-posttest designs. Included studies evaluated VBIs in all male ( n  = 238), mixed gender ( n  = 172) or all female ( n  = 17) samples. VBIs employed included video modelling ( n  = 273), video self-modelling ( n  = 82), point-of-view modelling ( n  = 61), video prompting ( n  = 57), video feedback ( n  = 12) and computer-based video instruction ( n  = 4). The most frequently used models were adults ( n  = 191) and peers ( n  = 135). In relation to social outcomes, almost half evaluated social engagement ( n  = 199) with limited studies looking at safety ( n  = 9) and community ( n  = 7) skills., Authors' Conclusions: This EGM provides a valuable resource for policy-makers, practitioners, researchers, funders and members of the public to access evidence on VBIs promoting social behavioural skills in autistic children and young people. The map has identified areas of sufficient research where evidence can undergo synthesis. In addition, important gaps in the evidence were highlighted and suggest further research is warranted in all female samples and less frequently evaluated types of VBIs and social outcomes. Evidence included in this EGM will be further explored via systematic review and meta-analysis on control group designs., (© 2024 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Introduction: The COVID-19 pandemic posed a significant lifecourse rupture, not least to those who had specific physical vulnerabilities to the virus, but also to those who were suffering with mental ill health. Women and birthing people who were pregnant, experienced a perinatal bereavement, or were in the first post-partum year (i.e., perinatal) were exposed to a number of risk factors for mental ill health, including alterations to the way in which their perinatal care was delivered., Methods: A consensus statement was derived from a cross-disciplinary collaboration of experts, whereby evidence from collaborative work on perinatal mental health during the COVID-19 pandemic was synthesised, and priorities were established as recommendations for research, healthcare practice, and policy., Results: The synthesis of research focused on the effect of the COVID-19 pandemic on perinatal health outcomes and care practices led to three immediate recommendations: what to retain, what to reinstate, and what to remove from perinatal mental healthcare provision. Longer-term recommendations for action were also made, categorised as follows: Equity and Relational Healthcare; Parity of Esteem in Mental and Physical Healthcare with an Emphasis on Specialist Perinatal Services; and Horizon Scanning for Perinatal Mental Health Research, Policy, & Practice., Discussion: The evidence base on the effect of the pandemic on perinatal mental health is growing. This consensus statement synthesises said evidence and makes recommendations for a post-pandemic recovery and re-build of perinatal mental health services and care provision., Competing Interests: SAS (King's College London) is in receipt of a Personal Doctoral Fellowship from the NIHR ARC South London Capacity Building Theme [NIHR-INF-2170]. KDB (King's College London) is in receipt of an NIHR Doctoral Research Fellowship [NIHR302565]. CAW (King's College London) is supported by the NIHR as an Academic Clinical Lecturer. MN and JS (King's College London) are currently supported by the National Institute for Health Research Applied Research Collaboration South London [NIHR ARC South London] at King's College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. CS (The International Stillbirth Alliance) is a Trustee for Mothers for Mothers, a perinatal mental health charity. VF (University of Liverpool) and KSS (University of the West of England Bristol) are currently serving committee members of the Society for Reproductive & Infant Psychology, with VF being a core officer (Treasurer) and KSS being the Communications Officer and one of the co-ordinators for the Research Development Workshop Grant scheme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Some of the authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Jackson, Greenfield, Payne, Burgess, Oza, Storey, Davies, De Backer, Kent-Nye, Pilav, Worrall, Bridle, Khazaezadeh, Rajasingam, Carson, De Pascalis, Fallon, Hartley, Montgomery, Newburn, Wilson, Harrold, Howard, Sandall, Magee, Sheen and Silverio.)

Introduction: In the UK, 1600 babies die every year before, during or immediately after birth at 20-28 weeks' gestation. This bereavement has a similar impact on parental physical and psychological well-being to late stillbirth (>28 weeks' gestation). Improved understanding of potentially modifiable risk factors for late stillbirth (including supine going-to-sleep position) has influenced international clinical practice. Information is now urgently required to similarly inform clinical practice and aid decision-making by expectant mothers/parents, addressing inequalities in pregnancy loss between 20 and 28 weeks., Methods and Analysis: This study focuses on what portion of risk of pregnancy loss 20-28 weeks' gestation is associated with exposures amenable to public health campaigns/antenatal care adaptation. A case-control study of non-anomalous singleton baby loss (via miscarriage, stillbirth or early neonatal death) 20 +0 to 27 +6 (n=316) and randomly selected control pregnancies (2:1 ratio; n=632) at group-matched gestations will be conducted. Data is collected via participant recall (researcher-administered questionnaire) and extraction from contemporaneous medical records. Unadjusted/confounder-adjusted ORs will be calculated. Exposures associated with early stillbirth at OR≥1.5 will be detectable (p<0.05, β>0.80) assuming exposure prevalence of 30%-60%., Ethics and Dissemination: NHS research ethical approval has been obtained from the London-Seasonal research ethics committee (23/LO/0622). The results will be presented at international conferences and published in peer-reviewed open-access journals. Information from this study will enable development of antenatal care and education for healthcare professionals and pregnant people to reduce risk of early stillbirth., Trial Registration Number: NCT06005272., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear., Objectives: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference., Design: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis., Setting: This took place in UK general practice., Participants: Participants were pregnant women with depression., Interventions: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation., Main Outcome Measures: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability., Data Sources: UK Clinical Practice Research Datalink., Results: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratio initiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratio continuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratio multivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratio propensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratio multivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratio propensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratio multivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratio propensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratio multivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratio propensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers., Limitations: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured., Conclusions: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation., Future Work: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment ; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.

Introduction: Previous studies in 2018 and 2022 have suggested increasing inpatient burden of pneumothorax and widespread variation in management. Local trends have never been elucidated. Northumbria Healthcare NHS Foundation Trust (NHCT) has a well-established pleural service, serving just over 600,000. Thus, we set up a local retrospective study to look at trends in pneumothorax presentation, management strategies, length of stay, and recurrence., Methods: A coding search for 'pneumothorax' was performed for all patients attending NHCT between 2010 and 2020 was performed with local Caldicott approval. A total of 1840 notes were analysed to exclude iatrogenic, traumatic, and paediatric events. After excluding those cases, 580 remained for further analysis, consisting of 183 primary pneumothoraces (PSP) and 397 secondary pneumothoraces (SSP)., Results: Median age for PSP was 26.5 years (IQR 17) with 69% male, and for SSP 68 years (IQR 11.5), 62% male; 23.5% of PSP and 8.6% of SSP were never smokers. The proportion of smokers and ex-smokers has not really changed over time: > 65% every year have been smokers or ex-smokers. Yearly pneumothorax incidence shows a downward trend for PSP but upwards for SSP. Median length of stay (LoS) for PSP was 2 days (IQR 2), and SSP 5 days (IQR 8), with a clear downward trend. From 2010 to 2015 > 50% PSP were managed with drain, but in 2019-2020 at least 50% managed conservatively, with a significant reduction in aspiration. Trends of recurrence for PSP are increasing, whereas for SSP is decreasing. Seventy-six (20 PSP, 56 SSP) went for surgery at the index time with 5.3% recurrence (20% recurrence in those without surgery)., Conclusions: This is the first known analysis of pneumothorax trends in a large trust in the northeast of England. The data in this study have certain limitations, including the lack of information on the size of pneumothorax and frailty indicators that may influence the decision for conservative management. Additionally, there is a reliance on clinical coding, which can introduce potential inaccuracies, and not all patient notes were accessible for analysis. Updated larger datasets should help elucidate trends better., (© 2023. The Author(s).)

Intertidal macroalgae, such as coralline algae, represent an essential structural element and substrate in rocky coastal zones. They have a high degree of flexibility allowing their survival in environments with severe mechanical stress during tidal cycles. This study characterised the genicula and intergenicula of the calcifying red algae Corallina officinalis across its geographic distribution in the Northeast Atlantic. Poleward populations have constructed more sturdy cell walls compared to equatorward populations, potentially due to greater local adaptations to higher frequency and intensity of environmental factors like storms and wave action. Southern populations showed a lack of local adaptation culminating in survival rather than thriving within their current environment, hence, they are located at the margin of this species' favourable conditions. Results clarify significant differences between latitudes and indicate a north-to-south gradient in this species' skeletal elemental composition. Northern populations were dominated by cadmium, whereas chromium was the major trace element found in southern populations. In the future, these characteristics could lead to a permanent decline and a decrease in the ecosystem functions of C. officinalis in the southern locations in the Northeast Atlantic, which may be accelerated by predicted future climatic changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified., Methods: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors., Results: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid β-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively)., Conclusions: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions., (Copyright © 2023 AGA Institute. All rights reserved.)

Background: Despite progress, stillbirth rates in many high- and upper-middle income countries remain high, and the majority of these deaths are preventable. We introduce the Ending Preventable Stillbirths (EPS) Scorecard for High- and Upper Middle-Income Countries, a tool to track progress against the Lancet's 2016 EPS Series Call to Action, fostering transparency, consistency and accountability., Methods: The Scorecard for EPS in High- and Upper-Middle Income Countries was adapted from the Scorecard for EPS in Low-Income Countries, which includes 20 indicators to track progress against the eight Call to Action targets. The Scorecard for High- and Upper-Middle Income Countries includes 23 indicators tracking progress against these same Call to Action targets. For this inaugural version of the Scorecard, 13 high- and upper-middle income countries supplied data. Data were collated and compared between and within countries., Results: Data were complete for 15 of 23 indicators (65%). Five key issues were identified: (1) there is wide variation in stillbirth rates and related perinatal outcomes, (2) definitions of stillbirth and related perinatal outcomes vary widely across countries, (3) data on key risk factors for stillbirth are often missing and equity is not consistently tracked, (4) most countries lack guidelines and targets for critical areas for stillbirth prevention and care after stillbirth and have not set a national stillbirth rate target, and (5) most countries do not have mechanisms in place for reduction of stigma or guidelines around bereavement care., Conclusions: This inaugural version of the Scorecard for High- and Upper-Middle Income Countries highlights important gaps in performance indicators for stillbirth both between and within countries. The Scorecard provides a basis for future assessment of progress and can be used to help hold individual countries accountable, especially for reducing stillbirth inequities in disadvantaged groups., (© 2023. The Author(s).)

Background: It is unclear whether hybrid closed-loop (HCL) therapy attenuates the metabolic impact of missed or suboptimal meal insulin bolus compared with sensor-augmented pump (SAP) therapy in children with type 1 diabetes in free-living conditions. Methods: This is an ancillary study from a multicenter randomized controlled trial that compared 24/7 HCL with evening and night (E/N) HCL for 36 weeks in children between 6 and 12 years old. In the present study, the 60 children from the E/N arm underwent a SAP phase, an E/N HCL for 18 weeks, then a 24/7 phase for 18 weeks, extended for 36 more weeks. The last 28-30 days of each of the four phases were analyzed according to meal bolus management (cumulated 6817 days). The primary endpoint was the percentage of time that the sensor glucose was in the target range (TIR, 70-180 mg/dL) according to the number of missed boluses per day. Findings: TIR was 54% ± 10% with SAP, 63% ± 7% with E/N HCL, and steadily 67% ± 7% with 24/7 HCL. From the SAP phase to 72 weeks of HCL, the percentage of days with at least one missed meal bolus increased from 12% to 22%. Estimated marginal (EM) mean TIR when no bolus was missed was 54% (95% confidence intervals [CI] 53-56) in SAP and it was 13% higher (95% CI 11-15) in the 24/7 HCL phase. EM mean TIR with 1 and ≥2 missed boluses/day was 49.5% (95% CI 46-52) and 45% (95% CI 39-51) in SAP, and it was 15% (95% CI 14-16) and 17% higher (95% CI 6-28), respectively, in the 24/7 HCL phase ( P  < 0.05 for all comparisons vs. SAP). Interpretation: HCL persistently improves glycemic control compared with SAP, even in case of meal bolus omission. ClinicalTrials.gov (NCT03739099).

Background: There is a need to shift pharmacy payment models, given the expanding role of the community pharmacist in improving patient outcomes, misaligned incentives of the existing reimbursement model, and deleterious effects of a lack of transparency on prescription costs., Objectives: The primary objective of this paper was to develop a payment strategy for a Membership Pharmacy Model within an independent community pharmacy setting. A secondary objective of this paper is to explore the early impact of a novel value-based pharmacy payment model on patients, pharmacies, and self-insured employers., Practice Description: Good Shepherd Pharmacy, a nonprofit Membership Pharmacy founded in Memphis, TN, in 2015., Practice Innovation: We discuss a novel, value-based payment model for community pharmacy, which involves a partnership between pharmacy and employer, without the use of a pharmacy benefit manager, using a recurring (i.e., membership pharmacy) business revenue model., Evaluation Methods: The pilot program was assessed using the RE-AIM framework., Results: The pilot enrolled 34 patients for whom 1399 prescriptions were filled spanning 13 quarterly refill cycles from January 2019-March 2022. After the intervention, proportion of days covered for diabetes and cholesterol medications both increased: 96.7% and 100% (P < 0.05); 90.3% and 98.1% (P > 0.05). Financial savings for the employer group were realized across both fee charges and prescription medication costs. The net savings provided to the employer was $67,843, a 35% reduction in topline pharmacy spending. Revenue for the pharmacy was realized exclusively through synchronization fees of $30 per fill. Synchronization fees for the entire study totaled $41,970, and the average revenue per quarterly batch refill was $3228., Conclusion: The Membership Pharmacy Model represents a potentially viable alternative to traditional fee-for-service, buy-and-bill pharmacy payment models through its use of medication pricing based on actual acquisition costs, lean pharmacy operations, and value-based reimbursement methods., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: Pneumocystis pneumonia (PcP) is an opportunistic infection occurring in immunocompromised patients. Cushing's syndrome (CS) impairs the immune system, and several authors have reported PcP in patients with CS. The present study aimed to characterize PcP occurring in a CS context and its management in French tertiary centers, in order to highlight the similarities in clinical presentation and treatment according to whether prophylaxis is implemented or not., Methods: This was a multicenter retrospective study conducted in several French University Hospitals and Cancer Centers. Patients with PcP and confirmed CS regardless of etiology were included. We excluded patients with other known causes of acquired immunodeficiency with increased risk of PcP., Results: Twenty-five patients were included. CS etiology was neoplastic in 84.0% of cases. CS clinical presentation associated predominant catabolic signs (76.0%), hypokalemia (91.7%) and lymphopenia (89.5%). CS was intense in most patients, with mean plasma cortisol levels at diagnosis of 2.424±1.102nmol/L and urinary free cortisol>10× the upper limit of normal in 85.0%. In all patients, PcP onset followed introduction of cortisol blockers, at a median 5.5 days. Patients were treated with 1 to 3 cortisol blockers, mainly metyrapone (88%), which significatively lowered plasma cortisol levels to 667±541nmol/L at the onset of PcP (P<0.001). PcP occurred in 7 patients despite prophylaxis. Finally, 60.0% patients were admitted to intensive care, and 20.0% died of PcP., Conclusion: High mortality in patients with PcP implies that clinicians should be better informed about this rare infectious complication. Prophylaxis remains controversial, requiring comparative studies., (Copyright © 2022. Published by Elsevier Masson SAS.)

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response to mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well as young patients with autoantibodies neutralizing type I IFNs due to autoimmune polyendocrine syndrome type-1 (APS-1) and older individuals with age-associated autoantibodies to type I IFNs. The receptor-binding domain spike protein (RBD)-specific memory B cell response in all patients was quantitatively and qualitatively similar to healthy donors. Sustained germinal center responses led to accumulation of somatic hypermutations in immunoglobulin heavy chain genes. The amplitude and duration of, and viral neutralization by, RBD-specific IgG serological response were also largely unaffected by TLR7, IRF7, or IFNAR1 deficiencies up to 7 mo after vaccination in all patients. These results suggest that induction of type I IFN is not required for efficient generation of a humoral response against SARS-CoV-2 by mRNA vaccines., (© 2022 Sokal et al.)

Objectives: Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency., Study Design: We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST., Results: Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency., Conclusions: Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Laulhé, Dumaine, Chevenne, Leye, Faye, Dozières, Strullu, Viala, Hogan, Houdouin, Léger, Simon, Carel, Storey, Guilmin-Crépon and Martinerie.)

Introduction: Globally, the COVID-19 pandemic has significantly disrupted the provision of healthcare and efficiency of healthcare systems and is likely to have profound implications for pregnant and postpartum women and their families including those who experience the tragedy of stillbirth or neonatal death. This study aims to understand the psychosocial impact of COVID-19 and the experiences of parents who have accessed maternity, neonatal and bereavement care services during this time., Methods and Analysis: An international, cross-sectional, online and/or telephone-based/face-to-face survey is being administered across 15 countries and available in 11 languages. New, expectant and bereaved parents during the COVID-19 pandemic will be recruited. Validated psychometric scales will be used to measure psychosocial well-being. Data will be analysed descriptively and by assessing multivariable associations of the outcomes with explanatory factors. In seven of these countries, bereaved parents will be recruited to a nested, qualitative interview study. The data will be analysed using a grounded theory analysis (for each country) and thematic framework analysis (for intercountry comparison) to gain further insights into their experiences., Ethics and Dissemination: Ethics approval for the multicountry online survey, COCOON, has been granted by the Mater Misericordiae Human Research Ethics Committee in Australia (reference number: AM/MML/63526). Ethics approval for the nested qualitative interview study, PUDDLES, has been granted by the King's College London Biomedical & Health Sciences, Dentistry, Medicine and Natural & Mathematical Sciences Research Ethics Subcommittee (reference number: HR-19/20-19455) in the UK. Local ethics committee approvals were granted in participating countries where required. Results of the study will be published in international peer-reviewed journals and through parent support organisations. Findings will contribute to our understanding of delivering maternity care services, particularly bereavement care, in high-income, lower middle-income and low-income countries during this or future health crises., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Video modelling (VM) interventions have been used to improve the fluency of individuals with learning disabilities and reading difficulties; this study aimed to replicate these findings with autism spectrum disorder (ASD) students. Four children with ASD (aged between 8 and 15) experienced two VM interventions, across 10 sessions, during an alternating treatments design: VM using a teacher model, and feedforward video self-modelling (FFVSM) where the student acted as the model. For two participants, FFVSM was found to be an effective intervention but overall, results for both interventions were inconsistent with previous research. Talking Mats Interviews were used to include these individuals within the social validation process of behavioural research., (© 2021. The Author(s).)

Obesity is associated with inflammation, insulin resistance, and type 2 diabetes, which are major risk factors for CVD. One dietary component of ruminant animal foods, 10,12-conjugated linoleic acid (10,12 CLA), has been shown to promote weight loss in humans. Previous work has shown that 10,12 CLA is atheroprotective in mice by a mechanism that may be distinct from its weight loss effects, but this exact mechanism is unclear. To investigate this, we evaluated HDL composition and function in obese LDL receptor (Ldlr -/- ) mice that were losing weight because of 10,12 CLA supplementation or caloric restriction (CR; weight-matched control group) and in an obese control group consuming a high-fat high-sucrose diet. We show that 10,12 CLA-HDL exerted a stronger anti-inflammatory effect than CR- or high-fat high-sucrose-HDL in cultured adipocytes. Furthermore, the 10,12 CLA-HDL particle (HDL-P) concentration was higher, attributed to more medium- and large-sized HDL-Ps. Passive cholesterol efflux capacity of 10,12 CLA-HDL was elevated, as was expression of HDL receptor scavenger receptor class B type 1 in the aortic arch. Murine macrophages treated with 10,12 CLA in vitro exhibited increased expression of cholesterol transporters Abca1 and Abcg1, suggesting increased cholesterol efflux potential of these cells. Finally, proteomics analysis revealed elevated Apoa1 content in 10,12 CLA-HDL-Ps, consistent with a higher particle concentration, and particles were also enriched with alpha-1-antitrypsin, an emerging anti-inflammatory and antiatherosclerotic HDL-associated protein. We conclude that 10,12 CLA may therefore exert its atheroprotective effects by increasing HDL-P concentration, HDL anti-inflammatory potential, and promoting beneficial effects on cholesterol efflux., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Aims/hypothesis: Caused by biallelic mutations of the gene encoding the transcription factor RFX6 , the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function., Methods: Clinical records were analyzed and described in detail. The functional impact of two RFX6 R181W and RFX6 V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function., Results: All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6 V506G and RFX6 R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function., Conclusions/interpretation: Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Passone, Vermillac, Staels, Besancon, Kariyawasam, Godot, Lambe, Talbotec, Girard, Chardot, Berteloot, Hachem, Lapillonne, Poidvin, Storey, Neve, Stan, Dugelay, Fauret-Amsellem, Capri, Cavé, Ybarra, Chandra, Scharfmann, Bismuth, Polak, Carel, Pigneur and Beltrand.)

The best protocol for severe inaugural diabetic ketoacidosis (DKA) in children remains unclear. We compared two protocols by assessing effects during the first 24 h on osmolality, serum sodium, and glucose variations, which are associated with the risk of cerebral oedema, the most dreaded complication of DKA. We also recorded complications. We retrospectively included children aged 28 days to 18 years and admitted for severe DKA to either of two paediatric intensive care units (PICUs) in Paris (France). The two protocols differed regarding hydration volume, glucose intake, and sodium intake. From 17 June 2010 to 17 June 2015, 93 patients were included, 29 at one PICU, and 64 at the other. We compared severe glycaemic drops (> 5.5 mmol/L/h), mean glycaemia variations, serum sodium, serum osmolality, and the occurrence of cerebral oedema (CE) during the first 24 h after PICU admission. Severe glycaemic drops occurred in 70% of patients, with no between-group difference. Blood glucose, serum sodium, and serum osmolality variations were comparable. Seven (7.5%) patients were treated for suspected CE, (4 [10.3%)] and 3 [6.3%]) in each PICU; none had major residual impairments., Conclusion:  The two paediatric DKA-management protocols differing in terms of fluid-volume, glucose, and sodium intakes had comparable effects on clinical and laboratory-test changes within 24 h. Major drops in glycaemia and osmolality were common with both protocols. No patients had residual neurological impairments., What Is Known: • Cerebral oedema is the most severe complication of diabteic ketoacidosis in children.The risk of cerebral oedema is dependant on both patient related and treatment-related factors. • The optimal protocol for managing severe inaugural diabetic ketoacidosis in children remains unclear, and few studies have targeted this specific population., What Is New: • Two management protocols that complied with ISPAD guidelines but differed regarding the amounts of fluids, glucose, and sodium administered produced similar outcomes in children with severe inaugural diabetic ketoacidosis. • Cerebral oedema was rare with both protocols and caused no lasting impairments., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 versus only evening and night (E/N), and on extended 24/7 use, in free-living children with type 1 diabetes., Materials and Methods: Prepubertal children (n = 122; 49 females/73 males; age, 8.6 ± 1.6 years; diabetes duration, 5.2 ± 2.3 years; insulin pump use, 4.6 ± 2.5 years; HbA1c 7.7% ± 0.7%/61 ± 5 mmol/mol) from four centres were randomized for 24/7 versus E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. The primary outcome was the percentage of time spent in the 70-180 mg/dL glucose range (TIR)., Results: HCL was active 94.1% and 51.1% of the time in the 24/7 and E/N modes, respectively. TIR from baseline increased more in the 24/7 versus the E/N mode (52.9% ± 9.5% to 67.3% ± 5.6% [+14.4%, 95% CI 12.4%-16.7%] vs. 55.1% ± 10.8% to 64.7% ± 7.0% [+9.6%, 95% CI 7.4%-11.6%]; P = .001). Mean percentage time below range was similarly reduced, from 4.2% and 4.6% to 2.7%, and the mean percentage time above range decreased more in the 24/7 mode (41.9% to 30.0% [-11.9%, 95% CI 9.7%-14.6%] vs. 39.8% to 32.6% [-7.2%, 95% CI 5.0%-9.9%]; P = .007). TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during the extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycaemia occurred., Conclusions: The current study shows the safety and efficacy of the Tandem Control-IQ system in free-living children with type 1 diabetes for both E/N and 24/7 use; 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issues., (© 2021 John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic poses an unprecedented risk to the global population. Maternity care in the UK was subject to many iterations of guidance on how best to reconfigure services to keep women, their families and babies, and healthcare professionals safe. Parents who experience a pregnancy loss or perinatal death require particular care and support. PUDDLES is an international collaboration investigating the experiences of recently bereaved parents who suffered a late miscarriage, stillbirth, or neonatal death during the global COVID-19 pandemic, in seven countries. In this study, we aim to present early findings from qualitative work undertaken with recently bereaved parents in the United Kingdom about how access to healthcare and support services was negotiated during the pandemic., Methods: In-depth semi-structured interviews were undertaken with parents (N = 24) who had suffered a late miscarriage (n = 5; all mothers), stillbirth (n = 16; 13 mothers, 1 father, 1 joint interview involving both parents), or neonatal death (n = 3; all mothers). Data were analysed using a template analysis with the aim of investigating bereaved parents' access to services, care, and networks of support, during the pandemic after their bereavement., Results: All parents had experience of utilising reconfigured maternity and/or neonatal, and bereavement care services during the pandemic. The themes utilised in the template analysis were: 1) The Shock & Confusion Associated with Necessary Restrictions to Daily Life; 2) Fragmented Care and Far Away Families; 3) Keeping Safe by Staying Away; and 4) Impersonal Care and Support Through a Screen. Results suggest access to maternity, neonatal, and bereavement care services were all significantly reduced, and parents' experiences were notably affected by service reconfigurations., Conclusions: Our findings, whilst preliminary, are important to document now, to help inform care and service provision as the pandemic continues and to provide learning for ongoing and future health system shocks. We draw conclusions on how to enable development of safe and appropriate services during this pandemic and any future health crises, to best support parents who experience a pregnancy loss or whose babies die., (© 2021. The Author(s).)

Context: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established., Objective: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity., Methods: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities., Results: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI., Conclusion: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A composite material of plasmonic nanoparticles embedded in a scaffold of nano-porous silicon offers unmatched capabilities for use as a SERS substrate. The marriage of these components presents an exclusive combination of tightly focused amplification of Localised Surface Plasmon (LSP) fields inside the material with an extremely high surface-to-volume ratio. This provides favourable conditions for a single molecule or extremely low concentration detection by SERS. In this work the advantage of the composite is demonstrated by SERS detection of Methylene Blue at a concentration as low as a few picomolars. We systematically investigate the plasmonic properties of the material by imaging its morphology, establishing its composition and the effect on the LSP resonance optical spectra.

Background: Stillbirth, the death of a baby before birth, is associated with significant psychological and social consequences that can be mitigated by respectful and supportive bereavement care. The absence of high-level evidence to support the broad scope of perinatal bereavement practices means that offering a range of options identified as valued by parents has become an important indicator of care quality. This study aimed to describe bereavement care practices offered to parents across different high-income and middle-income countries., Methods: An online survey of parents of stillborn babies was conducted between December 2014 and February 2015. Frequencies of nine practices were compared between high-income and middle-income countries. Differences in proportions of reported practices and their associated odds ratios were calculated to compare high-income and middle-income countries., Results: Over three thousand parents (3041) with a self-reported stillbirth in the preceding five years from 40 countries responded. Fifteen countries had atleast 40 responses. Significant differences in the prevalence of offering nine bereavement care practices were reported by women in high-income countries (HICs) compared with women in middle-income countries (MICs). All nine practices were reported to occur significantly more frequently by women in HICs, including opportunity to see and hold their baby (OR = 4.8, 95% CI 4.0-5.9). The widespread occurrence of all nine practices was reported only for The Netherlands., Conclusions: Bereavement care after stillbirth varies between countries. Future research should look at why these differences occur, their impact on parents, and whether differences should be addressed, particularly how to support effective communication, decision-making, and follow-up care., (© 2021 Wiley Periodicals LLC.)

Objective: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management., Methods: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center., Results: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156))., Conclusion: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

[Figure: see text].

This is the protocol for a Campbell review. The primary objective for this review is summarising the effectiveness of video-based interventions (VBI) in promoting prosocial behaviours in a population of young people with autism spectrum disorders (ASD). The research questions employed to fulfil this objective include: (1) Do VBI improve prosocial behaviours in children with ASD? (2) Which social skills and interactive behaviours are most successful? (3) Do VBI generally have successful rates of skill generalisation and response maintenance? (4) Do demographic characteristics (age, gender) of participants influence the effectiveness of VBI's?, Competing Interests: The authors declare that there are no conflict of interests., (© 2021 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Objective: When a formal review of care takes places after the death of a baby, parents are largely unaware it takes place and are often not meaningfully involved in the review process. Parent engagement in the process is likely to be essential for a successful review and to improve patient safety. This study aimed to evaluate an intervention process of parental engagement in perinatal mortality review (PNMR) and to identify barriers and facilitators to its implementation., Design: Mixed-methods study of parents' engagement in PNMR., Setting: Single tertiary maternity unit in the UK., Participants: Bereaved parents and healthcare professionals (HCPs)., Interventions: Parent engagement in the PNMR (intervention) was based on principles derived through national consensus and qualitative research with parents, HCPs and stakeholders in the UK., Outcomes: Recruitment rates, bereaved parents and HCPs' perceptions., Results: Eighty-one per cent of bereaved parents approached (13/16) agreed to participate in the study. Two focus groups with bereaved parents (n=11) and HCP (n=7) were carried out postimplementation to investigate their perceptions of the process.Overarching findings were improved dialogue and continuity of care with parents, and improvements in the PNMR process and patient safety. Bereaved parents agreed that engagement in the PNMR process was invaluable and helped them in their grieving. HCP perceived that parent involvement improved the review process and lessons learnt from the deaths; information to understand the impact of aspects of care on the baby's death were often only found in the parents' recollections., Conclusions: Parental engagement in the PNMR process is achievable and useful for parents and HCP alike, and critically can improve patient safety and future care for mothers and babies. To learn and prevent perinatal deaths effectively, all hospitals should give parents the option to engage with the review of their baby's death., Competing Interests: Competing interests: Authors include the chair and members of the national Perinatal Mortality Review Tool (PMRT) group., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols., Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers., Design and Setting: Retrospective multicentric study in 6 referral centers., Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled., Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up., Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD)., Design and Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder., Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4)., Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP., Design and Methods: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years., Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance., Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Endovascular embolization of arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs) has become the mainstay in treatment for these pathologies. Traditional techniques required the formation of a proximal plug of Onyx around the microcatheter prior to embolization to avoid reflux. Recently, dual-lumen balloon catheters have been introduced as a potential solution to this issue. We sought to compare our institutional experience with dual-lumen balloons to traditional microcatheters in the endovascular embolization of AVMs and DAVFs. A retrospective analysis of consecutive patients treated with Scepter between 2016 and 2020 was obtained. A control cohort treated with Marathon between 2012 and 2020 was also obtained. Variables collected included patient demographics, procedure times, pedicles treated, operative complications, obliteration rate, and retreatment rate. A total of 44 trial (30 DAVFs and 14 AVMs) and 25 control (15 DAVFs and 10 AVMs) subjects were identified. Average Scepter procedure times were 66.0 and 68.0 min for DAVFs and AVMs, respectively. Average Scepter volume of Onyx injected was 2.2 and 1.4 mL for DAVFs and AVMs, respectively. Complete angiographic occlusion Scepter rate was 86.7% and 50.0% for DAVFs and AVMs, respectively. The Scepter retreatment rate was 13.3% and 50.0% for DAVFs and AVMs, respectively. Predictors of angiographic occlusion included the number of pedicles (OR 0.54, 95%CI 0.30-0.97, p = 0.04). Predictors of retreatment included DAVF (OR 0.16, 95%CI 0.04-0.66, p = 0.01) and Marathon (OR 3.34, 95%CI 1.00-11.56, p = 0.05). Our study shows that dual-lumen balloon catheters are a viable option in the embolization of DAVFs and AVMs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims/hypothesis: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes., Methods: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m 2 , given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 + T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders., Results: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m -2  day -1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4 + cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders., Conclusions/interpretation: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention., Trial Registration: ClinicalTrials.gov NCT01862120., Funding: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).

Objective: To develop global consensus on a set of evidence-based core principles for bereavement care after stillbirth., Methods: A modified policy-Delphi methodology was used to consult international stakeholders and healthcare workers with experience in stillbirth between September 2017 and October 2018. Five sequential rounds involved two expert stakeholder meetings and three internet-based surveys, including a global internet-based survey targeted at healthcare workers in a wide range of settings., Results: Initially, 23 expert stakeholders considered 43 evidence-based themes derived from systematic reviews, identifying 10 core principles. The global survey received 236 responses from participants in 26 countries, after which nine principles met a priori criteria for inclusion. The final stakeholder meeting and internet-based survey of all participants confirmed consensus on eight core principles. Highest quality bereavement care should be enabled through training of healthcare staff to reduce stigma and establish respectful care, including acknowledgement and support for grief responses, and provision for physical and psychologic needs. Women and families should be supported to make informed choices, including those concerning their future reproductive health., Conclusion: Consensus was established for eight principles for stillbirth bereavement care. Further work should explore implementation and involve the voices of women and families globally., (© 2020 International Federation of Gynecology and Obstetrics.)

Visualizing mitochondria in living Dictyostelium discoideum cells using fluorescent dyes is often problematic due to variability in staining, metabolism of the dyes, and unknown potential effects of the dyes on mitochondrial function. We show that fluorescent labelling of mitochondria, using an N-terminal mitochondrial localization sequence derived from the D. discoideum protein GcvH1 (glycine cleavage system H1) attached to a red fluorescent protein enables clear mitochondrial imaging. We also show that this labelling has no effect upon mitochondria load or respiratory function., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Introduction Specialist consultant services in the UK NHS provide a decision-making support service to other health professionals. There is a drive to deliver this service in a more patient-centred, cost-effective and efficient manner. Remote clinical consultations (RCC), using secure, live, super-fast internet connectivity and high-resolution, multi-channel audio-visual streaming, has the potential for the delivery of this service.Aim To conduct a clinical service evaluation to assess the viability and efficiency of conducting a RCC for the management of primary care referrals in restorative dentistry, compared to an in-person consultation.Design A RCC was conducted for every participating patient and immediately followed with a 'verification' in-person consultation.Materials and method Twenty-three patients of even gender distribution participated in this study across the three specialisms of restorative dentistry. A thematic questionnaire was completed by each member of the study intervention team and the patient after each consultation.Results In all the cases, the consultant was able to conduct an effective and safe clinical consultation, not inferior to an in-person process, regardless of gender and age. The GDP, the nurse and the patient were able to participate effectively in the process and with each other.Conclusion This proof-of-concept study suggests that the RCC concept is a feasible way of delivering specialist consultations in restorative dentistry with high levels of patient acceptability and that it can be delivered in a practical and simple manner.

Background: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro., Methods: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients., Results: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R . Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation., Conclusion: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Biomarkers of placental function can potentially aid the diagnosis and prediction of pregnancy complications. This randomised controlled pilot trial assessed whether for women with reduced fetal movement (RFM), intervention directed by the measurement of a placental biomarker in addition to standard care was feasible and improved pregnancy outcome compared with standard care alone., Methods: Women aged 16-50 years presenting at eight UK maternity units with RFM between 36 +0 and 41 +0  weeks' gestation with a viable singleton pregnancy and no indication for immediate delivery were eligible. Participants were randomised 1:1 in an unblinded manner to standard care and a biomarker blood test result revealed and acted on (intervention arm) or standard care where the biomarker result was not available (control arm). The objectives were to determine the feasibility of a main trial by recruiting 175-225 participants over 9 months and to provide proof of concept that informing care by measurement of placental biomarkers may improve outcome. Feasibility was assessed via the number of potentially eligible women, number recruited, reasons for non-recruitment and compliance. Proof of concept outcomes included the rates of the induction of labour and caesarean birth, and a composite adverse pregnancy outcome., Results: Overall, 2917 women presented with RFM ≥ 36 weeks, 352 were approached to participate and 216 (61%) were randomised (intervention n = 109, control n = 107). The main reason for not approaching women was resource/staff issues ( n = 1510). Ninety-seven women declined the trial, mainly due to not liking blood tests ( n = 24) or not wanting to be in a trial ( n = 21). Compliance with the trial interventions was 100% in both arms. Labour was induced in 97 (45%) participants (intervention n = 49, control n = 48), while 17 (9%) had planned caesarean sections (intervention n = 9, control n = 8). Overall, 9 (8%) babies in the intervention arm had the composite adverse pregnancy outcome versus 4 (4%) in the control arm., Conclusions: A main trial using a placental biomarker in combination with delivery, as indicated by the biomarker, in women with RFM is feasible. The frequency of adverse outcomes in this population is low, hence, a large sample size would be required along with consideration of the most appropriate outcome measures., Trial Registration: ISRCTN, ISRCTN12067514; registered 8 September 2017., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Aim: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France., Methods: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019., Results: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography., Conclusion: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations., (© 2020 S. Karger AG, Basel.)

Background: Bilateral hemispheric dysfunction is devastating to consciousness. We present a unique case of a patient who developed bilateral middle cerebral artery infarcts with significant neurological improvement post bilateral thrombolysis in cerebral infarction (TICI) 3 thrombectomies., Case Description: The patient is a 64-year-old woman who presented 3 hours after her husband was awakened and found her with left hemiplegia. She had a history of atrial fibrillation and had her apixaban held for 5 days before the coronary angiogram that she received the day before arrival. Upon presentation, she was antigravity on the right side and withdrawing on the left side. Computed tomography angiogram showed a right M1 occlusion and an left M2 occlusion. Computed tomography perfusion revealed a mismatch with large penumbra, and she was taken for mechanical thrombectomy. Mechanical thrombectomy was performed using a combination of stent retriever and aspiration catheter with a TICI 3 revascularization. By the following morning, the patient was full strength on the right and antigravity on the left with a left facial droop. The patient recovered her speech and was fully oriented before leaving for rehabilitation on postoperative day 3., Conclusions: The transient hypercoagulable state that was created with the withdrawal of apixaban likely increased our patient's risk of stroke. The literature supports continuing oral anticoagulants for endovascular procedures. The devastating consequences of thromboembolic events, whether stroke or pulmonary embolism, can be catastrophic, but luckily, mechanical thrombectomy provides the means to minimize the morbidity and mortality from bilateral infarctions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To review what is known about the relationship between stillbirth and inequalities from different disciplinary perspectives to inform stillbirth prevention strategies., Design: Systematic review using the meta-narrative method., Setting: Studies undertaken in the UK., Data Sources: Scoping phase: experts in field, exploratory electronic searches and handsearching. Systematic searches phase: Nine databases with no geographical or date restrictions. Non-English language studies were excluded., Study Selection: Any investigation of stillbirth and inequalities with a UK component., Data Extraction and Synthesis: Three authors extracted data and assessed study quality. Data were summarised, tabulated and presented graphically before synthesis of the unfolding storyline by research tradition; and then of the commonalities, differences and interplays between narratives into resultant summary meta-themes., Results: Fifty-four sources from nine distinctive research traditions were included. The evidence of associations between social inequalities and stillbirth spanned 70 years. Across research traditions, there was recurrent evidence of the social gradient remaining constant or increasing, fuelling repeated calls for action (meta-theme 1: something must be done). There was less evidence of an effective response to these calls. Data pertaining to socioeconomic, area and ethnic disparities were routinely collected, but not consistently recorded, monitored or reported in relation to stillbirth (meta-theme 2: problems of precision). Many studies stressed the interplay of socioeconomic status, deprivation or ethnicity with aggregated factors including heritable, structural, environmental and lifestyle factors (meta-theme 3: moving from associations towards intersectionality and intervention(s)). No intervention studies were identified., Conclusion: Research investigating inequalities and stillbirth in the UK is underdeveloped. This is despite repeated evidence of an association between stillbirth risk and poverty, and stillbirth risk, poverty and ethnicity. A specific research forum is required to lead the development of research and policy in this area, which can harness the multiple relevant research perspectives and address the intersections between different policy areas., Prospero Registration Number: CRD42017079228., Competing Interests: Competing interests: CK, SD, NC, KWF and CS report a grant from SANDS, the Stillbirth and Neonatal Death Charity, during the conduct of the study. CS also reports her position as vicechair of the International Stillbirth Alliance (ISA). DR and MAT have nothing to disclose., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hyponatremia is one of the most common electrolyte disorders in hospitalized children. The underlying mechanisms are poorly understood and potentially multifactorial, making management difficult, particularly in neonates. This retrospective study aimed to determine the incidence and etiologies of hyponatremia in hospitalized children under the age of 100 days, in our pediatric tertiary care hospital over a 1-year period. The etiology of hyponatremia was determined by reviewing the data noted in each patient's medical reports. Neonatal hyponatremia had a prevalence of 4.3% (86/2012 patients) and was mostly hospital-acquired (74/86 patients). Fifty-nine patients (68.9%) were preterm neonates. The etiology was iatrogenic in 26 cases (30.2%). In other cases, hyponatremia was due to transient (23 patients, 26.7%) or genetic abnormalities of the renal mineralocorticoid pathway (3 patients, 3.4%), SIADH (12 patients, 14%), digestive disease (3 patients, 3.5%), acute renal failure (3 patients, 3.5%), or heart failure (1 patient, 1.2%).Conclusion: Our findings confirm that hyponatremia is a frequent electrolyte disorder in neonates. Various mechanisms underlie this condition, most of which could be prevented by optimized management. The prevalence of genetic hypoaldosteronism and pseudohypoaldosteronism was higher than expected. We provide a simple diagram to help physicians identify the mechanisms underlying neonatal hyponatremia. What is Known: • In neonates, hyponatremia may be multifactorial, making it difficult to treat. • Newborns display partial resistance to aldosterone, and preterms have a defect in aldosterone secretion. What is New: • Four percent of hospitalized neonates had hyponatremia, 86% hospital-acquired. Hyponatremia was due to a transient or constitutional defect of the mineralocorticoid pathway in 26/86 patients (30%) which is higher than expected. • We propose a tree diagram for improving the management of hyponatremia in neonates.