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Tertiary hospitals with expertise in hypertrophic cardiomyopathy (HCM) are assuming a greater role in confirming and correcting HCM diagnoses at referring centers. The objectives were to establish the frequency of alternate diagnoses from referring centers and identify predictors of accuracy of an HCM diagnosis from the referring centers. Imaging findings from echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging (CMR) in 210 patients referred to an HCM Center of Excellence between September 2020 and October 2022 were reviewed. Clinical and imaging characteristics from pre-referral studies were used to construct a model for predictors of ruling out HCM or confirming the diagnosis using machine learning methods (least absolute shrinkage and selection operator logistic regression). Alternative diagnoses were found in 38 of the 210 patients (18.1%) (median age 60 years, 50% female). A total of 17 of the 38 patients (44.7%) underwent a new CMR after their initial visit, and 14 of 38 patients (36.8%) underwent review of a previous CMR. Increased left ventricular end-diastolic volume, indexed, greater septal thickness measurements, greater left atrial size, asymmetric hypertrophy on echocardiography, and the presence of an implantable cardioverter-defibrillator were associated with higher odds ratios for confirming a diagnosis of HCM, whereas increasing age and the presence of diabetes were more predictive of rejecting a diagnosis of HCM (area under the curve 0.902, p <0.0001). In conclusion, >1 in 6 patients with presumed HCM were found to have an alternate diagnosis after review at an HCM Center of Excellence, and both clinical findings and imaging parameters predicted an alternate diagnosis.

This book provides early years practitioners with clear strategies for supporting vulnerable children. Tackling topics such as inequality, poverty and the attainment gap, experienced practitioners from the field set out practical advice for ensuring all children are given a positive foundation for their future lives.

Turbulent and radiative exchanges of heat between the ocean and atmosphere (hereafter heat fluxes), ocean surface wind stress, and state variables used to estimate them, are Essential Ocean Variables (EOVs) and Essential Climate Variables (ECVs) influencing weather and climate. This paper describes an observational strategy for producing 3-hourly, 25-km (and an aspirational goal of hourly at 10-km) heat flux and wind stress fields over the global, ice-free ocean with breakthrough 1-day random uncertainty of 15 W m-2 and a bias of less than 5 W m-2. At present this accuracy target is met only at OceanSITES reference station moorings and research vessels (RVs) that follow best practices. To meet these targets globally, in the next decade, satellite-based observations must be optimized for boundary layer measurements of air temperature, humidity, sea surface temperature, and ocean wind stress. In order to tune and validate these satellite measurements, a complementary global in situ flux array, built around an expanded OceanSITES network of time series reference station moorings, is also needed. The array would include 500 - 1000 measurement platforms, including autonomous surface vehicles, moored and drifting buoys, RVs, the existing OceanSITES network of 22 flux sites, and new OceanSITES expanded in 19 key regions. This array would be globally distributed, with 1 - 3 measurement platforms in each nominal 10° by 10° boxes. These improved moisture and temperature profiles and surface data, if assimilated into Numerical Weather Prediction (NWP) models, would lead to better representation of cloud formation processes, improving state variables and surface radiative and turbulent fluxes from these models. The in situ flux array provides globally distributed measurements and metrics for satellite algorithm development, product validation, and for improving satellite-based, NWP and blended flux products. In addition, some of these flux platforms will also measure direct turbulent fluxes, which can be used to improve algorithms for computation of air-sea exchange of heat and momentum in flux products and models. With these improved air-sea fluxes, the ocean’s influence on the atmosphere will be better quantified and lead to improved long-term weather forecasts, seasonal-interannual-decadal climate predictions, and regional climate projections.

Dexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimed to identify which patients are most likely to benefit from dexamethasone treatment. We did a meta-analysis of individual patient data from the randomised, double-blind, placebo-controlled trials of dexamethasone for bacterial meningitis in patients of all ages for which raw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelae at first follow-up, and death or severe bilateral hearing loss at first follow-up. Combined odds ratios (ORs) and tests for heterogeneity were calculated using conventional Mantel-Haenszel statistics. We also did exploratory analysis of hearing loss among survivors and other exploratory subgroup analyses by use of logistic regression. Data from 2029 patients from five trials were included in the analysis (833 [41·0%] aged <15 years). HIV infection was confirmed or likely in 580 (28·6%) patients and bacterial meningitis was confirmed in 1639 (80·8%). Dexamethasone was not associated with a significant reduction in death (270 of 1019 [26·5%] on dexamethasone vs 275 of 1010 [27·2%] on placebo; OR 0·97, 95% CI 0·79–1·19), death or severe neurological sequelae or bilateral severe deafness (42·3% vs 44·3%; 0·92, 0·76–1·11), death or any neurological sequelae or any hearing loss (54·2% vs 57·4%; 0·89, 0·74–1·07), or death or severe bilateral hearing loss (36·4% vs 38·9%; 0·89, 0·73–1·69). However, dexamethasone seemed to reduce hearing loss among survivors (24·1% vs 29·5%; 0·77, 0·60–0·99, p=0·04). Dexamethasone had no effect in any of the prespecified subgroups, including specific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Pooling of the mortality data with those of all other published trials did not significantly change the results. Adjunctive dexamethasone in the treatment of acute bacterial meningitis does not seem to significantly reduce death or neurological disability. There were no significant treatment effects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven. Wellcome Trust UK.

Background The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement. Main text Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations. Conclusion Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments.

Introduction Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs. Methods We used a mixed‐methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open‐ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively. Results Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co‐developed, centralized, high‐level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision‐making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development. Conclusion This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy. Patient or Public Contribution In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions.

Risk factors for severe outcomes of SARS-CoV-2 infection are not well established in children. We sought to describe pediatric hospital admissions associated with SARS-CoV-2 infection in Canada and identify risk factors for more severe disease. We conducted a national prospective study using the infrastructure of the Canadian Paediatric Surveillance Program (CPSP). Cases involving children who were admitted to hospital with microbiologically confirmed SARS-CoV-2 infection were reported from Apr. 8 to Dec. 31 2020, through weekly online questionnaires distributed to the CPSP network of more than 2800 pediatricians. We categorized hospital admissions as related to COVID-19, incidental, or for social or infection control reasons and determined risk factors for disease severity in hospital. Among 264 hospital admissions involving children with SARS-CoV-2 infection during the 9-month study period, 150 (56.8%) admissions were related to COVID-19 and 100 (37.9%) were incidental infections (admissions for other reasons and found to be positive for SARS-CoV-2 on screening). Infants (37.3%) and adolescents (29.6%) represented most cases. Among hospital admissions related to COVID-19, 52 (34.7%) had critical disease, 42 (28.0%) of whom required any form of respiratory or hemodynamic support, and 59 (39.3%) had at least 1 underlying comorbidity. Children with obesity, chronic neurologic conditions or chronic lung disease other than asthma were more likely to have severe or critical COVID-19. Among children who were admitted to hospital with SARS-CoV-2 infection in Canada during the early COVID-19 pandemic period, incidental SARS-CoV-2 infection was common. In children admitted with acute COVID-19, obesity and neurologic and respiratory comorbidities were associated with more severe disease.

Abstract The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk. The Testosterone Trials were conducted to determine if testosterone treatment would benefit older men with low testosterone. This report describes the Trials' development and results and the lessons learned.

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.