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Artificial intelligence (AI)-enabled electrocardiography (ECG) can be used to predict risk of future disease and mortality but has not yet been adopted into clinical practice. Existing model predictions do not have actionability at an individual patient level, explainability, or biological plausibi. We sought to address these limitations of previous AI-ECG approaches by developing the AI-ECG risk estimator (AIRE) platform.

IMPORTANCE: Catheter dislodgement is a common complication for children with tunneled or peripherally inserted noncuffed central venous catheters (CVCs). A subcutaneous anchor securement system (SASS) may reduce this risk compared with traditional adhesive securement. OBJECTIVE: To compare dislodgement of noncuffed CVCs secured with SASS with dislodgement of noncuffed CVCs secured with sutureless securement devices (SSDs). DESIGN, SETTING, AND PARTICIPANTS: The SECURED (Securing Central Venous Catheters to Prevent Dislodegment) trial was a pragmatic, multicenter, superiority randomized clinical trial with an internal pilot and was conducted from August 5, 2020, to August 30, 2022, at 2 Australian quaternary pediatric hospitals. Data analysis was performed in January 2023. Patients aged 0 to 18 years requiring a noncuffed CVC (≥3F catheter) were eligible for inclusion. Follow-up duration was 8 weeks or until device removal. INTERVENTIONS: Patients were randomly assigned 1:1 to receive an SASS or SSD, stratified by hospital and catheter type. Only 1 catheter was studied per patient. MAIN OUTCOMES AND MEASURES: The primary outcome was dislodgement (partial or total), defined as movement of the catheter tip by greater than 1 cm (change in external catheter length) at any point during catheter dwell. Dislodgement, reported as a risk ratio (RR), was estimated using a generalized linear model with binomial family and log link. Secondary outcomes were reported as incidence rate ratios and were analyzed using Poission regression. Outcomes reported as mean differences (MDs) were analyzed using linear regression. RESULTS: Of 310 randomized patients, 175 patients (56.5%) were male and median (IQR) patient age was 48 (16-120) months. A total of 307 patients had a catheter device inserted, of which 153 (49.8%) were SASS and 154 (50.2%) were SSD, and were included in the intention-to-treat (ITT) analysis. Device dislodgement was lower with SASS (8 dislodgements in 153 patients [5.2%]) compared with SSD (35 dislodgements in 154 patients [22.7%]) (RR, 0.23; 95% CI, 0.11-0.48; P < .001). The per-protocol analysis was consistent with the ITT analysis. Partial dislodgement accounted for most dislodgement events, including 6 partial dislodgements in the SASS group (3.9%) and 30 partial dislodgements in the SSD group (19.5%) (RR, 0.18; 95% CI, 0.08-0.42). This contributed to fewer complications during dwell in the SASS group (37 reported complications [24.2%]) vs the SSD group (60 reported complications [39.0%]) (RR, 0.62; 95% CI, 0.44-0.87). Staff reported greater difficulty removing devices anchored with SASS vs SSD (mean [SD], 29.1 [31.3] vs 5.3 [17.0], respectively; MD, 23.8; 95% CI, 16.7-31.0). However, use of SASS resulted in reduced per-participant health care costs of A$36.60 (95% credible interval, 4.25-68.95; US $24.36; 95% credible interval, 2.83-45.89). CONCLUSIONS AND RELEVANCE: In the SECURED trial, noncuffed CVCs secured with SASS had fewer dislodgements compared with SSDs, with a lower cost per patient and an acceptable safety profile. Future efforts should be directed at SASS implementation at the health service level. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12620000783921

Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a ‘phenotype-first’ approach. This approach substantially overestimates the penetrance of variants because of ascertainment bias. The recent availability of whole-genome sequencing data in individuals from very-large-scale population-based cohorts now allows ‘genotype-first’ estimates of penetrance for many conditions. Although this type of population-based study can underestimate penetrance owing to recruitment biases, it provides more accurate estimates of penetrance for secondary or incidental findings. Here, we provide guidance for the conduct of penetrance studies to ensure that robust genotypes and phenotypes are used to accurately estimate penetrance of variants and groups of similarly annotated variants from population-based studies.

With the emerging focus on designing health‐literate organisations and health care systems, it is essential to understand the health literacy profiles of the medical workforce including medical students, as medical professionals play a key role in within these systems. Medical professionals contribute to good patient health outcomes through enabling access to appropriate health care, provision of quality health information and collaborative shared decision‐making, which are fundamental health literacy competencies. The aim of this study is to identify health literacy strengths and weaknesses of medical students enrolled in an Australian Doctor of Medicine programme. Students from all 4 years of an Australian Doctor of Medicine programme were invited to complete an anonymous, online survey in January 2021. Health literacy profiles were identified using the 9‐domain, 44‐item multi‐dimensional Health Literacy Questionnaire, a validated tool which comprehensively evaluates health literacy strengths and weaknesses from diverse perspectives. Demographic characteristics and social attributes were also recorded. The results were compared with Australian Bureau of Statistics data. Eighty‐six participants completed the survey. Most participants were female students (57%) who spoke English at home (88%) with tertiary‐educated fathers (60%) and resided in locations associated with high socioeconomic status during adolescence (61%). Males scored significantly higher in three domains which explored health information access and appraisal, and ability to actively engage with health care providers. Students’ scores were significantly lower than the Australian general population in Domain 6 (Ability to actively engage with health care providers) and Domain 7 (Navigating the health care system). Medical students’ health literacy profiles indicate areas of weakness in their ability to engage with health care providers and to navigate the health system. Medical educators will need to create opportunities to address these weaknesses within medical curricula. Gender differences identified in self‐rated ability to access and appraise health information requires further exploration. Further understanding of health literacy profiles of medical students may influence design of medical school curricula.

Introduction:First-insertion success rates for peripheral vascular access devices (PVADs) in patients with difficult venous access (DIVA) are low, which negatively affects staff workload, patient experience, and organizational cost. There is mixed evidence regarding the impact of a peripheral vascular access device with retractable coiled tip guidewire (GW; AccuCath™, BD) on the first-insertion success rate. The aim of this study is to investigate whether the use of long GW-PVADs, compared with standard PVADs, reduces the risk of first-time insertion failure, in patients admitted to emergency departments (EDs).Methods and analysis:A parallel-group, two-arm, randomized controlled trial will be carried out in two Australian EDs to compare long GW-PVADs (5.8 cm length) against standard care PVADs (short or long). Patients ≥18 years of age meeting DIVA criteria will be eligible for the trial. The sample size is 203 participants for each arm. Web-based central randomization will be used to ensure allocation concealment. Neither clinicians nor patients can be blinded to treatment allocation. Primary outcome is the first-insertion success rate. Secondary outcomes include the number of insertion attempts, time to insert PVAD, all-cause failure, dwell-time, patient-reported pain, serious adverse events, complications, subsequent vascular access devices required, patient satisfaction, staff satisfaction, and healthcare costs. Differences between the two groups will be analyzed using Cox proportional hazards regression. Cost-effectiveness analysis will also be conducted. Intention-to-treat analysis will be used.Ethics and dissemination:The study is approved by Metro South Ethics Committee (HREC/2022/QMS/82264) and Griffith University (2022/077). The findings will be published in a peer-reviewed journal.Trial registration:ACTRN12622000299707

Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.

In the past decade, genetic testing for cardiac disease has become part of routine clinical care. A genetic diagnosis provides the possibility to clarify risk for relatives. For family planning, a genetic diagnosis provides reproductive options, including prenatal diagnosis and preimplantation genetic testing, that can prevent an affected parent from having a child with the genetic predisposition. Owing to the complex genetic architecture of cardiac diseases, characterized by incomplete disease penetrance and the interplay between monogenic and polygenic variants, the risk reduction that can be achieved using reproductive genetic testing varies among individuals. Globally, disparities, including regulatory and financial barriers, in access to reproductive genetic tests exist. Although reproductive options are gaining a prominent position in the management of patients with inherited cardiac diseases, specific policies and guidance are lacking. Guidelines recommend that prenatal diagnosis and preimplantation genetic testing are options that should be discussed with families. Health-care professionals should, therefore, be aware of the possibilities and feel confident to discuss the benefits and challenges. In this Review, we provide an overview of the reproductive options in the context of inherited cardiac diseases, covering the genetic, technical, psychosocial and equity considerations, to prepare health-care professionals for discussions with their patients.

IMPORTANCE: Peripheral intravenous catheters (PIVCs) frequently fail during treatment causing therapy interruption, pain, recatheterization, and additional health care costs. Midline catheters (MCs) may improve functional dwell time and reduce failure compared with traditional PIVCs. OBJECTIVE: To compare device failure of MCs with PIVCs DESIGN, SETTING, AND PARTICIPANTS: This was a pragmatic, randomized clinical superiority trial with an embedded internal pilot study conducted from July 2020 to May 2022. The study took place in a quaternary pediatric hospital in Brisbane, Queensland, Australia. Inclusion criteria were patients aged 1 to 18 years requiring peripherally compatible intravenous therapy for 4 days or longer. INTERVENTIONS: Patients were randomly assigned 1:1 to receive a PIVC or MC, stratified by age (≤5 years, >5 years). One catheter was studied per patient. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause device failure, defined as premature cessation of device function. Secondary outcomes included number of insertion attempts, insertion failure, pain (on insertion), procedural time, patient/parent satisfaction (with insertion), device dwell time, device complications during dwell time, additional vascular access devices required to complete treatment, clinician satisfaction (at removal), and health care costs. RESULTS: Of the 128 patients randomly assigned to study groups, 127 patients (median [IQR] age, 7 [2-13] years; 71 male [56%]) had a device inserted, with 65 (51.2%) in the PIVC group and 62 (48.8%) in the MC group. All patients were included in the intention-to-treat analysis. Device failure was lower in patients in the MC group (10 [16.1%]) compared with those in the PIVC group (30 [46.2%]; odds ratio [OR], 0.22; 95% CI, 0.10-0.52; P <.001). MCs were associated with fewer insertion attempts (mean difference [MD], −0.3; 95% CI, −0.5 to 0; P = .04), increased dwell time (MD, 66.9 hours; 95% CI, 36.2-97.5 hours; P <.001), and fewer patients required additional vascular access devices to complete treatment in the MC group (4 [6.5%]) and PIVC group (19 [29.2%]; OR, 0.17; 95% CI, 0.05-0.52; P = .002). Compared with PIVCs, use of MCs was associated with greater patient (9.0 vs 7.1 of 10; P = .002) and parent (9.1 vs 8.2 of 10; P = .02) satisfaction and lower health care costs (AUS −$151.67 [US −$101.13] per person; 95% credible interval, AUS −$171.45 to −$131.90 [US −$114.20 to −$87.95]). CONCLUSIONS AND RELEVANCE: Findings suggest that MC insertion for patients requiring peripherally compatible intravenous therapy for 4 days or longer should be prioritized to reduce the resource intensive, expensive, and burdensome sequelae of device failure. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12620000724976

Medicines are the most frequent health care intervention type; their safe use provides significant benefits, but inappropriate use can cause harm. Systemic primary care approaches can manage serious medication‐related problems in a timely manner. ACTMed (ACTivating primary care for MEDicine safety) uses information technology and financial incentives to encourage pharmacists to work more closely with general practitioners to reduce the risk of harm, improve patients’ experience of care, streamline workflows, and increase the efficiency of medical care. The stepped wedge cluster randomised trial in 42 Queensland primary care practices will assess the effectiveness of the ACTMed intervention. The primary outcome will be the proportion of people at risk of serious medication‐related problems — patients with atrial fibrillation, heart failure, cardiovascular disease, type 2 diabetes, or asthma or chronic obstructive pulmonary disease — who experience such problems. We will also estimate the cost per averted serious medication‐related problem and the cost per averted potentially preventable medication‐related hospitalisation. The University of Queensland Human Research Ethics Committee approved the pilot (2021/HE002189) and trial phases of the ACTMed study (2022/HE002136). Access to Patron data was granted by the Patron Data Governance Committee (PAT052ACTMed). Access to linked hospitalisations and deaths data are subject to Public Health Actapproval (pending). A comprehensive dissemination plan will be co‐developed by the researchers, the ACTMed steering committee and consumer advisory group, project partners, and trial site representatives. Aboriginal and Torres Strait Islander communities will be supported in leading community‐level dissemination. Australian New Zealand Clinical Trials Registry (pilot: ACTRN12622000595718; 21 April 2022; full trial: ACTRN12622000574741; 14 April 2022).

IMPORTANCE: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. OBJECTIVE: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. DESIGN, SETTING, AND PARTICIPANTS: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. EXPOSURES: Amount and intensity of physical activity. MAIN OUTCOMES AND MEASURES: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient’s exercise category. RESULTS: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Background: Abdominal obesity remains a high public health concern. Within the United States, there are noted disparities among different ethnic/racial groups in relation to obesity, especially for females. Purpose: The purpose of this secondary analysis project was to examine the differences in nutritional intake, food sources, and meal planning and food shopping between Hispanic, White, Black, and Asian females by abdominal obesity level in the United States. Methods: The 2017–2018 National Health Nutrition Examination data was used. Major variables included race/ethnicity, waist circumference (WC), nutritional intake, food source, and food shopping and meal planning behaviors. Descriptive statistics, correlational analyses, a series of two-way factorial analysis of variance, and odds ratio analyses were conducted to address research questions. Findings: When comparing nutritional intake and food source by different racial/ethnic groups and abdominal obesity level, there were no interaction effects for all categories across groups. However, for the racial/ethnic main effects and obesity main effects, significant differences among groups were noted for nutritional intake and food source categories. There were no differences in food shopping and meal preparation between abdominal obesity and non-obese participants in each racial/ethnic group. Conclusions: Similarities and differences were noted between racial/ethnic groups for nutritional intake and sources of food. However, no significant differences were noted between racial/ethnic groups for food shopping and meal preparation behaviors. More research should be done to confirm these findings and further understand food shopping and meal preparation behaviors.

Rotavirus vaccine performance varies between high and low income countries. One possible explanation is inherited histo-blood group antigens (HBGAs) the expression of which differs between populations. HBGAs are polymorphic glycans on mucosal surfaces. Their presence indicates the secretor phenotype, while their absence identifies a non-secretor status. HBGAs can act as rotavirus receptors and might influence live-attenuated rotavirus vaccine virus replication and shedding. Studies in low and middle income countries of the human rotavirus vaccine Rotarix (RV1), suggest HBGA secretor phenotype is important for vaccine immunogenicity. We investigated in a high income country the association between HBGA phenotype (secretor and Lewis) and the bovine-human reassortment vaccine RotaTeq (RV5) vaccine shedding in the stools of infants following each vaccine dose. Eighty-two infants from an Australian birth cohort provided saliva and weekly stool samples after RV5 vaccination doses. Lewis and secretor HBGA phenotyping was identified from saliva samples and confirmed by genotyping. Vaccine virus strains were detected by real-time polymerase chain reaction assays. No significant association between secretor status and vaccine virus shedding was identified. The proportion of infants who shed rotavirus following the first RV5 dose for secretor and non-secretor infants was 57/64 (89%) and 17/18 (94%), respectively, decreasing to 24/64 (33%) and 9/18 (50%) after the second dose and 26/64 (42%) and 8/18 (44%) following the third vaccine dose, respectively. Similarly, no significant differences were observed in vaccine virus shedding by Lewis, or combined Lewis and secretor status, after each vaccine dose. We found HBGAs were not associated with RV5 vaccine virus shedding in Australian infants.

To compare the findings of standard clinical assessments and of complementary clinical and laboratory methods for determining whether community‐wide treatment for trachoma is warranted in a remote Queensland community. Three cross‐sectional screening surveys, 2019–2021, complemented by laboratory pathology testing. Small community in northwest Queensland with geographic and cultural ties to Northern Territory communities where trachoma persists. Children aged 1–14 years; opportunistic screening of people aged 15 years or more. Prevalence of clinical signs of trachoma, Chlamydia trachomatisinfection, ocular non‐chlamydial infections, and seropositivity for antibodies to the C. trachomatisPgp3 protein. During the three surveys, 73 examinations of 58 children aged 1–4 years, 309 of 171 aged 5–9 years, and 142 of 105 aged 10–14 years for trachoma were undertaken, as were 171 examinations of 164 people aged 15 years or more; 691 of 695 examinations were of Aboriginal or Torres Strait Islander people (99%), 337 were of girls or young women (48%). Clinical signs consistent with trachomatous inflammation–follicular were identified in 5–9‐year‐old children 23 times (7%), including in eleven with non‐chlamydial infections and one with a C. trachomatisinfection. One child (10–14 years) met the criteria for trachomatous scarring. Two of 272 conjunctival swab samples (all ages) were polymerase chain reaction‐positive for C. trachomatis(0.7%). Two of 147 people aged 15 years or more examined in 2019 had trichiasis, both aged 40 years or more. Seven of 53 children aged 1–9 years in 2019 and seven of 103 in 2021 were seropositive for anti‐Pgp3 antibodies. Despite the prevalence of clinical signs consistent with trachomatous inflammation–follicular among 5–9‐year‐old children exceeding the 5% threshold for community‐wide treatment, laboratory testing indicated that childhood exposure to ocular C. trachomatisis rare in this community. Laboratory testing should be integrated into Australian trachoma guidelines.

Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.

We describe an innovative, low-power, high-performance, programmable signal processor (DSP) for digital communications. The architecture of this processor is characterized by its explicit design for low-power implementations, its innovative ability to jointly exploit instruction-level parallelism and data-level parallelism to achieve high performance, its suitability as a target for an optimizing high-level language compiler, and its explicit replacement of hardware resources by compile-time practices. We describe the methodology used in the development of the processor, highlighting the techniques deployed to enable application/architecture/compiler/implementation co-development, and the optimization approach and metric used for power-performance evaluation and tradeoff analysis. We summarize the salient features of the architecture, provide a brief description of the hardware organization, and discuss the compiler techniques used to exercise these features. We also summarize the simulation environment and associated software development tools. Coding examples from two representative kernels in the digital communications domain are also provided. The resulting methodology, architecture, and compiler represent an advance of the state of the art in the area of low-power, domain-specific microprocessors.

The learning curve of nurse practitioners (NPs) to accurately diagnose paediatric distal forearm fractures using point‐of‐care ultrasound (POCUS) was investigated. Each NP’s learning curve was calculated as cumulative diagnostic accuracy against a number of scans performed. The curve’s plateau represented the attainment of competency. Secondary outcomes were the comparisons before and after this cut‐off of diagnostic accuracy, classification of diagnostic errors, pain scores, duration and preference. Five NPs performed 201 POCUS studies with diagnostic accuracy plateauing at 90%, providing a ‘cut‐off’ point at scan 15. Accuracy of POCUS scanning before and after the fifteenth scan was 81% (95% CI 70%–89%) and 90% (95% CI 84%–94%), respectively, demonstrating 9% improvement (P = 0.07). There was a 10% reduction in image interpretation errors. After fifteen scans, POCUS became faster (mean difference (MD) 2.6 min [95% CI 2.0–3.3], P < 0.001), less painful (MD 0.61 points FPSR scale [95% CI 0.04–1.18], P = 0.04) and more preferred by NPs (63% vs 77%, P = 0.03). The learning curve of POCUS‐novice NPs independently scanning paediatric distal forearm injuries plateaued with mean diagnostic accuracy of 90% after 15 scans, suggesting competency was attained at this cut‐off, supported by higher accuracy, being faster, less painful and more preferred by NPs. Future training packages in forearm POCUS should further address image interpretation and provide ongoing expert feedback. The findings from this study suggest that competency in paediatric distal forearm POCUS can be attained by novices after a short training course and approximately 15 scans.

We investigated the association between a range of commonly tested organisms in stool and acute diarrheal disease in healthy Australian children aged <2 years, identified the leading organisms, and highlighted the high rates of asymptomatic shedding of potentially pathogenic organisms.

Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.

To determine if non‐pharmaceutical interventions (NPIs) impacted on respiratory virus detections in Queensland, Australia, during the COVID‐19 pandemic year of 2020.

Point‐of‐care ultrasound (POCUS) diagnosis of distal forearm fractures relies on the identification of buckling or breach of hyperechoic bone cortex. We describe the pronator quadratus hematoma (PQH) formation visualized on POCUS, the PQH sign, as it may aid diagnosis of pediatric distal forearm cortical breach fractures. A prospective cohort of children presenting to an emergency department with isolated, clinically non‐angulated distal forearm injuries received POCUS by an expert emergency physician sonologist who identified the presence or absence of the PQH sign. They secondarily recorded the difference between the size of the pronator quadratus (PQ) muscle on both the affected and non‐affected forearms (PQ delta thickness). Children received an x‐ray subsequent to POCUS and were diagnosed based on an x‐ray reported by a radiologist masked to POCUS findings. Thirty‐eight children were recruited. All 22 patients with cortical breach fracture had PQH sign present (100%; 95%CI: 85–100%), while all 16 patients without cortical breach fracture had PQH sign absent (100%; 95%CI: 79–100%). PQ delta thickness ranged from 2.1 to 10.2 mm in cortical breach fractures, 0.0 to 1.1 mm in buckle fractures, and 0.2 to 0.8 mm in patients without fracture. The PQH sign correctly distinguished all children with, and without, cortical breach fractures. All PQ delta thicknesses were ≧2.1 mm when cortical breach fracture was present and ≦1.1 mm when cortical breach fracture was absent. The PQH sign and PQ delta thickness are promising measurements to identify pediatric distal forearm cortical breach fractures, and their utility should be confirmed in larger studies with sonologists of different abilities.

IntroductionNusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown.AimTo assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment.MethodsA prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test.ResultsTwenty-eight patients (15 male, aged 0.08–18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was −0.58 (95% CI −0.75 to −0.41), and post initiation was −0.25 (95% CI −0.46 to −0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea–Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1–10.1) at initiation to 2.7 events/hour (IQR 0.7–5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen.ConclusionThe first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

ObjectiveThe effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM.MethodsProspective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited.ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in midwall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 95% CI 0.73 to 2.26, p=0.38) during median follow-up of 3.9 years.ConclusionDCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.

Endotracheal suction is one of the most common and harmful procuedres performed on mechanically ventilated children. The aim of the study was to establish the feasibility of a randomised controlled trial (RCT) examining the effectiveness of normal saline instillation (NSI) and a positive end-expiratory pressure recruitment manoeuvre (RM) with endotracheal suction in the paediatric intensive care unit.

Variants in MYBPC3causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3VUS associated with increased clinical risk.

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.

In Indigenous Australian children, the 3 main respiratory pathogens are associated with OM, particularly their bacterial loads and co-colonization. Corynebacterium pseudodiphtheriticumand Dolosigranulum pigrumare related to upper respiratory and ear health. This provides potential targets for preventative biotherapeutics.

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g?=?0.34?±?0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene–disease relationships, e.g., distinct consequences of gain-of-function versus loss-of-function variants. We hypothesized that incorporating disease-specific information would improve tool performance.

Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

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Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.In a community-based birth cohort of 158 Australian infants followed to age 2 years, the incidence rate of human parainfluenza virus (HPIV) was 0.42 (95% CI = 0.33, 0.54) episodes per child-year with episodes occurring year-round, peaking in the spring season. HPIV-3 was the dominant subtype. Overall, 41% of detections were asymptomatic; only 32% of HPIV episodes led to healthcare contact with 1 hospitalization.

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

Most acute respiratory infection (ARI) research focuses on severe disease and overlooks the burden of community-managed illness. For community-based studies, home-based specimen collection by parents could be a resource-saving alternative to collection by healthcare workers (HCWs). In this study, we compared parent and HCW groups for their likelihood to collect specimens and the timeliness and quality of such collection.

Supplemental Digital Content is available in the text.