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Fever is an easily-recognizable primary sign for many serious childhood infections. In Bangladesh, 31% of children aged less than five years (under-five children) die from serious infections, excluding confirmed acute respiratory infections or diarrhoea. Understanding healthcare-seeking behaviour for children with fever could provide insights on how to reduce this high rate of mortality. Data from a cross-sectional survey in the catchment areas of two tertiary-level paediatric hospitals in Dhaka, Bangladesh, were analyzed to identify the factors associated with the uptake of services from trained healthcare providers for under-five children with reported febrile illness. Health and demographic data were collected in a larger study of 7,865 children using structured questionnaires. Data were selected from 1,290 of these under-five children who were taken to any healthcare provider for febrile illness within two months preceding the date of visit by the study team. Certified doctors were categorized as 'trained', and other healthcare providers were categorized as 'untrained'. Healthcare-seeking behaviours were analyzed in relation to these groups. A wealth index was constructed using principal component analysis to classify the households into socioeconomic groups. The odds ratios for factors associated with healthcare-seeking behaviours were estimated using logistic regression with adjustment for clustering. Forty-one percent of caregivers (n=529) did not seek healthcare from trained healthcare providers. Children from the highest wealth quintile were significantly more likely [odds ratio (OR)=5.6, 95% confidence interval (CI) 3.4-9.2] to be taken to trained healthcare providers compared to the poorest group. Young infants were more likely to be taken to trained healthcare providers compared to the age-group of 4-<5 years (OR=1.6, 95% CI 1.1-2.4). Male children were also more likely to be taken to trained healthcare providers (OR=1.5, 95% CI 1.2-1.9) as were children with decreased level of consciousness (OR=5.3, 95% CI 2.0-14.2). Disparities across socioeconomic groups and gender persisted in seeking quality healthcare for under-five children with febrile illness in urban Dhaka. Girls from poor families were less likely to access qualified medical care. To reduce child mortality in the short term, health education and behaviour-change communication interventions should target low-income caregivers to improve their recognition of danger-signs; reducing societal inequalities remains an important long-term goal. [ABSTRACT FROM AUTHOR]

Enforcement of legislation restricting retail access to tobacco is increasingly relied on to reduce adolescent smoking rates. In 1996, health authorities in the Northern Sydney Health Area began monitoring tobacco retailer compliance (PROOF program) with staged purchase attempts by adolescents below the legal age (18 years). Repeat cross-sectional surveys before (1995) and after (2000) the introduction of PROOF monitored changes in adolescent smoking behaviour. Students aged 12 to 17 years from 11 Northern Sydney metropolitan public secondary schools were surveyed for self-reported smoking and tobacco purchasing behavior in 1995 (n = 5,206) and 2000 (n = 4,120). Between 1996 and 2000, 545 retailer compliance checks found 34% unlawfully sold cigarettes to minors and 28% of these repeated the offence. Nine prosecutions resulted. Modelling revealed a significant association between the intervention and never having smoked (adjusted OR = 1.16, 95% CI = 1.01-1.33) although there was no significant association with being a current smoker. The odds of being a smoker were greater for students from coeducational schools, with this effect being modified by gender. There was no reduction in adolescent smoking with active enforcement of tobacco access laws despite an apparent increase in students who reported never to have smoked. [ABSTRACT FROM AUTHOR]

Background: Studies exploring early life-course BMI trajectories and subsequent mental health outcomes are limited but may provide important insights for early intervention. We investigated associations between BMI trajectories from 0 to 18 years and mental health outcomes in emerging adulthood., Methods: Data were obtained from 434 participants in the Melbourne Atopy Cohort Study (MACS). Anthropometric data were collected across 26 timepoints from infancy to age 25 and group-based trajectory modelling used to develop BMI trajectories from 0.1 to 18 years. Moderate-to-severe psychological distress (MSPD) and likely depression were assessed at age 18 and 25 years. Associations between BMI trajectories and mental health at 25 years and change in mental health between 18 and 25 years were estimated using logistic regression. History of asthma, hay fever or eczema were independently examined as potential effect modifiers., Results: Five BMI trajectories were identified from 1 month to 18 years. When compared to the stable average BMI trajectory, we found increased risk of MSPD (OR = 2.97; 95%CI: 1.09,8.06) and likely depression (3.56; 1.39,9.12) at age 25 in the average increasing to high trajectory. This group also had a greater likelihood of new-onset depression (4.82; 1.54,15.0) from 18 to 25 years of age., Limitations: MACS participants are not representative of the general population and mental health data was not available before 18 years of age., Conclusion: Excessive weight gain across the childhood transition was associated with poorer mental health in emerging adulthood, highlighting the importance of monitoring growth to allow for early identification and stratification of individuals are risk of poor mental health., 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 © 2024. Published by Elsevier B.V.)

Objective: This article presents a longitudinal analysis of COVID-19 infection and vaccination coverage in Melbourne metropolitan local government areas (LGAs) during the 2021 Delta wave., Methods: COVID-19 vaccination and infection data from 12 July to 27 November 2021 were sourced from government websites. Summary statistics and associated 95% confidence intervals (95% CI) were compared by LGA ranked according to socioeconomic status: total "burden" (total infections per thousand), "peak" (highest weekly infection rate), "lag" (interval between peak and 70% double vaccination)., Results: LGAs in the bottom five deciles for social advantage experienced higher infection rates (39.0 per thousand [95% CI: 38.5, 39.5] vs. 14.8 [14.7, 14.9]), and had lower two-dose vaccination coverage (23.8% [23.6, 23.9] vs. 32.7% [32.6, 32.7]) compared with LGAs in the top five deciles. LGAs that achieved 70% coverage two weeks or more after the infection peak experienced nearly twice the total infection burden (27.7 per 1000 [27.3, 28.0] compared with 14.9 [14.7, 15.0]) than LGAs with a shorter lag., Conclusions: Exposure and transmission risk factors cluster within disadvantaged LGAs. The potential for large local outbreaks is heightened if vaccination uptake trails in these communities., Implications for Public Health: In a pandemic, decision-makers must prioritise disease control and harm reduction interventions for at-risk LGAs., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: During COVID-19, countries utilised various quarantine systems to achieve specific outcomes. At different stages and durations, voluntary and mandatory quarantine occurred in homes, hotels and facilities based on local and national elimination strategies. Countries are incorporating quarantine lessons from COVID-19 into revising pandemic plans as part of the World Health Organization's Preparedness and Resilience for Emerging Threats (PRET) activities. This review aimed to amalgamate quarantine post implementation recommendations from a whole-of-system perspective., Methods: This review utilised MEDLINE, Embase, CINAHL, APA, and PsycINFO. To capture all pandemics, no date restriction was applied. Recommendations were synthesised and inductively grouped into quarantine capability categories. This review was registered in PROSPERO (CRD42023420765)., Results: A total of 449 published articles were screened, with 51 articles included and 156 recommendations extracted. Recommendations were grouped into 15 quarantine capability categories, comprising governance, preparation, infection prevention and control, ventilation, compliance, data, information and technology, safety-quality-risk, communication, healthcare model, home quarantine, hotel quarantine, facility quarantine, workforce, and resident considerations. The capability categories were further consolidated into strategic, structural, and operational domains to support the whole-of-system perspective., Conclusion: The quarantine implementation capability framework generated provides comprehensive and deeper insights into the essential capabilities required for quarantine systems to support governments in PRET activities, including reviewing and revising pandemic plans and developing quarantine preparedness exercises., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Australia rapidly developed COVID-19 quarantine programs to reduce the adverse outcomes of a novel pathogen imported by visitors and returned travellers. Different quarantine pathways were utilised over the pandemic, yet no definitive cohort map exists to guide future preparedness. We created a whole-of-system cohort journey map of Australian quarantine cohorts to inform future pandemic preparedness activities., Methods: Australian parliamentary websites and Google were searched for publicly available grey literature from 2019 to 2023. Data about quarantine cohorts, pandemic plans and documents, journey activities, viral escape events, and quarantine recommendations were extracted and plotted to produce a whole-of-system cohort journey map., Results: The system mapping process identified 22 distinct quarantine cohort journeys during COVID-19, yet few of the cohorts were mentioned in pandemic and emergency plans. Viral escape events were documented 27 times, and COVID-19 reviews and inquiries produced 282 quarantine-specific recommendations. Cohorts included international and domestic travellers who experienced home, hotel, and facility quarantine iterations. Other cohorts, such as humanitarian evacuations, diplomats, airline crews, community close contacts, and people experiencing homelessness, had distinctive quarantine journeys., Conclusions: This whole-of-system quarantine cohort map furthers the case for governments and policymakers to update pandemic plans to include the 22 identified cohorts and test plans through pandemic exercises. Recommendations from inquiries should be acquitted to reduce the risk of viral escape and to strengthen national preparedness if quarantine systems are required in future pandemic responses., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: This study investigated cause-specific mortality rates in 12 countries during the COVID-19 pandemic in 2020 and 2021., Methods: We collected weekly cause-specific mortality data from respiratory disease, pneumonia, cardiovascular disease (CVD) and cancer from national vital statistic databases. We calculated excess mortality for respiratory disease (excluding COVID-19 codes), pneumonia, and CVD in 2020 and 2021 by comparing observed weekly against expected mortality based on historical data (2015-2019), accounting for seasonal trends. We used multilevel regression models to investigate the association between country-level pandemic-related variables and cause-specific mortality., Results: Significant reductions in cumulative mortality from respiratory disease and pneumonia were observed in 2020 and/or 2021, except for Georgia, Northern Ireland, Kazakhstan, and Ukraine, which exhibited excess mortality for one or both causes. Australia, Austria, Cyprus, Georgia, and Northern Ireland experienced excess cumulative CVD mortality in 2020 and/or 2021. Australia, Austria, Brazil, Cyprus, Georgia, Northern Ireland, Scotland and Slovenia, experienced increased crude cumulative cancer mortality during 2020 and/or 2021 compared to previous years. Among pandemic-related variables, reported COVID-19 incidence was negatively associated with increased cancer mortality, excess respiratory, (2020) and pneumonia (2021) mortality, and positively associated with respiratory and CVD mortality (2021). Stringency of control measures were negatively associated with excess respiratory disease, CVD, and increased cancer mortality (2021)., Conclusions: This study provides evidence of substantial excess mortality from CVD, and notable reductions in respiratory disease and pneumonia in both years across most countries investigated. Our study also highlights the beneficial impact of stringent control measures in mitigating excess mortality from most causes in 2021., (© 2024. The Author(s).)

Introduction: To examine the impact of the COVID-19 pandemic on mortality, we estimated excess all-cause mortality in 24 countries for 2020 and 2021, overall and stratified by sex and age., Methods: Total, age-specific and sex-specific weekly all-cause mortality was collected for 2015-2021 and excess mortality for 2020 and 2021 was calculated by comparing weekly 2020 and 2021 age-standardised mortality rates against expected mortality, estimated based on historical data (2015-2019), accounting for seasonality, and long-term and short-term trends. Age-specific weekly excess mortality was similarly calculated using crude mortality rates. The association of country and pandemic-related variables with excess mortality was investigated using simple and multilevel regression models., Results: Excess cumulative mortality for both 2020 and 2021 was found in Austria, Brazil, Belgium, Cyprus, England and Wales, Estonia, France, Georgia, Greece, Israel, Italy, Kazakhstan, Mauritius, Northern Ireland, Norway, Peru, Poland, Slovenia, Spain, Sweden, Ukraine, and the USA. Australia and Denmark experienced excess mortality only in 2021. Mauritius demonstrated a statistically significant decrease in all-cause mortality during both years. Weekly incidence of COVID-19 was significantly positively associated with excess mortality for both years, but the positive association was attenuated in 2021 as percentage of the population fully vaccinated increased. Stringency index of control measures was positively and negatively associated with excess mortality in 2020 and 2021, respectively., Conclusion: This study provides evidence of substantial excess mortality in most countries investigated during the first 2 years of the pandemic and suggests that COVID-19 incidence, stringency of control measures and vaccination rates interacted in determining the magnitude of excess mortality., 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.)

We investigated 328 SARS-CoV-2 cases in Barwon South West, Victoria, Australia, in the 2020 pre-vaccination period, comparing infections with symptoms to those that remained asymptomatic. De-identified self-reported data on case characteristics and symptom progression from three sequential questionnaires were examined. Multivariable logistic regression was used to model associations between demographic profiles and symptoms. Asymptomatic infections were more than three times as likely to be seen in ethnic minority groups than the Caucasian population after adjusting for gender and age [OR 3.2, 95% CI 1.5-6.7, p < 0.01] and were more common among cases of Asian background [OR 2.8, 95%CI 1.2-6.4]. Asymptomatic infections were also more common in youth and younger adults, but cases were approximately seven times more likely to be in seniors (≥65 years) compared with those 24 years of age or younger after adjusting for sex and ethnicity [OR 6.9, 95% CI 1.3-35.8]. The overrepresentation of ethnic minority groups among asymptomatic infections is suggestive of genetic haplotype variability by ethnic group, conferring greater cross-protection from other coronaviruses in the initial phase of the COVID-19 pandemic. Replication of this analysis in the post-vaccination era and reassessment of symptom expression according to ethnicity in a community with established vaccine and infection-induced immunity would determine whether this is a sustained association or one confined to the early stages of a pandemic in an immunologically naive population. These findings may, in part, reflect differences in testing patterns by ethnicity and true differences in disease expression, both of which are important to understand in order to inform transmission prevention strategies and tailored risk messaging according to ethnic background.

Background: This scoping review aims to identify and critically review quarantine preparedness in New Zealand and Australia pre-COVID-19 by categorising, comparing, and evaluating quarantine information contained within pandemic plans and exercises from both countries., Methods: Parliamentary websites, including Archives New Zealand, ParlInfo and Google Scholar, were searched for publicly available plans and exercise reports from 2002 to 2019. Data were extracted from documents meeting the inclusion criteria and analysed using directive content analysis based on the Australian Disaster Preparedness Framework categories. This scoping review followed the Joanna Briggs Institute methodology for scoping reviews, which guided the data extraction, analysis, and presentation of results., Results: A total of 16 documents mentioned quarantine and were included in this scoping review. The emphasis and level of detail regarding quarantine characteristics and capabilities varied between New Zealand's five documents (one plan and four exercise reports) and Australia's 11 documents (one Influenza pandemic plan, eight state plans and two exercise reports). New Zealand's plan forecasted the need for both voluntary quarantine at home and involuntary quarantine in facilities for incoming travellers, whilst the Australian Influenza pandemic plan and state plans primarily considered voluntary quarantine within private residences. Capability gaps identified during exercises were not consistently incorporated into revised plans. Some government documents containing information on quarantine may not be publicly available, limiting the available evidence for this review., Conclusion: This scoping review highlights the need to incorporate a range of possible quarantine options into plans and preparation activities to test and identify gaps in government and responsible agencies' capabilities. Pandemic preparedness will be strengthened by incorporating quarantine scale and duration variables into exercise scenarios., Competing Interests: Declaration of Competing Interest Matiu Bush, Stéphane L Bouchoucha, Ana Hutchinson, and Catherine M Bennett declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

COVID-19 responses have cast a spotlight on the uneven impacts of public health policy with particular populations or sites targeted for intervention. Perhaps the starkest example in Australia was the 'hard' lockdown of nine public housing complexes in inner-city Melbourne from 4 to 18 July 2020, where residents were fully confined to their homes. These complexes are home to diverse migrant communities and the lockdown drew public criticism for unfairly stigmatising ethnic minorities. This article draws on media articles published during the lockdown and the Victorian Ombudsman's subsequent investigation to explore the implications of broad, top-down public health measures for culturally and linguistically diverse (CALD) communities. Drawing on Lea's (2020) conceptualisation of policy ecology, we analyse the lockdown measures and community responses to explore the normative assumptions underpinning health policy mechanisms, constituting 'target populations' in narrow, exclusionary terms. We argue that the lockdown measures and use of police as compliance officers positioned tower residents as risky subjects in risky places. Tracing how such subject positions are produced, and resisted at the grassroots level, we highlight how policy instruments are not neutral interventions, but rather instantiate classed and racialised patterns of exclusion, reinforcing pervasive social inequalities in the name of public health.

The emergency phase of the coronavirus disease 2019 (COVID-19) pandemic is over. Still, the work goes on in understanding the SARS-CoV-2 virus and its evolution, infection impacts - acute and long term - as well as therapeutics and the lessons for preventing and responding to future pandemics. Research into the long-term post-infection effects and therapeutic interventions also expands as the post-infection period lengthens. We provide an overview of the leading edge of COVID-19 research across clinical, epidemiological and social domains., Competing Interests: CB declares honorarium from Novavax as part of the Australian Vaccine Advisory Group; acting as an expert witness on a range of legal cases relating to the pandemic and other epidemiological matters; and payment from Moderna for presenting on COVID-19 issues. BR is employed by the ASHM, which convened the Australasian COVID-19 Conference 2023. SM reports a grant from the Health Research Council of New Zealand for participation in ASCOT and REMAP-CAP trials for COVID-19 treatment; was a member of the Therapeutics Advisory Group to the New Zealand Ministry of Health and a member of the NZ national guidelines writing group for COVID-19. KH reports a grant and consulting fees/honorarium from Gilead Sciences and consulting fees and travel support from Moderna to attend meetings.

While microscopy-based cellular assays, including microfluidics, have significantly advanced over the last several decades, there has not been concurrent development of widely-accessible techniques to analyze time-dependent microscopy data incorporating phenomena such as fluid flow and dynamic cell adhesion. As such, experimentalists typically rely on error-prone and time-consuming manual analysis, resulting in lost resolution and missed opportunities for innovative metrics. We present a user-adaptable toolkit packaged into the open-source, standalone Interactive Cellular assay Labeled Observation and Tracking Software (iCLOTS). We benchmark cell adhesion, single-cell tracking, velocity profile, and multiscale microfluidic-centric applications with blood samples, the prototypical biofluid specimen. Moreover, machine learning algorithms characterize previously imperceptible data groupings from numerical outputs. Free to download/use, iCLOTS addresses a need for a field stymied by a lack of analytical tools for innovative, physiologically-relevant assays of any design, democratizing use of well-validated algorithms for all end-user biomedical researchers who would benefit from advanced computational methods., (© 2023. Springer Nature Limited.)

Background: To understand the impact of the COVID-19 pandemic on mortality, this study investigates overall, sex- and age-specific excess all-cause mortality in 20 countries, during 2020., Methods: Total, sex- and age-specific weekly all-cause mortality for 2015-2020 was collected from national vital statistics databases. Excess mortality for 2020 was calculated by comparing weekly 2020 observed mortality against expected mortality, estimated from historical data (2015-2019) accounting for seasonality, long- and short-term trends. Crude and age-standardized rates were analysed for total and sex-specific mortality., Results: Austria, Brazil, Cyprus, England and Wales, France, Georgia, Israel, Italy, Northern Ireland, Peru, Scotland, Slovenia, Sweden, and the USA displayed substantial excess age-standardized mortality of varying duration during 2020, while Australia, Denmark, Estonia, Mauritius, Norway, and Ukraine did not. In sex-specific analyses, excess mortality was higher in males than females, except for Slovenia (higher in females) and Cyprus (similar in both sexes). Lastly, for most countries substantial excess mortality was only detectable (Austria, Cyprus, Israel, and Slovenia) or was higher (Brazil, England and Wales, France, Georgia, Italy, Northern Ireland, Sweden, Peru and the USA) in the oldest age group investigated. Peru demonstrated substantial excess mortality even in the <45 age group., Conclusions: This study highlights that excess all-cause mortality during 2020 is context dependent, with specific countries, sex- and age-groups being most affected. As the pandemic continues, tracking excess mortality is important to accurately estimate the true toll of COVID-19, while at the same time investigating the effects of changing contexts, different variants, testing, quarantine, and vaccination strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We profiled T- and B-cell subsets longitudinally and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the 12 patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC, and sirolimus therapy did not result in significant decreases in T-, B- and NK-cell numbers. However, the expansion and activation of circulating T follicular helper and the Th1 bias noted before the initiation of sirolimus were significantly decreased. Features of chronic T-cell activation and exhaustion within effector memory compartments of CD4+ and CD8+ T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow-up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B-cell maturation., (© 2023 by The American Society of Hematology.)

Background: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed across sarcoma subtypes. We hypothesised that generation of anti-ganglioside antibodies would control micrometastases and improve outcomes in sarcoma patients who were disease-free after metastasectomy., Methods: We conducted a randomised phase II trial of the immunological adjuvant OPT-821 with a KLH-conjugated ganglioside vaccine targeting GM2, GD2 and GD3, versus OPT-821 alone in patients with metastatic sarcoma following complete metastasectomy. Patients received 10 subcutaneous injections at Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84 and were followed for evidence of recurrent disease. The primary end-point was relapse-free survival. Secondary end-points included overall survival and serologic response., Results: A total of 136 patients were randomised, 68 to each arm. The mean age was 51.2, 52.2% were male, 90.4% had relapsed disease, 86.8% had high-grade tumours and 14% had ≥4 metastases resected. Histologies included leiomyosarcoma (33%), spindle cell sarcoma (14%), undifferentiated pleomorphic sarcoma (13%), osteosarcoma (10%), synovial sarcoma (9%), liposarcoma (9%) and others (12%). Most adverse events were Grade ≤2 (83.8% and 70.6% in the vaccine and adjuvant arms, respectively). The most common (≥20% of patients) were injection site reaction (89.7%), fatigue (44.1%) and pyrexia (27.9%) on the vaccine arm, and injection site reaction (69.1%) on the adjuvant only arm. The 1-year relapse-free survival rate (34.5% and 34.8% in the vaccine and OPT-821 monotherapy arm, respectively) did not differ between arms (P = 0.725). One-year overall survival rates were 93.1% and 91.5% in the vaccine and OPT-821 monotherapy arm, respectively (P = 0.578). Serologic responses at week 9 were more frequent on the vaccine arm (96.5% of patients) than in the adjuvant arm (32.8%), and the difference between groups was durable., Conclusions: A sustained serologic response to vaccination was induced with the vaccine, but no difference in recurrence-free or overall survival was observed between treatment arms., Clinicaltrials: gov identifier: NCT01141491., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

Background: Defined by the emergence of antibiotic resistant strains, Staphylococcus aureus is a priority bacterial species with high antibiotic resistance. However, a rise in the prevalence of penicillin-susceptible S. aureus (PSSA) bloodstream infections has recently been observed worldwide, including in Australia, where the proportion of methicillin-susceptible S. aureus causing bacteremia identified phenotypically as penicillin-susceptible has increased by over 35%, from 17.5% in 2013 to 23.7% in 2020., Objectives: To determine the population structure of PSSA causing community- and hospital-onset bacteremia in Australia and to evaluate routine phenotypic antimicrobial susceptibility methods to reliably confirm penicillin resistance on blaZ -positive S. aureus initially classified as penicillin-susceptible by the Vitek ® 2 automated microbiology system., Results: Whole genome sequencing on 470 PSSA collected in the 2020 Australian Group on Antimicrobial Resistance Australian Staphylococcus aureus Sepsis Outcome Programme identified 84 multilocus sequence types (STs), of which 79 (463 isolates) were grouped into 22 clonal complexes (CCs). The dominant CCs included CC5 (31.9%), CC97 (10.2%), CC45 (10.0%), CC15 (8.7%), and CC188 (4.9%). Many of the CCs had multiple STs and spa types and, based on the immune evasion cluster type, isolates within a CC could be classified into different strains harboring a range of virulence and resistance genes. Phylogenetic analyses of the isolates showed most CCs were represented by one clade. The blaZ gene was identified in 45 (9.6%) PSSA. Although multiclonal, approximately 50% of blaZ -positive PSSA were from CC15 and were found to be genetically distant from the blaZ -negative CC15 PSSA. The broth microdilution, Etest ® and cefinase, performed poorly; however, when the appearance of the zone edge was considered; as per the EUCAST and CLSI criteria, disc diffusion detected 100% of blaZ -positive PSSA., Conclusions: In Australia, PSSA bacteremia is not caused by the expansion of a single clone. Approximately 10% of S. aureus classified as penicillin-susceptible by the Vitek ® 2 harbored blaZ . Consequently, we recommend that confirmation of Vitek ® 2 PSSA be performed using an alternative method, such as disc diffusion with careful interpretation of the zone edge.

Mastitis is commonly experienced by breastfeeding women. While Staphylococcus aureus is usually implicated in infectious mastitis, coagulase-negative staphylococci (CoNS) are a possible alternative pathogen. This case-control study examined the role of CoNS in mastitis using isolates cultured from breast milk of 20 women with mastitis and 16 women without mastitis. Gene sequencing determined bacterial species, and random amplified polymorphic DNA (RAPD) analysis investigated strain-level variation. The majority of CoNS isolates were Staphylococcus epidermidis (182/199; 91%). RAPD analysis identified 33 unique S. epidermidis profiles, with no specific profile associated with mastitis cases., (© 2022 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: The genomic era has led to enormous progress in clinical care and a multi-disciplinary team (MDT) approach is imperative for integration of genomics into epilepsy patient care., Methods: The MDT approach involved patient selection, genomic testing choice, variant discussions and return of results. Genomics analysis included cytogenomic testing and whole exome sequencing (WES). Neurologist surveys were undertaken at baseline and after genomic testing to determine if genomic diagnoses would alter their management, and if there was a change in confidence in genomic testing and neurologist perceptions of the MDT approach., Results: The total diagnostic yield from all genomic testing was 17% (11/66), with four diagnoses from cytogenomic analyses. All chromosomal microarray (CMA) diagnoses were in patients seen by adult neurologists. Diagnostic yield for WES was 11% (7/62). The most common gene with pathogenic variants was DCX , reported in three patients, of which two were mosaic. The genomic diagnosis impacted management in 82% (9/11). There was increased confidence with integrating genomics into clinical care (Pearson chi square = 83, p = 0.004) and qualitative comments were highly supportive of the MDT approach., Conclusions: We demonstrated diagnostic yield from genomic testing, and the impact on management in a cohort with drug-resistant epilepsy. The MDT approach increased confidence in genomic testing and neurologists valued the input from this approach. The utility of CMA was demonstrated in epilepsy patients seen by adult neurologists as was the importance of considering mosaicism for previously undiagnosed patients.

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease or COVID-19 pandemic is associated with more than 230 million cases and has challenged healthcare systems globally. Many healthcare workers (HCWs) have acquired the infection, often through their workplace, with a significant number dying. The epidemiology of COVID-19 infection in HCWs continues to be explored, with manifold exposure risks identified, leading to COVID-19 being recognised as an occupational disease for HCWs. The physical illness due to COVID-19 in HCWs is similar to the general population, with some HCWs experiencing a long-term illness, which may impact their ability to return to work. HCWs have also been affected by the immense workplace and psychosocial disruption caused by the pandemic. The impacts on the psychological well-being of HCWs globally have been profound, with high prevalence estimates for mental health symptoms, including emotional exhaustion. Globally, governments, healthcare organisations and employers have key responsibilities, including: to be better prepared for crises with comprehensive disaster response management plans, and to protect and preserve the health workforce from the physical and psychological impacts of the pandemic. While prioritising HCWs in vaccine rollouts globally has been critical, managing exposures and outbreaks occurring in healthcare settings remains challenging and continues to lead to substantial disruption to the health workforce. Safeguarding healthcare workforces during crises is critical as we move forward on the new path of 'COVID normal'., (© 2022 Asian Pacific Society of Respirology.)

Background: Non-communicable Diseases (NCDs) and their risk factors are the leading contributors to morbidity and mortality globally, particularly in low- and middle-income countries including Ethiopia. To date, there has been no synthesis of the literature on the relative prevalence of NCD risk factors in Ethiopia., Methodology: We conducted a systematic review and meta-analysis of primary studies reporting on the prevalence of NCD risk factors in Ethiopia published in English from 2012 to July 2020. Pre-tested NCD search terms were applied to Medline, Embase, Scopus, CINAHL, and Global Health. Three reviewers screened and appraised the quality of the identified papers. Data extraction was conducted using a pilot tested proforma. Meta-analysis was conducted using Stata 16 and pooled prevalence estimated with associated 95% confidence intervals. Clinically heterogeneous studies that did not fulfil the eligibility criteria for meta-analysis were narratively synthesised. I 2 was used to assess statistical heterogeneity., Results: 47 studies fulfilled the inclusion criteria and contributed 68 NCD risk factor prevalence estimates. Hypertension was the most frequently examined NCD risk factor, with a pooled prevalence of 21% ( n = 27 studies). The pooled prevalence percentages for overweight and obesity were 19.2% and 10.3%, respectively ( n = 7 studies each), with a combined prevalence of 26.8% ( n = 1 study). It was not possible to pool the prevalence of alcohol consumption, smoking, metabolic disorders, or fruit consumption because of heterogeneity across studies. The prevalence of alcohol use, as reported from the included individual studies, ranged from 12.4% to 13.5% ( n = 7 studies). More than 90% of participants met the WHO-recommended level of physical activity ( n = 5 studies). The prevalence of smoking was highly variable, ranging between 0.8% and 38.6%, as was the prevalence of heavy alcohol drinking (12.4% to 21.1%, n = 6 studies) and metabolic syndrome (4.8% to 9.6%, n = 5 studies). Fruit consumption ranged from 1.5% up to the recommended level, but varied across geographic areas ( n = 3 studies)., Conclusion and Recommendations: The prevalence of NCD risk factors in Ethiopia is relatively high. National NCD risk factor surveillance is required to inform the prioritisation of policies and interventions to reduce the NCD burden in Ethiopia.

Background: This study aimed to investigate overall and sex-specific excess all-cause mortality since the inception of the COVID-19 pandemic until August 2020 among 22 countries., Methods: Countries reported weekly or monthly all-cause mortality from January 2015 until the end of June or August 2020. Weekly or monthly COVID-19 deaths were reported for 2020. Excess mortality for 2020 was calculated by comparing weekly or monthly 2020 mortality (observed deaths) against a baseline mortality obtained from 2015-2019 data for the same week or month using two methods: (i) difference in observed mortality rates between 2020 and the 2015-2019 average and (ii) difference between observed and expected 2020 deaths., Results: Brazil, France, Italy, Spain, Sweden, the UK (England, Wales, Northern Ireland and Scotland) and the USA demonstrated excess all-cause mortality, whereas Australia, Denmark and Georgia experienced a decrease in all-cause mortality. Israel, Ukraine and Ireland demonstrated sex-specific changes in all-cause mortality., Conclusions: All-cause mortality up to August 2020 was higher than in previous years in some, but not all, participating countries. Geographical location and seasonality of each country, as well as the prompt application of high-stringency control measures, may explain the observed variability in mortality changes., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Pediatric Evans syndrome (pES) is increasingly identified as the presenting manifestation of several inborn errors of immunity. Despite an improved understanding of genetic defects in pES, the underlying immunobiology of pES is poorly defined, and characteristic diagnostic immune parameters are lacking. We describe the immune characteristics of 24 patients with pES and compared them with 22 patients with chronic immune thrombocytopenia (cITP) and 24 healthy controls (HCs). Compared with patients with cITP and HC, patients with pES had increased circulating T-follicular helper cells (cTfh), increased T-cell activation, and decreased naïve CD4+ T cells for age. Despite normal or high immunoglobulin G (IgG) in most pES at presentation, class-switched memory B cells were decreased. Within the cTfh subset, we noted features of postactivation exhaustion with upregulation of several canonical checkpoint inhibitors. T-cell receptor β chain (TCR-β) repertoire analysis of cTfh cells revealed increased oligoclonality in patients with pES compared with HCs. Among patients with pES, those without a known gene defect had a similar characteristic immune abnormality as patients with defined genetic defects. Similarly, patients with pES with normal IgG had similar T-cell abnormalities as patients with low IgG. Because genetic defects have been identified in less than half of patients with pES, our findings of similar immune abnormalities across all patients with pES help establish a common characteristic immunopathology in pES, irrespective of the underlying genetic etiology., (© 2022 by The American Society of Hematology.)

Background: Understanding the impact of the burden of COVID-19 is key to successfully navigating the COVID-19 pandemic. As part of a larger investigation on COVID-19 mortality impact, this study aims to estimate the Potential Years of Life Lost (PYLL) in 17 countries and territories across the world (Australia, Brazil, Cape Verde, Colombia, Cyprus, France, Georgia, Israel, Kazakhstan, Peru, Norway, England & Wales, Scotland, Slovenia, Sweden, Ukraine, and the United States [USA])., Methods: Age- and sex-specific COVID-19 death numbers from primary national sources were collected by an international research consortium. The study period was established based on the availability of data from the inception of the pandemic to the end of August 2020. The PYLL for each country were computed using 80 years as the maximum life expectancy., Results: As of August 2020, 442,677 (range: 18-185,083) deaths attributed to COVID-19 were recorded in 17 countries which translated to 4,210,654 (range: 112-1,554,225) PYLL. The average PYLL per death was 8.7 years, with substantial variation ranging from 2.7 years in Australia to 19.3 PYLL in Ukraine. North and South American countries as well as England & Wales, Scotland and Sweden experienced the highest PYLL per 100,000 population; whereas Australia, Slovenia and Georgia experienced the lowest. Overall, males experienced higher PYLL rate and higher PYLL per death than females. In most countries, most of the PYLL were observed for people aged over 60 or 65 years, irrespective of sex. Yet, Brazil, Cape Verde, Colombia, Israel, Peru, Scotland, Ukraine, and the USA concentrated most PYLL in younger age groups., Conclusions: Our results highlight the role of PYLL as a tool to understand the impact of COVID-19 on demographic groups within and across countries, guiding preventive measures to protect these groups under the ongoing pandemic. Continuous monitoring of PYLL is therefore needed to better understand the burden of COVID-19 in terms of premature mortality., (© 2022. The Author(s).)

Development of first-generation thrombopoietins (TPOs) was halted due to antibodies that neutralized endogenous TPO, causing protracted thrombocytopenia in some patients. The second-generation TPO receptor agonist romiplostim, having no homology to TPO, was developed to circumvent potential immunogenicity. We examined the development of binding and neutralizing antibodies to romiplostim and TPO among pediatric patients with primary immune thrombocytopenia (ITP) in 5 clinical trials and a global postmarketing registry. In the trials, 25 of 280 (8.9%) patients developed anti-romiplostim binding antibodies. The first positive result was detected 67 weeks (median) after romiplostim treatment was initiated. The median romiplostim dose was 8 µg/kg, and the median platelet count was 87 × 109/L. Most patients who developed anti-romiplostim binding antibodies (18 of 25 [72%]) had ≥90% of platelet assessments showing a response. Anti-romiplostim neutralizing antibodies developed in 8 of 280 (2.9%) patients. The development of anti-romiplostim neutralizing antibodies was unrelated to the romiplostim dose, and most patients who developed the antibodies (7 of 8 [88%]) had platelet response. Nine of 279 (3.2%) patients developed anti-TPO binding antibodies, and 1 (0.4%) developed transient anti-TPO neutralizing antibodies. In 8 patients who developed anti-romiplostim neutralizing antibodies, no TPO cross-reactivity was observed. In the postmarketing registry, 3 of 19 (15.8%) patients developed anti-romiplostim binding antibodies; 1 (5.3%) patient developed anti-romiplostim neutralizing antibodies. These results suggest that immunogenicity to romiplostim occurs infrequently in pediatric patients with ITP and is generally not associated with loss of platelet response or other negative clinical sequelae., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The emergence of the Delta variant of SARS-CoV-2 has made Australia's 'COVID-zero' strategy unviable. As signalled by the Australian Government's National plan to transition Australia's national COVID-19 response, we need to plan a pathway forward for life beyond lockdown. However, this plan must be guided by long overdue discussions on our tolerance for serious illness, and hospital and intensive care unit capacity. The modelling that informs the national transition plan remains relevant, even with increases in case numbers, but one crucial thing that does change if cases continue to escalate is the effectiveness of test, trace and isolate models. As we move into suppression mode with higher rates of the population fully vaccinated, we will no longer need to find every case. This is among the many shifts in approach that will shape our transition by early 2022 to living with - and controlling - the disease., Competing Interests: CB was an independent expert adviser on the AstraZeneca Australia COVID-19 vaccine expert advisory committee.

Introduction: Immune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP., Methods and Analysis: Randomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×10 9 /L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites., Ethics and Dissemination: The study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023., Trial Registration Number: NCT03939637., Competing Interests: Competing interests: KAS: Research funding: Novartis, Pfizer, Daiichi Sankyo, Alexion; Consultancies: Dova. RFG: Research funding: Novartis, Agios, Pfizer; Consultancies: Agios, Dova. JD: Research funding: Amgen, Novartis; Consultancies: Amgen, Novartis, Dova. EN: Advisory boards: Genentech, NovoNordisk, Novartis; Honoraria: Octapharma; DSMB service: Bayer, ApoPharma, Acceleron, Imara; Consultancies: Pfizer, Celgene. RJK: Speaker: Takeda, Biogen Canada LMT, Octapharma, Pfizer; Consultancies: Agios, Amgen, Hoffman-LaRoche, Takeda, NovoNordisk Canada. CM: Research funding: Novartis. WL: DSMB member: ArQule, Jubliant Draximage. CEN: Research funding: PDSA., (© 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.)

Background: The decision to initiate second-line treatment in children with immune thrombocytopenia (ITP) is complex and involves many different factors., Methods: In this prospective, observational, longitudinal cohort study of 120 children from 21 centers, the factors contributing to the decision to start second-line treatments for ITP were captured. At study entry, clinicians were given a curated list of 12 potential reasons the patient required a second-line treatment. Clinicians selected all that applied and ranked the top three reasons., Results: Quality of life (QOL) was the most frequently cited reason for starting a second-line therapy. Clinicians chose it as a reason to treat in 88/120 (73%) patients, as among the top three reasons in 68/120 (57%), and as the top reason in 32/120 (27%). Additional factors ranked as the top reason to start second-line treatment included severity of bleeding (22/120, 18%), frequency of bleeding (19/120, 16%), and severity of thrombocytopenia (18/120, 15%). Patients for whom QOL (p = .006) or sports participation (p = .02) were ranked reasons were more likely to have chronic ITP, whereas those for whom severity (p = .003) or frequency (p = .005) of bleeding were ranked reasons were more likely to have newly diagnosed or persistent ITP. Parental anxiety, though rarely the primary impetus for treatment, was frequently cited (70/120, 58%) as a contributing factor., Conclusion: Perceived QOL is the most frequently selected reason pediatric patients start second-line therapies for ITP. It is critical that studies of treatments for childhood ITP include assessments of their effects on QOL., (© 2021 Wiley Periodicals LLC.)

Myeloproliferative neoplasms (MPN) are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there are no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest patients with MPN., (© 2020 Wiley Periodicals LLC.)

VGF is a peptide precursor expressed in neuroendocrine cells that is suggested to play a role in the regulation of energy homeostasis. VGF is proteolytically cleaved to yield multiple bioactive peptides. However, the specific actions of VGF-derived peptides on energy homeostasis remain unclear. The aim of the present work was to investigate the role of VGF-derived peptides in energy homeostasis and explore the pharmacological actions of VGF-derived peptides on body weight in preclinical animal models. VGF-derived peptides (NERP-1, NERP-2, PGH-NH 2 , PGH-OH, NERP-4, TLQP-21, TLQP-30, TLQP-62, HHPD-41, AQEE-30, and LQEQ-19) were synthesized and screened for their ability to affect neuronal activity in vitro on hypothalamic brain slices and modulate food intake and energy expenditure after acute central administration in vivo. In addition, the effects of NERP-1, NERP-2, PGH-NH 2 , TLQP-21, TLQP-62, and HHPD-41 on energy homeostasis were studied after chronic central infusion. NERP-1, PGH-NH 2 , HHPD-41, and TLQP-62 increased the functional activity of hypothalamic neuronal networks. However, none of the peptides altered energy homeostasis after either acute or chronic ICV administration. The present data do not support the potential use of the tested VGF-derived peptides as novel anti-obesity drug candidates., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Methyl mercury (MeHg) is a neurotoxicant that with sufficient exposure can seriously impair the central nervous system and cause mental retardation, cerebral palsy, and neuromotor dysfunction. The level of exposure needed to adversely affect the nervous system is unknown. Human exposure to low levels of MeHg is common from consumption of fish. We examined the relationship between MeHg exposure and development of articulatory-phonologic speech skills in children whose mothers consumed a diet high in fish during pregnancy to determine whether any adverse associations could be detected. A total of 544 children from the Republic of Seychelles were given a speech assessment when they were 66 months of age. Exposure level was determined by measuring MeHg in maternal hair growing during pregnancy. No adverse associations between articulatory- phonologic speech skills and prenatal MeHg exposure were detected. The findings of this investigation are compatible with previous developmental assessments of Seychellois children that have indicated no adverse effects of prenatal MeHg exposure from fish consumption., (Copyright © 2021. Published by Elsevier B.V.)

Background: Although the impact of early life acetaminophen on asthma risk is still not clear, potential interactions with glutathione S-transferase (GST) genes due to reduced antioxidant function in particular polymorphisms, and possible impact on lung function, have never been investigated in adolescents., Objective: We aimed to investigate associations between early life acetaminophen use and adolescent asthma and lung function and to assess potential interactions by GST polymorphisms., Methods: Acetaminophen use was recorded 18 times up to age 2 years (n = 575 [92.7%]). Participants were genotyped for GST polymorphisms (GSTM1/T1/P1) (n = 429 [69.2%]). Asthma and lung function were measured at 12 (n = 365 [58.9%]) and 18 years (n = 413 [66.6%]). Regression models assessed associations and interactions., Results: Doubling of days of acetaminophen use was associated with reduced prebronchodilator FEV 1 /forced vital capacity (β coefficient, -0.10; 95% CI, -0.19 to -0.01) and midexpiratory flow (-0.09; 95% CI, -0.18 to 0) at 18 years, but this association was not found when restricted for nonrespiratory reasons, suggesting confounding by indication. However, in children with GSTM1 null and GSTT1 present, increasing acetaminophen use for nonrespiratory reasons was associated with reduced FEV 1 and midexpiratory flow at 18 years (interaction between GSTM1/T1 and acetaminophen P < .05). Increased acetaminophen use was associated with asthma at 18 years for children with GSTP1 Ile/Ile (odds ratio, 1.66; 95% CI, 1.07 to 2.57), but not other GSTP1 genotypes., Conclusions: These novel findings need to be investigated for consistency in other studies but suggest that children carrying risk genotypes may be susceptible to respiratory consequences from acetaminophen use., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The novel severe acute respiratory syndrome coronavirus 2 is a worldwide pandemic. The severe morbidity and mortality associated with coronavirus disease 2019 has mostly affected the elderly or those with underlying medical conditions. We present a case of a 12-year-old girl with no past medical history who presented with fever, cough, and vomiting. Laboratory evaluation revealed severe thrombocytopenia and elevated markers of inflammation. The patient progressed to respiratory failure, and testing results for the severe acute respiratory syndrome coronavirus 2 returned positive. Because of the severity of her thrombocytopenia, she was treated with intravenous immunoglobulin and steroids with prompt improvement in platelets. The patient's severe acute respiratory distress syndrome was managed with mechanical ventilation, inhaled nitric oxide, and then airway pressure release ventilation. After azithromycin and hydroxychloroquine were given without improvement, our patient received tocilizumab, an anti-interleukin-6 receptor antibody, and remdesivir, a broad antiviral agent, with significant clinical benefit soon afterward. Given that severe pediatric coronavirus disease 2019 is rare, we hope to inform pediatric providers on the clinical course and management considerations as this pandemic continues to spread., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years ("early prophylaxis"); 18 initially randomized to episodic treatment, starting "delayed prophylaxis" at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844., (© 2020 by The American Society of Hematology.)

Background: Although there is ongoing debate regarding the impact of early postnatal exposure to antibiotics on the development of asthma, the possibility that antibiotic exposure may impair lung function has not previously been examined. Furthermore, it is unclear if specific types of antibiotics may have a greater effect, or if children with genetic mutations in the oxidative stress response glutathione S-transferase (GST) superfamily may be at greater risk., Methods: Parent-reported data of childhood antibiotic use from birth to 2 years, including type and indication, were collected from a birth cohort of 620 infants with a family history of allergy. Spirometry was performed at age 12 and 18 years, and results are presented as z scores. Participants were genotyped for GST-P, GST-M, and GST-T polymorphisms. Linear regression models were used to investigate the associations while adjusting for confounding factors., Results: Neither increasing days of exposure nor earlier exposure to antibiotics was associated with reduced FEV 1 (at 18 years, per doubling of days of exposure = -0.03 z score units; 95% CI, -0.11 to 0.04) or FVC (< 0.01; 95% CI, -0.08 to 0.07). There was no evidence that GST-risk polymorphisms (M1, P1, and T1) increased susceptibility, and specific types of antibiotics also did not increase risk of lung function deficits., Conclusions: Increasing exposure to oral antibiotics in early postnatal life was not associated with reduced lung function in children with a family history of allergic diseases. Although unwarranted use of antibiotics in children should be minimized, concerns regarding long-term lung health should not be a driving influence for this rationalization of use., (Copyright © 2019. Published by Elsevier Inc.)

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×10 9 L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P =0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia., (Copyright© 2019 Ferrata Storti Foundation.)

Background: Exposure to high levels of pollen in infancy is a risk factor for allergic respiratory diseases in later childhood, but effects on lung function are not fully understood. We aim to examine associations between grass pollen exposure in the first months of life and lung function at 12 and 18 years, and explore potential modification., Methods: Using the Melbourne Atopy Cohort Study, a birth cohort of children with a family history of allergic diseases, we modeled the association between cumulative grass pollen exposure up to 3 months after birth, on FEV 1 , FVC, and FEV 1 /FVC ratio at 12 and 18 years. We also assessed modifying effects of residential greenness levels (derived from satellite imagery), asthma, and early life sensitization to ryegrass., Results: Grass pollen exposure in the first 7 days was associated with a reduction in FEV 1 (-15.5 mL; 95% CI: -27.6, -3.3 per doubling of pollen count) and FVC (-20.8 mL; -35.4, -6.1) at 12 years, but not at 18 years. Increase in cumulative grass pollen exposure up to 3 months was negatively associated with FVC at 12 and 18. Exposure to high residential greenness modified the association at 18 years., Conclusion: Early exposure to grass pollen was associated with decreased lung function in children and adolescents. Targeted interventions for pollen avoidance strategies that take into account local topography could be implemented alongside other clinical interventions such as immunotherapy., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)