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Abstract The impacts of climate change on human health are often underestimated or perceived to be in a distant future. Here, we present the projected impacts of climate change in the context of COVID-19, a recent human health catastrophe. We compared projected heat mortality with COVID-19 deaths in 38 cities worldwide and found that in half of these cities, heat-related deaths could exceed annual COVID-19 deaths in less than ten years (at + 3.0 °C increase in global warming relative to preindustrial). In seven of these cities, heat mortality could exceed COVID-19 deaths in less than five years. Our results underscore the crucial need for climate action and for the integration of climate change into public health discourse and policy.

There is an unspoken dichotomy between needing help and fearing those from whom you must receive it. Individuals of minority groups experience the cognitive dissonance of this ingrained fear, as [...]

Objective: Comprehensive sexuality education (CSE) allows for informed and healthy decisions. College students often lack understanding of sexual and reproductive health (SRH). Conversations and Pizza (CAP), an interactive curriculum, was designed to address gaps in CSE and improve SRH outcomes. Participants: 66 fraternity affiliated undergraduate students. Methods: A six-session intervention discussed gender norms, biology, consent, harassment, and bystander intervention. Pre- and post-quantitative surveys assessed attitudes and behaviors; plus-delta format was used for qualitative feedback. Results: Qualitative data reflected engagement. Post-intervention, multiple measures improved (McNemar p < 0.05): perceived self-efficacy in consent and peer norms (4/8 measures), bystander intervention (5/6), and awareness of harassment (2/5). Participants reported more conversations with partners (pregnancy and STI prevention, 50% to 75%); human papillomavirus (HPV) vaccination receipt increased (60% to 93%, McNemar p < 0.001). Conclusion: Reproductive health outcomes improved in this pilot, laying the groundwork for continued testing. CAP is a successful pilot program that can be evaluated for a variety of groups and formats.

ABSTRACT Surface waters function as ecological niches where Salmonella enterica can persist and disseminate to fresh produce production systems. We examined the genomic characteristics of S. enterica serotypes Agona (n = 86), Braenderup (n = 47), Muenchen (n = 53), and Panama (n = 69) isolates from surface waters in Chile, Mexico, and Brazil between 2019 and 2022. Mexican isolates consistently displayed a higher occurrence of genotypic antimicrobial resistance (AMR) than Chilean and Brazilian isolates. All S. Agona isolates exhibited the presence of fosA7.2, while qnrB19 emerged as the predominant AMR gene (ARG) among S. Braenderup isolates. S. Muenchen isolates from Chile displayed an absence of any ARGs, while those from Mexico and Brazil predominantly carried qnrB19. Among S. Panama isolates from Chile, aadA1, floR, sat2, and tet(B) were the most prevalent ARGs, whereas those from Mexico and Brazil harbored tet(A), and floR and tet(A) as the leading ARGs, respectively. ARG sharing among isolates and ARG co-occurrence within individual isolates were prevalent across countries and serotypes. All isolates containing integrons exhibited genotypic multidrug resistance. The principal coordinates analysis reveals distinct clustering patterns based on country, serotype, number of ARGs per isolate, and plasmid and integron presence/absence. The whole-genome phylogenetic analysis demonstrates clear clusters, each associated with their respective countries. However, a notable exception was observed with one S. Agona isolate from Brazil closely related to two isolates from Chile, differing by only 18 and 19 single-nucleotide polymorphisms, respectively.IMPORTANCEThis comprehensive study explored the intricate genomic landscapes of S. Agona, Braenderup, Muenchen, and Panama isolates from surface waters across Chile, Mexico, and Brazil. By filling important knowledge gaps related to the genomic characteristics of these serotypes, the research offers a nuanced understanding of these serotypes as potential reservoirs for multidrug resistance. Our findings emphasize the urgency of targeted interventions to mitigate the emergence and dissemination of multidrug-resistant Salmonella enterica. This work underscores the need for informed policies and collaborative efforts to address the risks posed by S. enterica in Latin American surface waters.

BackgroundThe interaction between genetics, epigenetics, and the environment plays a key role in the development of alcohol use disorder (AUD). Pharmacological treatments targeting histone deacetylases (HDACs) suggest that HDAC inhibitors (HDACi) may be potential pharmacotherapeutic treatments for AUD. The objective of the current study was to test the effects of different HDACi on ethanol intake in two rat lines selectively bred for high ethanol-consumption.MethodAdult naïve male high alcohol drinking line 1 (HAD1) or alcohol-preferring (P) rats were given continuous 24-h, 3-bottle, free-choice access to 15%, 30% ethanol concurrently with water for 8 weeks prior to testing entinostat (selective HDAC1i and HADC3i, 0, 1.25, 2.5, 5 mg/kg, i. p.), quisinostat (pan HADCi, 0, 0.5, 1.0, 2.0 mg/kg, i. p.), or tubastatin-A (selective HDAC6i, 0, 1.25, 2.5, 5 mg/kg, i. p.) over 4-5 consecutive days.ResultsIn HAD1 rats, entinostat reduced 2-, 4-, and 24-h ethanol intake across the 2nd – 5th test days; while, in P rats, entinostat’s effect was primarily seen at the 24-h time-point, at the highest dose and only across three test days. The high dose of quisinostat effectively reduced 24-h ethanol intake across the 1st—4th test days in HAD1 rats but was ineffective in P rats. Tubastatin-A did not alter ethanol intake in either rat line.ConclusionOverall, the results confirmed that a pan and a more selective (HDAC1 and HDAC3) HDACi effectively reduced ethanol intake in HAD1, while only the more selective HDACi reduced ethanol intake in P rats. Inhibition of HDAC6 does not appear to regulate ethanol intake in HAD1 or P rats.

The human genome is largely noncoding, yet the field is still grasping to understand how noncoding variants impact transcription and contribute to disease etiology. The massively parallel reporter assay (MPRA) has been employed to characterize the function of noncoding variants at unprecedented scales, but its application has been largely limited by the in vitro context. The field will benefit from establishing a systemic platform to study noncoding variant function across multiple tissue types under physiologically relevant conditions. However, to date, MPRA has been applied to only a handful of in vivo conditions. Given the complexity of the central nervous system and its widespread interactions with all other organ systems, our understanding of neuropsychiatric disorder-associated noncoding variants would be greatly advanced by studying their functional impact in the intact brain. In this review, we discuss the importance, technical considerations, and future applications of implementing MPRA in the in vivo space with the focus on neuropsychiatric disorders.

ABSTRACT Karst ecosystems often contain extraordinary biodiversity, but the complex underground aquifers of karst regions present challenges for assessing and conserving stygobiont diversity and investigating their evolutionary history. We examined the karst‐obligate salamanders of the Eurycea neotenes species complex in the Edwards Plateau region of central Texas using population genomics data to address questions about population connectivity and the potential for gene exchange within the underlying aquifer system. The E. neotenes species complex has historically been divided into three nominal species, but their status, and spatial extent of species ranges, have remained uncertain. We discovered evidence of extensive admixture among species within the complex and with adjacent lineages. We observed relatively low levels of differentiation among all sampling localities which supports the hypothesis of recent divergence. Nominal taxonomy, aquifer region and geography each accounted for a modest amount of the overall population genomic variation; however, these predictors were largely confounded and difficult to disentangle. Importantly, current taxonomy of the three nominal species does not reflect the admixture apparent in clustering analyses. Inference of migration events revealed a complex pattern of gene exchange, suggesting that Eurycea salamanders have a dynamic history of dispersal through the aquifer system. These results highlight the need for greater understanding of how stygobiont populations are connected via dispersal and gene exchange through karst aquifers. These results also highlight the applicability of population genomics data as a powerful lever for investigating connectivity among populations in systems where direct detection of dispersal paths is difficult, as in underground, aquatic systems.

Summary: Background: Perivascular spaces (PVS) on brain MRI are surrogates for small parenchymal blood vessels and their perivascular compartment, and may relate to brain health. However, it is unknown whether PVS can predict dementia risk and brain atrophy trajectories in participants without dementia, as longitudinal studies on PVS are scarce and current methods for PVS assessment lack robustness and inter-scanner reproducibility. Methods: We developed a robust algorithm to automatically assess PVS count and size on clinical MRI, and investigated 1) their relationship with dementia risk and brain atrophy in participants without dementia, 2) their longitudinal evolution, and 3) their potential use as a screening tool in simulated clinical trials. We analysed 46,478 clinical measurements of cognitive functioning and 20,845 brain MRI scans from 10,004 participants (71.1 ± 9.7 years-old, 56.6% women) from three publicly available observational studies on ageing and dementia (the Alzheimer’s Disease Neuroimaging Initiative, the National Alzheimer’s Coordinating Centre database, and the Open Access Series of Imaging Studies). Clinical and MRI data collected between 2004 and 2022 were analysed with consistent methods, controlling for confounding factors, and combined using mixed-effects models. Findings: Our fully-automated method for PVS assessment showed excellent inter-scanner reproducibility (intraclass correlation coefficients >0.8). Fewer PVS and larger PVS diameter at baseline predicted higher dementia risk and accelerated brain atrophy. Longitudinal trajectories of PVS markers differed significantly in participants without dementia who converted to dementia compared with non-converters. In simulated placebo-controlled trials for treatments targeting cognitive decline, screening out participants at low risk of dementia based on our PVS markers enhanced the power of the trial independently of Alzheimer’s disease biomarkers. Interpretation: These robust cerebrovascular markers predict dementia risk and brain atrophy and may improve risk-stratification of patients, potentially reducing cost and increasing throughput of clinical trials to combat dementia. Funding: US National Institutes of Health.

Biological and psychological theories suggest complex impacts of heat on aggression and violence. Most previous studies considered temporal intervals of months to years and assumed linear associations. Evidence is needed on daily impacts of temperature on crime, applying non-linear models across different locations. This observational study examined non-linear relationships between daily summer temperature (May–September) and violent crime in 44 cities across 33 US states, 2005–2022. We calculated city-specific average temperature for the event day and previous day (lag0–1) and daily temperature anomalies (deviation from 1985 to 2010 average) using PRISM data. The Uniform Crime Reporting Program data were used to calculate daily city-specific number of violent crimes (n = 2,447,458 incidents). Generalized additive modeling was used to estimate relative risks (RRs) of violent crime. We identified three distinctive shapes (J-shaped, inverted J-shaped, linear) for relationships. The inverted J-shaped curve, indicating higher crime rates at high temperatures below extremely hot temperatures, was most predominant (26 cities). Across all cities, violent crime was 1.03 times higher at high compared to moderate temperatures (90th vs. 50th percentiles) (RR 1.03, 95 % CI: 1.02–1.04). Violent crime was also higher at moderate compared to cold temperatures (50th vs. 10th percentiles) [RR 1.04 (95 % CI: 1.03–1.06)], whereas risk did not differ between extremely high and hot temperature (99th vs. 90th percentiles). Risk during hot days versus moderate temperature days was significantly lower for cities with lower latitude, higher median temperature, higher urban greenspace, and higher percentage of occupied housing units with air conditioners. Risk was higher in cities with 90th percentile temperature anomalies that deviated from the historical temperature record, suggesting implications of climate change on heat-related violence. High daily temperatures are associated with violent crime with differences across locations. Disparities in risks by city-level social and environmental characteristics have implications for climate change strategies.

Summary: Background: Little is known about the impact of PM2.5 on people with disabilities. We aimed to explore the association between PM2.5 and hospitalization via the emergency department (ED admission) among people with disabilities, together with the attributable ED admission cases and costs. Methods: We applied a time-stratified case-crossover design adjusting ozone, holiday, and temperature using seven years (2015–2021) of claim-based data on ED admissions from the Korean National Health Insurance Database. The analysis included all ED admission cases of beneficiaries with disabilities living in Korea (physical, intellectual, and mental disabilities; brain lesion disorders; blindness or vision loss; deafness or hearing loss; and autism) as well as selected controls without disabilities. Findings: There were 900,311 ED admissions among the 3,624,590 people with disabilities. The odds ratios of ED admissions associated with a 10 μg/m3 increase in PM2.5 were 1.039 (95% CI: 1.036–1.042) in people with disabilities and 1.022 (95% CI: 1.019–1.025) in people without disabilities. Individuals with mental disability, intellectual disability, and brain lesion disorder showed higher risk estimates compared to other disabilities. The risk estimates of ED admissions for cardiovascular and genitourinary diseases were more prominent among people with disabilities than those without disabilities. Interpretation: The impacts of PM2.5 on ED admissions was generally higher in the population with disabilities than those without disabilities, especially for certain causes of admission. These results could contribute to establishing targeted action plans including early warning system referring different threshold concentrations. Funding: National Research Foundation.

Background: Emerging research has suggested a link between ambient temperature and mental and neurological conditions such as depression and dementia. This systematic review aims to summarize the epidemiological evidence on the effects of ambient temperature on mental and neurological conditions in older adults, who may be more vulnerable to temperature-related health effects compared to younger individuals. Methods: A systematic search was conducted in PubMed, Ovid/Embase, Web of Science, and Ovid/PsycINFO on July 17, 2023, and updated on July 31, 2024. We included epidemiological studies investigating the association between ambient temperature exposures and numerous mental and neurological conditions in populations aged 60 years and older. Exclusions were made for studies on indoor or controlled exposure, suicide, substance abuse, those not published as peer-reviewed journal articles, or those not written in English. The risk of bias of included studies was assessed using a tool developed by the World Health Organization (WHO). Qualitative synthesis was performed on all eligible studies, and random-effects meta-analyses were conducted on groups of at least four studies sharing similar study design, exposure metric, and health outcome. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework modified by the WHO. Results: From 16,786 screened articles, 76 studies were deemed eligible, primarily from mainland China and North America. There was notable heterogeneity in study variables and methodologies. The most commonly used exposure metrics were daily absolute temperature and heat waves, and time-series and case-crossover analyses were the most frequently employed study designs. Meta-analysis of four studies on the effect of a 1 °C increase in temperature on hospital admissions/visits for mental disorders showed a pooled risk ratio (RR) of 1.014 (95 % Confidence Interval, CI: 1.001, 1.026). Comparing heat wave days to non-heat wave days, pooled effect estimates showed increased risk in hospital admissions/visits (RR: 1.269; 95 % CI: 1.030, 1.564; six studies) and mortality related to mental disorders (RR: 1.266; 95 % CI: 0.956, 1.678; four studies). Despite the limited number of studies on cold exposures, they consistently reported that lower temperatures were associated with an increased risk of various mental and neurological conditions. Conclusions: This review presents epidemiological evidence of the adverse impacts of ambient temperature exposures, such as high temperatures and heat waves, on mental and neurological conditions among the older adult population, with overall moderate certainty. The findings highlight the need for greater attention to the mental and neurological health of older adults in the context of climate change and population aging.Registration number (PROSPERO ID): CRD42023428137.

Health. Disability. Vulnerability. These words are often used when discussing the risks of climate disruption. These discussions warn of the potential for climate impacts to “undermine 50 years of gains in public health” (as stated by the Lancet Countdown on Climate Change). Increasingly, such discussions also acknowledge climate injustice, examining who will benefit or lose out from climate change, how and why. The embodied vulnerability of disabled people is often assumed within such discussions, with less consideration of the social, economic or political conditions that create this vulnerability. By bringing disability justice and disability studies into correspondence with care, environmental and climate justice scholarship, this reflective paper challenges the master narratives that blur differentiated experiences of disability and climate impacts into a single story of inevitable vulnerability. Recognising disabled people as knowers, makers and agents of change, it calls for transformative climate action, underpinned by values of solidarity, mutuality and care.

BackgroundAdolescents and young adults frequently present to the emergency department (ED) for medical care and continue to have many unmet sexual health needs. Digital interventions show promise to improve adolescent and young adult sexual health; yet, few interventions focus on male ED patients, despite their infrequent use of contraceptives and rising rates of sexually transmitted infections. ObjectiveThis paper describes the design and development of Dr. Eric (Emergency Room Interventions to Improve Care), a digital app focused on promoting condom use among sexually active adolescent and young adult male ED patients. MethodsThis study followed 4 phases of app development, which were based on user-centered design and the software development lifecycle. In phase 1, define, we explored our target population and target health problem (infrequent condom use among male ED patients) by collecting key stakeholder input and conducting in-depth interviews with male patients and urban ED medical providers. In phase 2, discover, we partnered with a digital product agency to explore user experience and digital strategy. In phase 3, design, we refined Dr. Eric’s content, a 5-part sexual health educational module and a 10-week SMS text messaging program that focuses on condom use and partner communication about effective contraceptives. We conducted semistructured interviews with male adolescent and young adults to gather feedback on the app and perform usability testing, editing the app after each interview. We also interviewed informatics experts to assess the usability of a high-fidelity prototype. Interviews were recorded and analyzed via descriptive thematic analysis; informatic expert feedback was categorized by Nielsen’s heuristic principles. In phase 4, develop, we created the technical architecture and built a responsive web app. These findings were gathered leading to the final version of the digital Dr. Eric program. ResultsUsing data and key stakeholder input from phases 1 and 2, we iteratively created the Dr. Eric prototype for implementation in the ED setting. Interviews with 8 adolescent and young adult male ED patients suggested that users preferred (1) straightforward information, (2) a clear vision of the purpose of Dr. Eric, (3) open-ended opportunities to explore family planning goals, (4) detailed birth control method information, and (5) games presenting novel information with rewards. Five usability experts provided heuristic feedback aiming to improve the ease of use of the app. These findings led to the final version of Dr. Eric. ConclusionsFollowing these mobile health development phases, we created a digital sexual health mobile health intervention incorporating the principles of user experience and interface design. Dr. Eric needs further evaluation to assess its efficacy in increasing condom use among adolescent and young adult male ED patients. Researchers can use this framework to form future digital health ED-based digital interventions.

The U.S. Department of Agriculture (USDA) has performed European pear (Pyrus communis L.) scion breeding for over a century. The breeding program started in the early 1900s by Merton B. Waite in the Washington D.C. area and the program’s main goal was to develop host resistance to the devastating disease fire blight, caused by Erwinia amylovora. Most of the historic European pear cultivars being produced in the U.S. were susceptible to fire blight, prompting a need to breed for resistance. More than six generations of USDA breeders have continued this effort to breed disease-resistant European pears. Along with fire blight resistance, the pear breeding programs sought improved fruit quality, cold hardiness, and resistance to psylla (Cacopsylla pyricola Foërster), a significant insect pest of pear. Herein, we discuss the history of the program through each generation of breeder(s). We also present breeding aims, parental selection, and releases. In total, the program has released ten named pear varieties between 1938 and 2022.

Background: Epidemiological evidence on the association between wildfire-specific fine particulate matter (PM2.5) and its carbonaceous components with perinatal outcomes is limited.We aimed to examine the short-term effects of wildfire-specific PM2.5 and its carbonaceous components on perinatal outcomes. Methods: A multicentre cohort of 9743 singleton births during the wildfire seasons from 1 September 2009 to 31 December 2015 across six cities in New South Wales, Australia were linked with daily wildfire-specific PM2.5 and carbonaceous components (organic carbon and black carbon). Adjusted distributed lag Cox regression models with spatial clustering were performed to estimate daily and cumulative adjusted hazard ratios (aHRs) during the last four gestational weeks for preterm birth, stillbirth, nonvertex presentation, low 5-min Apgar score, special care nursery/neonatal intensive care unit (SCN/NICU) admission, and caesarean section. Results: Daily aHRs per 10 µg/m3 PM2.5 showed nearly inverted ‘U’-shaped positive associations and daily cumulative aHRs that increased with increasing duration of the exposures. The aHRs for lag 0–6 days were 1.17 (95 % CI: 1.04, 1.32) for preterm birth, 1.40 (95 % CI: 1.11, 1.78) for stillbirth, 1.20 (95 % CI: 1.08, 1.33) for nonvertex presentation, 1.12 (95 % CI: 0.93, 1.35) for low 5-min Apgar score, 0.99 (95 % CI: 0.83, 1.19) for SNC/NICU admission, and 1.01 (95 % CI: 0.94, 1.08) for caesarean section. Organic carbon and black carbon components for lag 0–6 days showed positive associations. The highest component-specific aHRs were 1.09 (95 % CI: 1.03, 1.15) and 4.57 (95 % CI: 1.96, 10.68) for stillbirth per 1 µg/m3 organic carbon and black carbon, respectively. The subgroups identified as most vulnerable were female births, births to mothers with low socioeconomic status, and births to mothers with high biothermal exposure. Conclusions: Positive associations of short-term wildfire-specific PM2.5 exposure and its carbonaceous components with adverse perinatal outcomes suggest that policies to reduce exposure would benefit public health.

Abstract Background Long-term exposure to PM2.5 has been linked to increased mortality risk. However, limited studies have examined the potential modifying effect of community-level characteristics on this association, particularly in Asian contexts. This study aimed to estimate the effects of long-term exposure to PM2.5 on mortality in South Korea and to examine whether community-level deprivation, medical infrastructure, and greenness modify these associations. Methods We conducted a nationwide cohort study using the National Health Insurance Service-National Sample Cohort. A total of 394,701 participants aged 30 years or older in 2006 were followed until 2019. Based on modelled PM2.5 concentrations, 1 to 3-year and 5-year moving averages of PM2.5 concentrations were assigned to each participant at the district level. Time-varying Cox proportional-hazards models were used to estimate the association between PM2.5 and non-accidental, circulatory, and respiratory mortality. We further conducted stratified analysis by community-level deprivation index, medical index, and normalized difference vegetation index to represent greenness. Results PM2.5 exposure, based on 5-year moving averages, was positively associated with non-accidental (Hazard ratio, HR: 1.10, 95% Confidence Interval, CI: 1.01, 1.20, per 10 µg/m3 increase) and circulatory mortality (HR: 1.22, 95% CI: 1.01, 1.47). The 1-year moving average of PM2.5 was associated with respiratory mortality (HR: 1.33, 95% CI: 1.05, 1.67). We observed higher associations between PM2.5 and mortality in communities with higher deprivation and limited medical infrastructure. Communities with higher greenness showed lower risk for circulatory mortality but higher risk for respiratory mortality in association with PM2.5. Conclusions Our study found mortality effects of long-term PM2.5 exposure and underlined the role of community-level factors in modifying these association. These findings highlight the importance of considering socio-environmental contexts in the design of air quality policies to reduce health disparities and enhance overall public health outcomes.

Abstract The majority of research into the mental health benefits of blue space (outdoor places where water is a central feature) has focussed on the associations between neighbourhood exposure to these spaces and population‐level incidence of unipolar depression or anxiety disorder. There has been little exploration of the therapeutic use of blue space by those navigating bipolar, schizophrenia or other psychotic conditions. Knowledge arising from such an exploration could assist in the design and optimisation of nature‐based care for people with these conditions, as well as with self‐management. We conducted semi‐structured online and telephone interviews with 19 adults who self‐reported experience of these conditions. Interviews were conducted in the United Kingdom from August to December 2021. We describe four of the key interpretive themes identified via an in‐depth inductive thematic analysis of the interview transcripts to highlight how participants sought out moments of affective sanctuary through their blue encounters. Blue spaces were described as having the potential to reset the mind, emotions and body. This was in part due to their socially undemanding nature, and ability to provide respite from a socially stressful world. Participants described developing a blue identity, whereby a sense of attachment to and shared history with these places was articulated as well as incorporating blue spaces into self‐ and emotion‐regulation practices. Finally, participants described experiences of and recommendations for a therapeutic blue intervention. The role of biodiversity in contributing to the benefits of blue spaces was implied primarily in terms of perceived soundscapes, but also through visual observations. Synthesis and applications. Blue care for people with bipolar, schizophrenia or other psychotic conditions should consider the need that some individuals have for solitude and proximity to their home when they visit blue spaces, as well as individual differences in the features of blue space interactions that provide the greatest benefit. Read the free Plain Language Summary for this article on the Journal blog.

Wildfires can have a significant impact on air quality in Australia during severe burning seasons, but incomplete knowledge of the injection heights of smoke plumes poses a challenge for quantifying smoke exposure. In this study, we use two approaches to quantify the fractions of fire emissions injected above the planetary boundary layer (PBL), and we further investigate the impact of plume injection fractions on daily mean surface concentrations of fine particulate matter (PM2.5) from wildfire smoke in key cities over northern and southeastern Australia from 2009 to 2020. For the first method, we rely on climatological, monthly mean vertical profiles of smoke emissions from the Integrated Monitoring and Modelling System for wildland fires (IS4FIRES) together with assimilated PBL heights from NASA Modern-Era Retrospective Analysis for Research and Application (MERRA) version 2. For the second method, we develop a novel approach based on the Multi-angle Imaging SpectroRadiometer (MISR) observations and a random forest, machine learning model that allows us to directly predict the daily plume injection fractions above the PBL in each grid cell. We apply the resulting plume injection fractions quantified by the two methods to smoke PM2.5 concentrations simulated by the Stochastic Time-Inverted Lagrangian Transport (STILT) model in target cities. We find that characterization of the plume injection heights greatly affects estimates of surface daily smoke PM2.5, especially during severe wildfire seasons, when intense heat from fires can loft smoke high in the troposphere. However, using climatological injection profiles cannot capture well the spatiotemporal variability in plume injection fractions, resulting in a 63 % underestimation of daily fire emission fluxes injected above the PBL in comparison with those fluxes derived from MISR injection fractions. Our random forest model successfully reproduces the daily injected fire emission fluxes against MISR observations (R2=0.88, normalized mean bias = 10 %) and predicts that 27 % and 45 % of total fire emissions rise above the PBL in northern and southeastern Australia, respectively, from 2009 to 2020. Using the plume behavior predicted by the random forest method also leads to better model agreement with observed surface PM2.5 in several key cities near the wildfire source regions, with smoke PM2.5 accounting for 5 %–52 % of total PM2.5 during fire seasons from 2009 to 2020.

Background: The incidence of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer (UBC) has continued to increase, despite an absent survival benefit except in populations at highest risk for developing contralateral breast cancer (CBC). CPM rates may be higher in rural populations but causes remain unclear. A study performed at our institution previously found that 21.8 % of patients with UBC underwent CPM from 2000 to 2009. This study aimed to evaluate the CPM trend at a single institution serving a rural population and identify the CPM rate in average-risk patients. Methods: Retrospective review of patients who underwent mastectomies for UBC at our institution from 2017 to 2021 was performed. Analysis utilized frequencies and percentages, descriptive statistics, chi-square, and independent sample t-tests. Results: A total of 438 patients were included, of whom 64.4 % underwent bilateral mastectomy for UBC (CPM). Patients who underwent CPM were significantly younger, underwent genetic testing, had germline pathogenic variants, had a family history of breast cancer, had smaller tumors, underwent reconstruction, and had more wound infections. Of CPM patients, 50.4 % had no identifiable factors for increased risk of developing CBC. Conclusions: The rate of CPM in a rural population at a single institution increased from 21.8 % to 64.4 % over two decades, with an average-risk CPM rate of 50.4 %. Those that undergo CPM are more likely to undergo reconstruction and have more wound infections. Identifying characteristics of patients undergoing CPM in a rural population and the increased associated risks allows for a better understanding of this trend to guide conversations with patients. Key message: This study demonstrates that the rate of contralateral prophylactic mastectomy for unilateral breast cancers performed at a single institution serving a largely rural population has nearly tripled over the last two decades, with half of these patients having no factors that increase the risk for developing contralateral breast cancers. Contralateral prophylactic mastectomy was significantly associated with smaller tumors, younger age, genetic testing, germline pathogenic variants, family history of breast cancer, breast reconstruction, and increased wound infections.

The emission and adsorption of mineral elements to dust from geogenic and anthropogenic sources are health challenges in residential areas. This study investigated, for the first time to the best of our knowledge, the presence of potentially toxic elements (PTEs), rare earth elements (REE) and fluorine (F) in collected dust samples from central Iran. Their associated health risks were estimated based on the Monte Carlo simulation. Results show that the morphology of the collected dust was uniform spherical particles and the predominant elements were Si and Ca. The highest concentration of PTEs was for Ca (mean: 36574 mg/kg) and Fe (mean: 30189 mg/kg) and the mean concentrations of As, Ni, Pb, Mn and Zn exceeded World Health Organization (WHO) guidelines, likely due to the anthropogenic activities such as metal melt factories. Fluorine averaged 159.4 mg/kg, and some detected elements originated from industrial and natural sources. The 5th, 50th, and 95th percentiles of the estimated Hazard Index (HI) were 0.13, 0.43, and 0.77, respectively, in adults and 1.00, 3.03, and 5.99, respectively, in children. The carcinogenic risk (LTCR) for adults and children exceeded the safety range (1 × 10−4), and their highest percentile was calculated at about 2.03 × 10−4 and 1.83 × 10−4, respectively. Furthermore, Ni was the most effective elements in LTCR. As a consequence, findings suggest a high potential carcinogenic risk due to the emission of dust in central Iran, especially for children, and the controlling of possible sources would benefit public health.

Background: Previous studies have linked exposure to concentrated animal feeding operations (CAFOs) with various health outcomes. However, relatively few studies evaluated the impacts of CAFOs on adverse birth outcomes, despite significant public health concerns regarding maternal and child health. Objectives: This cross-sectional study investigated the risk of adverse birth outcomes associated with CAFOs exposure and evaluated disparities in exposure to CAFOs and associated health outcomes. Methods: We obtained individual-level birth records from 2003 to 2020 from the Pennsylvania Department of Health. We considered two adverse birth outcomes: (1) preterm birth (PTB); and (2) low birth weight (LBW). Exposure was considered as a binary indicator (presence or absence of CAFO) and as categories based on level of exposure. Logistic regression was applied to estimate the association between CAFOs exposure and adverse birth outcomes. Models were adjusted for infant's sex, maternal demographics (age, race/ethnicity, education), prenatal BMI, prenatal care, smoking status, marital status, plurality, WIC status, and urban/rural indicator. We examined both disparities in exposure and in health response. Results: Presence of CAFOs was associated with higher risk of PTB, with an increasing trend with higher levels of CAFOs exposure. Compared to the no CAFO exposure group, the odds ratios for PTB were 1.022 (95 % confidence interval 1.003, 1.043), 1.066 (1.034, 1.100), 1.069 (1.042, 1.097) for low, medium, and high CAFOs exposure groups, respectively. Some maternal characteristics were associated with a higher CAFO-related risk of PTB. Similar associations were observed for LBW for some characteristics such as mother's race/ethnicity, education, WIC status, and urbanicity, although some findings were not statistically significant. Conclusions: Our findings suggest that presence of CAFOs increases risk of preterm birth. Our results indicate that some maternal characteristics may be associated with higher risk of CAFO-related PTB or LBW. This study can inform future research on disparities in CAFO exposure and associated health burden.

Dynamic gridded population data are crucial in fields such as disaster reduction, public health, urban planning, and global change studies. Despite the use of multi-source geospatial data and advanced machine learning models, current frameworks for population spatialization often struggle with spatial non-stationarity, temporal generalizability, and fine temporal resolution. To address these issues, we introduce a framework for dynamic gridded population mapping using open-source geospatial data and machine learning. The framework consists of (i) delineation of human footprint zones, (ii) construction of muliti-scale population prediction models using automated machine learning (AutoML) framework and geographical ensemble learning strategy, and (iii) hierarchical population spatial disaggregation with pycnophylactic constraint-based corrections. Employing this framework, we generated hourly time-series gridded population maps for China in 2016 with a 1-km spatial resolution. The average accuracy evaluated by root mean square deviation (RMSD) is 325, surpassing datasets like LandScan, WorldPop, GPW, and GHSL. The generated seamless maps reveal the temporal dynamic of population distribution at fine spatial scales from hourly to monthly. This framework demonstrates the potential of integrating spatial statistics, machine learning, and geospatial big data in enhancing our understanding of spatio-temporal heterogeneity in population distribution, which is essential for urban planning, environmental management, and public health.

Abstract Psychological theories on heat-aggression relationship have existed for decades and recent models suggest climate change will increase violence through varying pathways. Although observational studies have examined the impact of temperature on violent crime, the evidence for associations is primarily limited to coarse temporal resolution of weather and crime (e.g., yearly/monthly) and results from a few Western communities, warranting studies based on higher temporal resolution data of modern systemic crime statistics for various regions. This observational study examined short-term temperature impacts on violent crime using national crime data for the warm months (Jun.–Sep.) across South Korea (2016–2020). Distributed lag non-linear models assessed relative risks (RRs) of daily violent crime counts at the 70th, 90th, and 99th summer temperature percentiles compared to the reference temperature (10th percentile), with adjustments for long-term trends, seasonality, weather, and air pollution. Results indicate potentially non-linear relationships between daily summer temperature (lag0–lag10) and violent crime counts. Violent crimes consistently increased from the lowest temperature and showed the highest risk at the 70th temperature (~ 28.0 °C). The RR at the 70th and 90th percentiles of daily mean temperature (lag0–lag10), compared to the reference, was 1.11 (95% CI 1.09, 1.15) and 1.04 (95% CI 1.01, 1.07), indicating significant associations. Stratified analysis showed significant increases in assault and domestic violence for increases in temperature. The lagged effects, the influences of heat on subsequent crime incidence, did not persist 21 days after the exposure, possibly due to the displacement phenomenon. We found curvilinear exposure–response relationships, which provide empirical evidence to support the psychological theories for heat and violence. Lower public safety through increased violent crime may be an additional public health harm of climate change.

Abstract Successes in biocatalytic polyester recycling have raised the possibility of deconstructing alternative polymers enzymatically, with polyamide (PA) being a logical target due to the array of amide-cleaving enzymes present in nature. Here, we screen 40 potential natural and engineered nylon-hydrolyzing enzymes (nylonases), using mass spectrometry to quantify eight compounds resulting from enzymatic nylon-6 (PA6) hydrolysis. Comparative time-course reactions incubated at 40-70 °C showcase enzyme-dependent variations in product distributions and extent of PA6 film depolymerization, with significant nylon deconstruction activity appearing rare. The most active nylonase, a NylCK variant we rationally thermostabilized (an N-terminal nucleophile (Ntn) hydrolase, NylCK-TS, T m = 87.4 °C, 16.4 °C higher than the wild-type), hydrolyzes 0.67 wt% of a PA6 film. Reactions fail to restart after fresh enzyme addition, indicating that substrate-based limitations, such as restricted enzyme access to hydrolysable bonds, prohibit more extensive deconstruction. Overall, this study expands our understanding of nylonase activity distribution, indicates that Ntn hydrolases may have the greatest potential for further development, and identifies key targets for progressing PA6 enzymatic depolymerization, including improving enzyme activity, product selectivity, and enhancing polymer accessibility.

Abstract Background and aims Previously, we found that FK506 binding protein 51 (Fkbp51) knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism of Fkbp51 in liver injury. Methods Carbon tetrachloride (CCl4)-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury. Results Fkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers and lower serum liver enzyme levels. RNA-seq identified differentially expressed genes and involved pathways, such as fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin, pAKT, and ATP production. Conclusions Downregulation of FKBP51 represents a promising therapeutic target for liver disease treatment. Graphical Abstract

While we all have our own circumstances and experiences, being able to empathize is critical to recognizing injustice and considering the viewpoints of others in the community. In the human-centric field of biomedical engineering (BME), empathy is imperative to creating inclusive devices or equipment that are equally accessible to all who need them. To learn more about the importance of empathy in the discipline and the learning activities that can be used to promote it, we leveraged qualitative methods and interviewed six BME instructors and course coordinators. We applied Zaki's framework of empathy as the theoretical foundation for our investigation and analysis, which considers cognitive, emotional, and motivational factors. In this study, we sought to address: (1) The need of empathy for BME students; (2) The need of empathy for BME educators; and (3) How specific learning activities can be used to appreciate and imbue empathy. The analysis resulted in six themes, and the findings illustrated that empathy was considered important for students' personal and professional development. It can promote intercultural awareness, leadership, and may drive students to think and care about others and take action. Faculty perceived empathy as necessary for themselves as well and they described developing it over the course of their careers as they interacted with students and learned about the issues they faced. In turn, they mentioned how their own empathy served to strengthen their approach as educators, their interpersonal relationships, and their awareness of students in distress. We identified multiple learning activities which can foster empathy in students. Examples include writing personas to enhance perspective-taking or allowing students to share their own narrative to strengthen communication for the speaker and active listening and compassion from those hearing the stories. Requiring students to shadow physicians or conduct interviews with those that will use their products can serve to build compassion and help students to think about others. However, to impact values and mindsets such activities should not just be inserted at a single time point, but instead, should be considered throughout the BME curriculum. The findings from this work not only encourage professional development of BME students and their ability to solve problems addressing the needs of real people, but they also speak to the value of empathy for individual growth and considering diverse perspectives.

Soil associated with sea freight (shipping containers, flat racks and used machinery) arriving at New Zealand seaports was sampled for bacteria, fungi, nematodes, macro-invertebrates and plant seeds. Pseudomonads were selectively isolated, as several significant plant pathogens fall within this bacterial group. The mean and median sample weight collected from sea freight was found to be 417.3 and 152.7 g, respectively, with most recovered soil (73%) collected from the underside of shipping containers and flat rack containers. Likewise, for used machinery, most recovered soil (75%) was found under the machinery. Flat rack containers had significantly higher soil contamination compared to shipping containers and used machinery, but generally the counts and incidence of taxa were significantly lower compared to these other freight types. Viable bacteria, fungi, nematodes, seeds and arthropods were associated with the soil, with both counts g-1 and prevalence in samples varying with taxa, freight type, and location on the freight. Various regulated biosecurity organisms were recovered from the samples, including Aphelenchoides besseyi (rice white tip nematode), and seeds from genera such as Brachiaria, Cortaderia, Digitaria, Eragrostis and Sonchus. There were also live arthropod taxa that were not recorded as being present in New Zealand. No known plant pathogenic pseudomonads were identified through sequencing of the 16S ribosomal RNA gene. Shipping containers were found to be an important introduction pathway for exotic species, and therefore require careful monitoring and management. Comparisons of the incidence and mean number of organisms associated with soil on sea freight compared to a previous study with soil on footwear, generally showed that incidence and counts of many taxa were lower on sea freight, indicating that biosecurity risk can vary with pathway. However, prioritising one soil pathway over another according to the risks they present, and differentially allocating resources is problematic because the relative risk is dynamic, dictated by factors such as new pests or diseases entering the respective pathways.

Abstract Due to the lack of timely data on socioeconomic factors (SES), little research has evaluated if socially disadvantaged populations are disproportionately exposed to higher PM2.5 concentrations in India. We fill this gap by creating a rich dataset of SES parameters for 28,081 clusters (villages in rural India and census-blocks in urban India) from the National Family and Health Survey (NFHS-4) using a precision-weighted methodology that accounts for survey-design. We then evaluated associations between total, anthropogenic and source-specific PM2.5 exposures and SES variables using fully-adjusted multilevel models. We observed that SES factors such as caste, religion, poverty, education, and access to various household amenities are important risk factors for PM2.5 exposures. For example, we noted that a unit standard deviation increase in the cluster-prevalence of Scheduled Caste and Other Backward Class households was significantly associated with an increase in total-PM2.5 levels corresponding to 0.127 μg/m3 (95% CI 0.062 μg/m3, 0.192 μg/m3) and 0.199 μg/m3 (95% CI 0.116 μg/m3, 0.283 μg/m3, respectively. We noted substantial differences when evaluating such associations in urban/rural locations, and when considering source-specific PM2.5 exposures, pointing to the need for the conceptualization of a nuanced EJ framework for India that can account for these empirical differences. We also evaluated emerging axes of inequality in India, by reporting associations between recent changes in PM2.5 levels and different SES parameters.

Abstract Background There is now a relatively well-established evidence base suggesting that greener living environments and time spent in urban green and blue spaces (UGBS) can be beneficial for human health and wellbeing. However, benefits are not universal and there remain widespread social inequalities in access to such resources and experiences, particularly along axes of class, race, ethnicity, age and disability, and in relation to efforts to increase the availability and accessibility of such spaces. These injustices often relate to distributive, procedural and recognition-based processes. There is growing interest in how to ensure that efforts to increase access to or use of UGBS (whether through infrastructural or social programmes) result in equitable outcomes whilst minimising potential for exacerbating existing inequalities and injustices. Community engagement is considered an important step towards more inclusive UGBS decision-making, from planning and design to management and maintenance processes. It is thought to contribute to better and more widely trusted decisions, enhanced democracy, community satisfaction, civic interest and feelings of green space ownership, and greater longevity of UGBS projects. However, uneven representation and barriers to participation can create imbalances and undermine these benefits. Methods An iterative, multi-stage realist-inspired review will be conducted to ask what works, in what context and in what ways relating to the meaningful involvement of communities in UGBS decision-making, focusing on the skills, capacities and capabilities of different stakeholders and the role of contexts and processes. ‘Effectiveness’ (or what works) will be understood as a multifaceted outcome, encompassing both the processes and results of community engagement efforts. Following a scoping stage to identify initial programme theory, inclusion/exclusion criteria and derive search terms, relevant databases and grey literature will be searched to identify interdisciplinary literature in two phases. The first phase will be used to further develop programme theories, which will be articulated as ‘if then’ statements. The second phase searches will be used to identify sources to further explore and evidence the programme and formal theory. We will assess all includable evidence for conceptual richness, prioritising more conceptually rich sources if needed. Discussion The realist synthesis will explore the key context, mechanism and outcome configurations that appear to explain if and how different approaches to community-involved UGBS decision-making are or are not effective. We will consider factors such as different conceptualisations of community, and if and how they have been involved in UGBS decision-making; the types of tools and approaches used; and the socio-cultural and political or governance structures within which decision-making takes place.

Abstract Background Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated. Methods Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively. Results Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL. Conclusions Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.

ABSTRACTSurface waters are considered ecological habitats where Salmonella enterica can persist and disseminate to fresh produce production systems. This study aimed to explore the genomic profiles of S. enterica serotypes Typhimurium, Newport, and Infantis from surface waters in Chile, Mexico, and Brazil collected between 2019 and 2022. We analyzed the whole genomes of 106 S. Typhimurium, 161 S. Newport, and 113 S. Infantis isolates. Our phylogenetic analysis exhibited distinct groupings of isolates by their respective countries except for a notable case involving a Chilean S. Newport isolate closely related to two Mexican isolates, showing 4 and 13 single nucleotide polymorphisms of difference, respectively. The patterns of the most frequently detected antimicrobial resistance genes varied across countries and serotypes. A strong correlation existed between integron carriage and genotypic multidrug resistance (MDR) across serotypes in Chile and Mexico (R > 0.90, P < 0.01), while integron(s) were not detected in any of the Brazilian isolates. By contrast, we did not identify any strong correlation between plasmid carriage and genotypic MDR across diverse countries and serotypes.IMPORTANCEUnveiling the genomic landscape of S. enterica in Latin American surface waters is pivotal for ensuring public health. This investigation sheds light on the intricate genomic diversity of S. enterica in surface waters across Chile, Mexico, and Brazil. Our research also addresses critical knowledge gaps, pioneering a comprehensive understanding of surface waters as a reservoir for multidrug-resistant S. enterica. By integrating our understanding of integron carriage as biomarkers into broader MDR control strategies, we can also work toward targeted interventions that mitigate the emergence and dissemination of MDR in S. enterica in surface waters. Given its potential implications for food safety, this study emphasizes the critical need for informed policies and collaborative initiatives to address the risks associated with S. enterica in surface waters.

Background: Temperature variability (TV) is associated with increased mortality risk. However, it is still unknown whether intra-day or inter-day TV has different effects. Objectives: We aimed to assess the association of intra-day TV and inter-day TV with all-cause, cardiovascular, and respiratory mortality. Methods: We collected data on total, cardiovascular, and respiratory mortality and meteorology from 758 locations in 47 countries or regions from 1972 to 2020. We defined inter-day TV as the standard deviation (SD) of daily mean temperatures across the lag interval, and intra-day TV as the average SD of minimum and maximum temperatures on each day. In the first stage, inter-day and intra-day TVs were modelled simultaneously in the quasi-Poisson time-series model for each location. In the second stage, a multi-level analysis was used to pool the location-specific estimates. Results: Overall, the mortality risk due to each interquartile range [IQR] increase was higher for intra-day TV than for inter-day TV. The risk increased by 0.59% (95% confidence interval [CI]: 0.53, 0.65) for all-cause mortality, 0.64% (95% CI: 0.56, 0.73) for cardiovascular mortality, and 0.65% (95% CI: 0.49, 0.80) for respiratory mortality per IQR increase in intra-day TV0–7 (0.9 °C). An IQR increase in inter-day TV0–7 (1.6 °C) was associated with 0.22% (95% CI: 0.18, 0.26) increase in all-cause mortality, 0.44% (95% CI: 0.37, 0.50) increase in cardiovascular mortality, and 0.31% (95% CI: 0.21, 0.41) increase in respiratory mortality. The proportion of all-cause deaths attributable to intra-day TV0–7 and inter-day TV0–7 was 1.45% and 0.35%, respectively. The mortality risks varied by lag interval, climate area, season, and climate type. Conclusions: Our results indicated that intra-day TV may explain the main part of the mortality risk related to TV and suggested that comprehensive evaluations should be proposed in more countries to help protect human health.

Summary: Background: Multidrug-resistant (MDR) Salmonella Infantis has disseminated worldwide, mainly linked to the consumption of poultry products. Evidence shows dissemination of this pathogen in Chile; however, studies are primarily limited to phenotypic data or involve few isolates. As human cases of Salmonella Infantis infections have substantially increased in recent years, this study aimed to characterise the genomic epidemiology and antimicrobial-resistance profiles of isolates obtained from different sources, aiming to inform effective surveillance and control measures. Methods: We sequenced 396 Salmonella Infantis genomes and analysed them with all publicly available genomes of this pathogen from Chile (440 genomes in total), representing isolates from environmental, food, animal, and human sources obtained from 2009 to 2022. Based on bioinformatic and phenotypic methods, we assessed the population structure, dissemination among different niches, and antimicrobial resistance (AMR) profiles of Salmonella Infantis in the country. Findings: The genomic and phylogenetic analyses showed that Salmonella Infantis from Chile comprised several clusters of highly related isolates dominated by sequence type 32. The HC20_343 cluster grouped an important proportion of all isolates. This was the only cluster associated with pESI-like megaplasmids, and up to 12 acquired AMR genes/mutations predicted to result in an MDR phenotype. Accordingly, antimicrobial-susceptibility testing revealed a strong concordance between the AMR genetic determinants and their matching phenotypic expression, indicating that a significant proportion of HC20_343 isolates produce extended-spectrum β-lactamases and have intermediate fluoroquinolone resistance. HC20_343 Salmonella Infantis were spread among environmental, animal, food, and human niches, showing a close relationship between isolates from different years and sources, and a low intra-source genomic diversity. Interpretation: Our findings show a widespread dissemination of MDR Salmonella Infantis from the HC20_343 cluster in Chile. The high proportion of isolates with resistance to first-line antibiotics and the evidence of active transmission between the environment, animals, food, and humans highlight the urgency of improved surveillance and control measures in the country. As HC20_343 isolates predominate in the Americas, our results suggest a high prevalence of ESBL-producing Salmonella Infantis with intermediate fluoroquinolone resistance in the continent. Funding: Partially supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services as part of an award, FDU001818, with 30% percent funded by FDA/HHS; and by Agencia de Investigación y Desarrollo de Chile (ANID) through FONDECYT de Postdoctorado Folio 3230796 and Folio 3210317, FONDECYT Regular Folio 1231082, and ANID—Millennium Science Initiative Program—ICN2021_044.

Abstract Environmental DNA (eDNA) has been widely used for species surveillance. However, the lack of adequate quality control in many eDNA research projects and applications can lead to false‐negative results, greatly affecting biosecurity surveillance and conservation efforts. Exogenous DNA is routinely added to eDNA samples and used as a positive control, typically after DNA extraction. However, this type of positive control is only able to identify false negatives due to errors at the amplification stage. Therefore, errors in upstream processes, such as sample collection will not be identified by an exogenous control. We designed two independent sets of generic quality control qPCR assays (QCqPCR) targeting abundant endogenous DNA that is obtained during sample collection. Our QCqPCR assays target the chloroplast 16S and 23S ribosomal RNA sequences. In silico analyses indicated these regions were highly conserved among plants, algae and bacteria commonly found in freshwater, marine, or terrestrial environments. These QCqPCR assays were purposely mismatched against the human genome to avoid false positives resulting from human DNA contamination. Both assays remained highly efficient and sensitive under annealing temperatures between 58 and 62°C, allowing them to be multiplexed with most qPCR analyses. We validated our assays by multiplexing with a species‐specific Murray cod (Maccullochella peelii) assay on field‐collected environmental water samples. Potential false‐negative reactions can be identified by the failed or suppressed QCqPCR assay and the negative species‐specific assay. We recommend incorporating either one of the QCqPCR assays in qPCR‐based eDNA analysis to identify potential false negatives and improve the reliability of eDNA surveys.

Abstract Globally, the diversity of arthropods and the plants upon which they rely are under increasing pressure due to a combination of biotic and abiotic anthropogenic stressors. Unfortunately, conventional survey methods used to monitor ecosystems are often challenging to conduct on large scales. Pan traps are a commonly used pollinator survey method and environmental DNA (eDNA) metabarcoding of pan trap water may offer a high‐throughput alternative to aid in the detection of both arthropods and the plant resources they rely on. Here, we examined if eDNA metabarcoding can be used to identify arthropods and plant species from pan trap water, and investigated the effect of different DNA extraction methods. We then compared plant species identified by metabarcoding with observation‐based floral surveys and also assessed the contribution of airborne plant DNA (plant DNA not carried by arthropods) using marble traps to reduce putative false positives in the pan trap dataset. Arthropod eDNA was only detected in 17% of pan trap samples and there was minimal overlap between the eDNA results and morphological identifications. In contrast, for plants, we detected 64 taxa, of which 53 were unique to the eDNA dataset, and no differences were identified between the two extraction kits. We were able to significantly reduce the contribution of airborne plant DNA to the final dataset using marble traps. This study demonstrates that eDNA metabarcoding of pan trap water can detect plant resources used by arthropods and highlights the potential for eDNA metabarcoding to be applied to investigations of arthropod‐plant interactions.

Key Clinical Message Microscopic polyangiitis is a rare autoimmune vasculitis, that could present with renal‐pulmonary symptoms, posing diagnostic challenges in patients with preexisting kidney disease. Timely diagnosis is crucial to improve patient outcomes.

Abstract Background Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-β levels and EMT signaling. Given that many drugs targeting TGF-β have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-β/EMT axis. Results Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-β and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-β levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-β/SMAD2&3) and non-canonical (TGF-β/PI3K/AKT, TGF-β/RAS/RAF/MEK/ERK, and TGF-β/WNT/β-catenin) TGF-β signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, β-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. Conclusions Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-β and inhibiting EMT in a diverse range of cancers.

Background: Recent studies have reported that air pollution is related to kidney diseases. However, the global evidence on the risk of death from acute kidney injury (AKI) owing to air pollution is limited. Therefore, we investigated the association between short-term exposure to air pollution—particulate matter ≤ 2.5 μm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)—and AKI-related mortality using a multi-country dataset. Methods: This study included 41,379 AKI-related deaths in 136 locations in six countries during 1987–2018. A novel case time-series design was applied to each air pollutant during 0–28 lag days to estimate the association between air pollution and AKI-related deaths. Moreover, we calculated AKI deaths attributable to non-compliance with the World Health Organization (WHO) air quality guidelines. Results: The relative risks (95% confidence interval) of AKI-related deaths are 1.052 (1.003, 1.103), 1.022 (0.994, 1.050), and 1.022 (0.982, 1.063) for 5, 10, and 10 µg/m3 increase in lag 0–28 days of PM2.5, warm-season O3, and NO2, respectively. The lag-distributed association showed that the risk appeared immediately on the day of exposure to air pollution, gradually decreased, and then increased again reaching the peak approximately 20 days after exposure to PM2.5 and O3. We also found that 1.9%, 6.3%, and 5.2% of AKI deaths were attributed to PM2.5, warm-season O3, and NO2 concentrations above the WHO guidelines. Conclusions: This study provides evidence that public health policies to reduce air pollution may alleviate the burden of death from AKI and suggests the need to investigate the several pathways between air pollution and AKI death.

Background Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50–60%). Standard technique includes lying infants on their side and removing the stylet ‘late’, that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet ‘early’, that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives The aim of the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of ‘early’ rather than ‘late’ stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners’ seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators’ previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information. Plain language summary Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50–60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the ‘stylet’, which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. ‘early stylet removal’) or once the tip is thought to have reached the spinal fluid (i.e. ‘late stylet removal’). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and ‘early’ with ‘late’ stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide. Scientific summary Background The neonatal period carries the highest risk of bacterial meningitis (≈ 1 per 4000–5000 births), which is associated with significant mortality (≈ 10%) and morbidity (20–50%). Meningitis is diagnosed by analysis of cerebrospinal fluid (CSF), obtained via lumbar puncture (LP). LPs are frequently performed in newborns because of the non-specific clinical features of neonatal meningitis. However, LP success rates in newborns are much lower (50–60%) than in older children (78–87%). Unsuccessful LPs include those with heavily blood-stained CSF or LPs that fail to obtain CSF at all. Treatment for suspected or confirmed neonatal meningitis involves intravenous antibiotics, typically for 14–21 days. Unsuccessful LPs lead to repeated attempts, whereas LPs with equivocal or uninterpretable CSF results often prompt cautious treatment with extended courses of antibiotics. Prolonged antibiotic use is associated with a range of complications, including induced antimicrobial resistance. Consequently, interventions to improve neonatal LP success rates should allow more accurate diagnosis of meningitis, which will help reduce unnecessary courses of antibiotic therapy and extended hospitalisation, and will save healthcare resources. There have been few modifications to the original LP technique. Thus far, the sitting position, as employed for older patients, and ‘early stylet removal’ (ESR) have been suggested. ESR promises advantages because, in neonates, a ‘loss of resistance’ on entering the CSF is often indistinguishable and a needle advanced too far can cause venous puncture and a blood-stained tap, impairing CSF interpretation. We conducted the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial to determine the optimal LP technique in neonates in terms of the effect of infant position (sitting vs. lying) and timing of stylet removal [ESR vs. late stylet removal (LSR)] on success [i.e. a CSF red blood cell (RBC) count of < 10,000/mm3] of first LP. Methods Trial design and oversight The NeoCLEAR trial was a 2 × 2 factorial open-label multicentre randomised controlled trial (RCT), with an internal pilot. The study protocol was published previously. The NeoCLEAR trial was co-ordinated by the National Perinatal Epidemiology Unit – Clinical Trials Unit. The University of Oxford (Oxford, UK) sponsored the trial. Trial oversight was conducted by the Trial Steering Committee and an independent Data Monitoring Committee. The funder [i.e. the National Institute for Health and Care Research (NIHR)] did not have a role in study design, conduct, data collection, analysis or interpretation. Ethics approval was obtained. Trial population Eligible infants were inpatients in UK neonatal units and maternity wards who required a LP at a corrected gestational age (CGA) of 27+0 to 44+0 weeks and with a working weight of ≥ 1000 g. Infants were excluded if they had already had a LP for the same indication, if they were unable to be held in sitting position or if sitting was deemed unsafe. Trial procedures Infants whose parents had provided consent were randomised 1 : 1 : 1 : 1 by a one-based system to the following four groups: (1) lying position and LSR, (2) lying position and ESR, (3) sitting position and LSR or (4) sitting position and ESR. Block randomisation was stratified according to site and CGA (four categories: 27+0 to 31+6 weeks, 32+0 to 36+6 weeks, 37+0 to 40+6 weeks and ≥ 41 weeks). Staff were trained in all four techniques. Any second LP required followed the same allocated technique. The need for any further LPs and the techniques used were determined by the clinical team. Blinding of practitioners was impossible, but the primary outcome was based on laboratory tests performed blinded to allocation. Outcomes Participants were followed up until discharge. The primary outcome was the proportion of infants with a successful first LP, defined as a CSF RBC count of < 10,000/mm3. Secondary outcomes included short-term clinical measures (e.g. number of procedures/attempts per infant, proportions with different CSF-based diagnoses, time taken per procedure, infant movement), resources (e.g. duration of antibiotics, length of stay) and safety (e.g. complications, adverse event reporting). Statistics and analysis The NeoCLEAR trial was designed with 90% power to detect a 10% absolute difference in the primary outcome (estimated comparator group event rate 59%), with a 5% two-sided significance level. Four hundred and eighty-three infants were required for each arm of each comparison (i.e. sitting vs. lying position and ESR vs. LSR). Allowing for 5% attrition, the recruitment target was 1020 infants. Outcomes were analysed by modified intention to treat (excluding participants who were withdrawn before collection of trial data or who did not undergo LP). For infant positioning, we compared groups (1) lying/LSR plus (2) lying/ESR with groups (3) sitting/LSR plus, (4) sitting/ESR. To assess the timing of stylet removal, we compared groups (1) plus (3) with groups (2) plus (4). We estimated risk ratios (RRs) for the primary outcome and all other dichotomous outcomes, the mean difference for normally distributed continuous outcomes and the median difference (Med D) for skewed continuous variables. The 95% confidence intervals (CIs) were calculated for all effect estimates. Groups were compared using regression analysis, adjusting for the stratification factors used at randomisation (i.e. centre and CGA) and allocation to the other intervention. The latter adjustment was advised after the final statistical analysis plan was signed off and is a noted deviation. Adjusted risk ratios (aRRs) were estimated using log-binomial regression, or using a Poisson regression model with a robust variance estimator in the event of non-convergence. Linear regression was used for normally distributed outcomes and quantile regression for skewed continuous outcomes. To mitigate multiple testing, inference was restricted to prespecified tested outcomes. A descriptive multiarm analysis was also performed for the primary outcome, other tested outcomes and baseline characteristics (i.e. for each of the four randomised groups). Effect modification between position (i.e. sitting/lying) and the timing of stylet removal (i.e. ESR/LSR) was investigated for the primary outcome using the statistical test for interaction. Prespecified subgroup analyses were conducted for working weight, day of life and CGA at trial entry. Two-sided p-values of ≤ 0.05 were considered to indicate statistical significance. Results From August 2018 to August 2020, 1082 participants from 21 centres in the UK were randomised in a 2 × 2 factorial design, resulting in two principal comparisons: (1) sitting position (n = 546) compared with lying position (n = 536) and (2) ESR (n = 549) compared with LSR (n = 533). A total of 1079 infants had a ‘first’ LP, and 166 (15.4%) infants had a second LP (each of these LP ‘procedures’ involved one or more ‘attempts’). Nine infants were withdrawn during the trial, but in the case of only one of these participants was consent withdrawn before data collection for the primary outcome. Three infants did not receive a LP, and in the case of a further two infants the consent form was missing. Overall, six infants were excluded, leaving 1076 infants for the final (modified intention-to-treat) analysis: (1) sitting position (n = 543) compared with lying position (n = 533) and (2) ESR (n = 545) compared with LSR (n = 531). All infants were followed up until discharge. Baseline characteristics were similar for the two groups in both comparisons, as recorded at trial entry and at time of first LP. The majority of infants were born at term, were < 3 days old and were not receiving respiratory support. Raised C-reactive protein was the most common indication for LP. First comparison: sitting position compared with lying position The primary outcome – a successful first LP – was achieved in 346 of 543 (63.7%) infants in the sitting arm and 307 of 533 (57.6%) infants in the lying arm [aRR 1.10 (95% CI 1.01 to 1.21); p = 0.03; adjusted absolute risk difference 6.1% (95% CI 0.7% to 11.4%), adjusted number needed to treat (NNT) 16 (95% CI 9 to 134)]. Infants allocated to the sitting position were less likely than infants allocated to the lying position to exhibit moderate or severe struggling at the time of needle insertion [169/541 (31.2%) vs. 202/527 (38.4%), aRR 0.82 (95% CI 0.71 to 0.94); p = 0.006]. Other secondary outcomes did not reach statistical significance, but predominantly favoured the sitting position. Based on microscopy of CSF extracted from the first and second LPs (and any culture/polymerase chain reaction results), infants who were sitting were more likely to be ‘negative’ for meningitis than infants who were lying [396/537 (73.7%) vs. 359/521 (68.9%)], and a result of ‘uninterpretable CSF’ (i.e. no sample obtained or CSF not possible to analyse, usually due to a heavily blood contaminated or clotted sample) was more likely to be recorded for infants who were lying than for infants who were sitting [139/521 (26.7%) vs. 114/537 (21.2%)]. Median duration of antibiotic treatment and length of stay were not significantly different in the sitting and lying arms {median 5 [interquartile range (IQR) 4–6] days in each arm, for both duration of antibiotic treatment and length of stay}. Four (0.3%) of 1241 first or second LPs, 1 in ESR and 1 in LSR arms, respectively, were abandoned because of cardiovascular deterioration. Lowest oxygen saturation (SpO2) during the first LP averaged 93% (IQR 89–96%) in the sitting arm and 90% (IQR 85–94%) in the lying arm (adjusted Med D 3.0%, 95% CI 2.1% to 3.9%; p < 0.001). Three of 1075 (0.3%) infants required increased respiratory support within 1 hour of their first LP (sitting arm, n = 1; lying arm, n = 2; not significantly different). The proportion of infants whose lowest SpO2 fell below 80% during the first LP (analysed post hoc) was 6.6% (35 of 532) in the sitting arm and 14.2% (72 of 508) in the lying LP arm, and this pattern was consistent in preterm and term-born babies. In 47 of 543 (8.7%) first LPs in infants allocated to the sitting position, at least one attempt involved switching to the lying position [compared with 4/533 (0.8%) infants allocated to the lying allocation, who were switched to sitting]. Of the 47 LPs where there was at least one attempt in which the allocated technique was not adhered to, the decision to change position was mostly made on the second (22/247) or third (24/257) attempt. The decision to change position was usually made by a clinical (45/47). Similarly, for the second LP, the sitting allocation was less often followed [for at least one attempt in 16/76 (22.5%) of infants allocated to sitting vs. 6/90 (7.0%) of infants allocated to lying]. There were no obvious differences in baseline infant characteristics between LPs that were carried out in the allocated position and those that were not. In prespecified subgroup analyses, the effect of position on the proportion of infants with a successful first LP was consistent across working weight and CGA at trial entry, but a difference in effect was observed between infants enrolled within 3 days of life (n = 836, RR 1.14, 95% CI 1.04 to 1.25) and those enrolled after 3 days (n = 140, RR 0.9, 95% CI 0.78 to 1.05; p = 0.001). Second comparison: early stylet removal compared with late stylet removal The primary outcome was achieved in 338 of 545 (62.0%) infants following ESR and in 315 of 531 (59.3%) infants following LSR. There was no significant difference between the groups (aRR 1.04, 95% CI 0.94 to 1.15; p = 0.45). There were also no obvious differences between the groups in any of the secondary outcomes. Either the first or the second LP (4/1242, 0.3%) was abandoned in four infants receiving LP (two in each arm) because of cardiovascular deterioration. Three of 1076 (0.3%) infants required increased respiratory support within 1 hour of their first LP (ESR, n =1; LSR, n =2; not significantly different). There were no differences in lowest SpO2, lowest heart rate (HR) or highest HR between the two arms. The allocated technique was not adhered to in 35 of 1076 (3.3%) first LPs, with similar numbers in each arm (untested outcome). In 13 of 78 infants allocated to ESR, the second LP involved at least one attempt without ESR, compared with 6 of 79 allocated to LSR; however, denominators were small and this was an untested outcome. The effect of timing of stylet removal on the proportion of infants with successful first LP was consistent across working weight at trial entry, CGA at randomisation and day of life at trial entry. Multiarm analysis: comparing four randomised groups (sitting plus early stylet removal, sitting plus late stylet removal, lying plus early stylet removal and lying plus late stylet removal) No significant interaction between infant position and timing of stylet removal was detected (p = 0.14). Multiarm baseline characteristics and analyses did not reveal any new obvious differences (only those previously described for the sitting position compared with the lying position; see First comparison: sitting position compared with lying position). Serious adverse events Four serious adverse events (SAEs) were reported during the trial. Three SAEs were deemed unrelated to LP. One infant, from the sitting/LSR group, developed a scrotal haematoma 2 days after LP. The infant did not undergo further investigations to identify a cause for this, and so a relationship with the LP could not be ruled out. Therefore, this event was deemed ‘possibly related’. Discussion The NeoCLEAR trial is, to the best of our knowledge, the first adequately powered RCT examining different LP techniques in newborns. The sitting position was superior to the lying position for achieving a successful first LP, with a NNT of 16. Sitting LP was also better tolerated in terms of infant struggling, SpO2 and HR. Timing of stylet removal did not influence LP success. Our results might be explained by the anatomical advantages of sitting position described in neonates: (1) the intervertebral spaces widen when the infants lean forward to adopt a (natural) kyphotic position; (2) the CSF passively sinks to the lowest point of the spinal canal and close to the entry site of the needle; and (3) this position is more comfortable for the baby, as evidenced by the reduced struggling we observed. At the time of the study, the only other paediatric RCT of sitting compared with lying position, by Hanson et al., involved 168 infants who were < 90 days of age in a paediatric emergency room setting.32 In that trial, the success rate did not differ significantly between groups (lateral group 63/82, 77%; sitting group, 61/85, 72%; difference 5.1%, 95% CI −8.2% to 18.3%). The suggestion that higher LP success rates could be achieved with ESR was based on reports of increased success rates with non-styletted needles. However, non-styletted needles are associated with iatrogenic intraspinal epidermoid tumour formation and, therefore, the technique of ESR was introduced. Subsequent observational studies suggested that ESR was associated with increased success rates in infants. At the time of the study, to the best of our knowledge, the NeoCLEAR trial is the first RCT to have investigated ESR and has demonstrated no significant benefit in it for neonatal LP. Therefore, we cannot advise for or against early or late stylet removal in neonates. Our safety analysis showed greater physiological stability for sitting LP, in keeping with previous observations. Other secondary outcomes lacked statistical significance, including resource outcomes. The NeoCLEAR trial has several strengths. To the best of our knowledge, it is the largest RCT, to date, investigating modifications to traditional LP technique, and the only such RCT in newborns. We chose to investigate modifications that came at no additional cost and were easily learned. The results are clear-cut, showing a significantly higher success rate for LPs with more interpretable CSF results when infants were held in a sitting position. Limitations include the fact that many practitioners were unfamiliar with sitting LP before the NeoCLEAR training sessions, and this may have led to more practitioners switching from the allocated sitting position to the lying position following an initially unsuccessful attempt. It could be speculated that success rates would have been even higher if there had been more experience of sitting position LP among practitioners, and if fewer practitioners had switched position. We did not investigate LPs carried out in infants with a CGA of under 27 weeks or over 44 weeks. Furthermore, most infants were born at or near term and had working weights above 2.5 kg and, therefore, we cannot extrapolate our results to infants born extremely pre or post term or to those of significantly different working weights. In addition, in the subgroup analyses of gestational ages, although the inconsistent effect of sitting position may well be a chance finding and/or due to confounders, the NeoCLEAR trial was underpowered to detect a significant difference for those beyond day 3 of life. In conclusion, the NeoCLEAR trial demonstrates that sitting position is superior to lying position for neonatal LP success rates (NNT 16), with no significant benefit for ESR. Adopting the sitting position is cost neutral, safe, well tolerated, and easy to learn. The results would be applicable in similar settings worldwide and should promote the sitting technique becoming the standard for neonatal lumbar puncture. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

Abstract Background Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, including IGF2BP1, and MYCN amplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment. Methods Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogene IGF2BP1 and its cross-talk with MYCN were characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models. Results We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho-adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1-driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficial in vitro and, for BTYNB, also. Conclusion We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feedforward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.

Abstract Tropical cyclones (TCs) pose a significant threat to human health, and research is needed to identify high-risk subpopulations. We investigated whether hospitalization risks from TCs in Florida (FL), United States, varied across individuals and communities. We modeled the associations between all storms in FL from 1999 to 2016 and over 3.5 million Medicare hospitalizations for respiratory (RD) and cardiovascular disease (CVD). We estimated the relative risk (RR), comparing hospitalizations during TC-periods (2 days before to 7 days after) to matched non-TC-periods. We then separately modeled the associations in relation to individual and community characteristics. TCs were associated with elevated risk of RD hospitalizations (RR: 4.37, 95% CI: 3.08, 6.19), but not CVD (RR: 1.04, 95% CI: 0.87, 1.24). There was limited evidence of modification by individual characteristics (age, sex, or Medicaid eligibility); however, risks were elevated in communities with higher poverty or lower homeownership (for CVD hospitalizations) and in denser or more urban communities (for RD hospitalizations). More research is needed to understand the potential mechanisms and causal pathways that might account for the observed differences in the association between tropical cyclones and hospitalizations across communities.

Unseen Agony In the shadow of blue lights, a cry goes unheard, A heart beats wild, but words are blurred. The weight of stigma, the shroud of fear, A call [...]

Abstract Background Undernutrition is a global public health crisis, causing nearly half of deaths for children under age 5 years. Little is known regarding the impact of air pollution in-utero and early childhood on health outcomes related to undernutrition. The aim of our study is to evaluate the association of prenatal and early-life exposure to PM2.5 and child malnutrition as captured by the height-for-age z-score (HAZ), and stunting in 32 countries in Africa. We also evaluated critical windows of susceptibility during pregnancy to each environmental risk. Methods We linked nationally representative anthropometric data from 58 Demographic and Health Surveys (DHS) (n = 264,207 children

Abstract While studies suggested adverse impacts of COVID-19 on scientific outputs and work routines for scientists, more evidence is required to understand detailed obstacles challenging scientists’ work and productivity during the pandemic, including how different people are affected (e.g., by gender). This online survey-based thematic analysis investigated how the pandemic affected scientists’ perception of scientific and academic productivity in the science, technology, engineering, and mathematics (STEM) and medicine fields. The analysis examined if inequitable changes in duties and responsibilities for caregiving for children, family, and/or households exist between scientists who are mothers compared to scientists who are fathers or non-parents. The survey collected data from 2548 survey responses in six languages across 132 countries. Results indicate that many scientists suffered from delays and restrictions on research activities and administrations due to the lockdown of institutions, as well as increased workloads from adapting to online teaching environment. Caregiving responsibility for children and family increased, which compromised time for academic efforts, especially due to the temporary shutdown of social supports. Higher percentages of female parent participants than male parent participants expressed such increased burdens indicating unequal divisions of caregiving between women and men. A range of physical and mental health issues was identified mainly due to overworking and isolation. Despite numerous obstacles, some participants reported advantages during the pandemic including the efficiency of online teaching, increased funding for COVID-related research, application of alternative research methodologies, and fluidity of the workday from not commuting. Findings imply the need for rapid institutional support to aid various academic activities and diminish gender inequity in career development among academicians, highlighting how crisis can exacerbate existing inequalities.