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BACKGROUND: Respiratory distress syndrome is a leading cause of neonatal intensive care unit admissions for late preterm (34–36 weeks gestational age) and term infants (37–41 weeks). The risk for respiratory morbidity appears to increase after an elective caesarean delivery and might be reduced after antenatal corticosteroids. However, before considering antenatal corticosteroids for women at high risk of preterm birth after 34 weeks, the incidence of respiratory distress syndrome and the effect of delivery mode on this incidence requires further evaluation. Therefore, this study aimed to investigate the relationship between respiratory distress syndrome incidence and delivery mode in late preterm and term infants. METHODS: In this retrospective cohort study, the clinical databases of the University Hospitals of Zurich and Basel were queried regarding all live births between 34 + 0 and 41 + 6 weeks. Neonatal intensive care unit admissions due to respiratory distress syndrome were determined and analysed in regard to the following delivery modes: spontaneous vaginal, operative vaginal, elective caesarean, secondary caesarean and emergency caesarean. RESULTS: After excluding malformations (n = 889) and incomplete or inconclusive data (n = 383), 37,110 infants out of 38,382 were evaluated. Of these, 5.34% (n = 1980) were admitted to a neonatal intensive care unit for respiratory distress syndrome. Regardless of gestational age, respiratory distress syndrome in infants after spontaneous vaginal delivery was 2.92%; for operative vaginal delivery, it was 4.02%; after elective caesarean delivery it was 8.98%; following secondary caesarean delivery, it was 8.45%, and after an emergency caesarean it was 13.3%. The risk of respiratory distress syndrome was higher after an elective caesarean compared to spontaneous vaginal delivery, with an odds ratio (OR), adjusted for gestational age, of 2.31 (95% CI 1.49–3.56) at 34 weeks, OR 5.61 (95% CI 3.39–9.3) at 35 weeks, OR 1.5 (95% CI 0.95–2.38) at 36 weeks, OR 3.28 (95% CI 1.95–5.54) at 37 weeks and OR 2.51 (95% CI 1.65–3.81) at 38 weeks. At 39 weeks, there was no significant difference between the risk of respiratory distress syndrome after an elective caesarean vs. spontaneous vaginal delivery. Over the study period, gestational age at elective caesarean delivery remained stable at 39.3 ± 1.65 weeks. CONCLUSION: The incidence of respiratory distress syndrome following an elective caesarean is up to threefold higher in infants born with less than 39 weeks gestational age compared to those born by spontaneous vaginal delivery. Therefore — and whenever possible — an elective caesarean delivery should be planned after 38 completed weeks to minimise the risk of respiratory morbidity in neonates.

Abstract Identification of taxonomically cryptic species is essential for the effective conservation of biodiversity. Freshwater‐limited organisms tend to be genetically isolated by drainage boundaries, and thus may be expected to show substantial cryptic phylogenetic and taxonomic diversity. By comparison, populations of diadromous taxa, that migrate between freshwater and marine environments, are expected to show less genetic differentiation. Here we test for cryptic diversity in Australasian populations (both diadromous and non‐diadromous) of two widespread Southern Hemisphere fish species, Galaxias brevipinnis and Galaxias maculatus. Both mtDNA and nuclear markers reveal putative cryptic species within these taxa. The substantial diversity detected within G. brevipinnis may be explained by its strong climbing ability which allows it to form isolated inland populations. In island populations, G. brevipinnis similarly show deeper genetic divergence than those of G. maculatus, which may be explained by the greater abundance of G. maculatus larvae in the sea allowing more ongoing dispersal. Our study highlights that even widespread, ‘high‐dispersal’ species can harbour substantial cryptic diversity and therefore warrant increased taxonomic and conservation attention.

Abstract Two literatures argue that time alone is harmful (i.e., isolation) and valuable (i.e., positive solitude). We explored whether people benefit from a balance between their daily solitude and social time, such that having ‘right’ quantities of both maximizes well-being. Participants (n = 178) completed a 21-day diary study, which quantified solitude time in hours through reconstructing daily events. This procedure minimized retrospective bias and tested natural variations across time. There was no evidence for a one-size-fits-all ‘optimal balance’ between solitude and social time. Linear effects suggested that people were lonelier and less satisfied on days in which they spent more hours in solitude. These detrimental relations were nullified or reduced when daily solitude was autonomous (choiceful) and did not accumulate across days; those who were generally alone more were not, on the whole, lonelier. On days in which people spent more time alone they felt less stress and greater autonomy satisfaction (volitional, authentic, and free from pressure). These benefits were cumulative; those who spent more time alone across the span of the study were less stressed and more autonomy satisfied overall. Solitude time risks lowering well-being on some metrics but may hold key advantages to other aspects of well-being. Protocol registration The stage 1 protocol for this Registered Report was accepted in principle on June 1, 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.17605/OSF.IO/5KXQ3 .

Abstract Despite belonging to the most abundant and widespread genus of freshwater fishes in the region, the carp gudgeons of eastern Australia (genus Hypseleotris) have proved taxonomically and ecologically problematic to science since the 19th century. Several molecular studies and a recent taxonomic revision have now shed light on the complex biology and evolutionary history that underlies this group. These studies have demonstrated that carp gudgeons include a sexual/unisexual complex (five sexual species plus an assortment of hemiclonal lineages), many members of which also co‐occur with an independent sexual relative, the western carp gudgeon (H. klunzingeri). Here, we fill yet another knowledge gap for this important group by presenting a detailed molecular phylogeographic assessment of the western carp gudgeon across its entire and extensive geographic range. We use a suite of nuclear genetic markers (SNPs and allozymes) plus a matrilineal genealogy (cytb) to demonstrate that H. klunzingeri s.l. also displays considerable taxonomic and phylogeographic complexity. All molecular datasets concur in recognizing the presence of multiple candidate species, two instances of historic between‐species admixture, and the existence of a natural hybrid zone between two of the three candidate species found in the Murray–Darling Basin. We also discuss the major phylogeographic patterns evident within each taxon. Together, these analyses provide a robust molecular, taxonomic, and distributional framework to underpin future morphological and ecological investigations on this prominent member of regional freshwater ecosystems in eastern Australia.

Abstract The term, "aerosol-generating procedures” (AGPs), was proposed during the prior SARS-CoV-1 epidemic in order to maximise healthcare worker and patient protection. The concept of AGPs has since expanded to include routine therapeutic processes such as various modes of oxygen delivery and non-invasive ventilation modalities. Evidence gained during the SARS-CoV-2 pandemic has brought into question the concept of AGPs with regard to intubation, airway management, non-invasive ventilation and high flow nasal oxygen delivery. Although encounters where these procedures occur may still be associated with increased risk of infectious transmission, this is a function of the clinical context and not because the procedure itself is aerosol-generating.

A complex interplay of genetic and environmental risk factors influence global brain structural alterations associated with brain health and disease. Epigenome-wide association studies (EWAS) of global brain imaging phenotypes have the potential to reveal the mechanisms of brain health and disease and can lead to better predictive analytics through the development of risk scores. We perform an EWAS of global brain volumes in Generation Scotland using peripherally measured whole blood DNA methylation (DNAm) from two assessments, (i) at baseline recruitment, ~6 years prior to MRI assessment (N = 672) and (ii) concurrent with MRI assessment (N=565). Four CpGs at baseline were associated with global cerebral white matter, total grey matter, and whole-brain volume (Bonferroni p≤7.41×10−8, βrange = −1.46x10−6 to 9.59 × 10−7). These CpGs were annotated to genes implicated in brain-related traits, including psychiatric disorders, development, and ageing. We did not find significant associations in the meta-analysis of the EWAS of the two sets concurrent with imaging at the corrected level. These findings reveal global brain structural changes associated with DNAm measured ~6 years previously, indicating a potential role of early DNAm modifications in brain structure. Although concurrent DNAm was not associated with global brain structure, the nominally significant findings identified here present a rationale for future investigation of associations between DNA methylation and structural brain phenotypes in larger population-based samples.

Abstract Background Carp gudgeons (genus Hypseleotris) are a prominent part of the Australian freshwater fish fauna, with species distributed around the western, northern, and eastern reaches of the continent. We infer a calibrated phylogeny of the genus based on nuclear ultraconserved element (UCE) sequences and using Bayesian estimation of divergence times, and use this phylogeny to investigate geographic patterns of diversification with GeoSSE. The southeastern species have hybridized to form hemiclonal lineages, and we also resolve relationships of hemiclones and compare their phylogenetic placement in the UCE phylogeny with a hypothesis based on complete mitochondrial genomes. We then use phased SNPs extracted from the UCE sequences for population structure analysis among the southeastern species and hemiclones. Results Hypseleotris cyprinoides, a widespread euryhaline species known from throughout the Indo-Pacific, is resolved outside the remainder of the species. Two Australian radiations comprise the bulk of Hypseleotris, one primarily in the northwestern coastal rivers and a second inhabiting the southeastern region including the Murray–Darling, Bulloo-Bancannia and Lake Eyre basins, plus coastal rivers east of the Great Dividing Range. Our phylogenetic results reveal cytonuclear discordance between the UCE and mitochondrial hypotheses, place hemiclone hybrids among their parental taxa, and indicate that the genus Kimberleyeleotris is nested within the northwestern Hypseleotris radiation along with three undescribed species. We infer a crown age for Hypseleotris of 17.3 Ma, date the radiation of Australian species at roughly 10.1 Ma, and recover the crown ages of the northwestern (excluding H. compressa) and southeastern radiations at 5.9 and 7.2 Ma, respectively. Range-dependent diversification analyses using GeoSSE indicate that speciation and extinction rates have been steady between the northwestern and southeastern Australian radiations and between smaller radiations of species in the Kimberley region and the Arnhem Plateau. Analysis of phased SNPs confirms inheritance patterns and reveals high levels of heterozygosity among the hemiclones. Conclusions The northwestern species have restricted ranges and likely speciated in allopatry, while the southeastern species are known from much larger areas, consistent with peripatric speciation or allopatric speciation followed by secondary contact. Species in the northwestern Kimberley region differ in shape from those in the southeast, with the Kimberley species notably more elongate and slender than the stocky southeastern species, likely due to the different topographies and flow regimes of the rivers they inhabit.

Abstract Background In our earlier study on the functional limits of the aneurysmal aortic root we determined the pig root is susceptible to failure at high aortic pressures levels. We established a pig rupture model using cardiopulmonary bypass to determine the most susceptible region of the aortic root under the highest pressures achievable using continuous flow, and what changes occur in these regions on a macroscopic and histological level. This information may help guide clinical management of aortic root and ascending aorta pathology. Methods Five pigs underwent 4D flow MRI imaging pre surgery to determine vasopressor induced wall sheer stress and flow parameters. All pigs were then placed on cardiopulmonary bypass (CPB) via median sternotomy, and maximal aortic root and ascending aorta flows were initiated until rupture or failure, to determine the most susceptible region of the aorta. The heart was explanted and analysed histologically to determine if histological changes mirror the macroscopic observations. Results The magnetic resonance imaging (MRI) aortic flow and wall sheer stress (WSS) increased significantly in all regions of the aorta, and the median maximal pressures obtained during cardiopulmonary bypass was 497 mmHg and median maximal flows was 3.96 L/m. The area of failure in all experiments was the non-coronary cusp of the aortic valve. Collagen and elastin composition (%) was greatest in the proximal regions of the aorta. Collagen I and III showed greatest content in the inner aortic root and ascending aorta regions. Conclusions This unique porcine model shows that the aortic root is most susceptible to failure at high continuous aortic pressures, supported histologically by different changes in collagen content and subtypes in the aortic root. With further analysis, this information could guide management of the aortic root in disease.

INTRODUCTION: Congenital heart disease (CHD) is the most frequent birth defect. As survival has significantly improved, attention has turned to neurodevelopmental outcomes of children undergoing heart surgery in early infancy. Since multiple risk factors contribute to neurodevelopmental alterations, a nationwide registry collecting data on medical characteristics, interventions, clinical course and neurodevelopment until school-age is needed to improve the quality of management, identify risk- and protective factors affecting neurodevelopment, and facilitate multicentre trials. METHODS AND ANALYSIS: The Swiss Outcome Registry for CHIldren with severe congenital heart Disease (ORCHID) is a nationwide, prospective, population-based patient registry developed (1) to collect baseline characteristics and clinical data of CHD patients operated with bypass-surgery or hybrid procedures in the first 6 weeks of life in Switzerland, (2) to monitor long-term neurodevelopment, and (3) to relate clinical characteristics and neurodevelopment to identify risk and protective factors in these children. This registry started data collection relating to pregnancy, birth, preoperative course, catheter-based and surgical treatment, postoperative course and reinterventions in 2019. The primary outcome includes standardised neurodevelopmental assessments at 9 to 12 months, 18 to 24 months and 5.5 to 6 years. We expect to include 80 to 100 children per year. Correlation and regression analyses will be used to investigate risk- and protective factors influencing neurodevelopment. ETHICS AND DISSEMINATION OF RESULTS: Swiss ORCHID received support by the Accentus Charitable Foundation, the Anna Mueller Grocholoski Stiftung, the Swiss Society of Paediatric Cardiology, the Verein Kinderherzforschung, and the Corelina – Stiftung für das Kinderherz, and was approved by the cantonal ethics committees. Findings will be presented at national and international scientific meetings, and published in peer-reviewed journals. Results will also be shared with patient organizations, primary health care providers, and public health stakeholders to ensure a widespread dissemination of the results.

Objectives Advancements in mental health research depend upon continuing development of the data landscape, including the creation of population cohorts that combine different types of data from a variety of sources. The present project aimed to produce a new, multi-faceted mental health e-cohort to benefit further research. Approach Taking advantage of a standing research resource – the SHARE Scotland research register (N ~ 285,000) – we administered an online survey of mental health, treatment use and wellbeing. Over 10,000 individuals (Mean age = 57.16 years; 63% female) took part in the survey; all participants consented to secure linkage of their routinely-collected health records with questionnaire data and over 90% also consented to the research use of genetic data gained from diverted blood samples. We linked questionnaire responses with routinely-collected health data and genetic data within a Trusted Research Environment to create a large cohort enhanced for mental health research. Results In this presentation we describe the cohort, summarise responses to the mental health questionnaire and give some example research uses of the linked data. Focussing on depression, we contrast the prevalence of self-reported diagnoses of depression (27% of the sample) with diagnostic codes from routinely-collected hospital admission and national prescribing data and examine predictors of each. Conclusions Combining mental health questionnaire data, longitudinal health records, and genetic data creates new opportunities for mental health research and allows researchers to compare the utility of each data source. By making this new e-cohort available to other researchers we hope to drive advancements in mental health research.

Abstract Defective DNA repair is being demonstrated to be a useful target in cancer treatment. Currently, defective repair is identified by specific gene mutations, however defective repair is a common feature of cancers without these mutations. DNA damage triggers cell cycle checkpoints that are responsible for co-ordinating cell cycle arrest and DNA repair. Defects in checkpoint signalling components such as ataxia telangiectasia mutated (ATM) occur in a low proportion of cancers and are responsible for reduced DNA repair and increased genomic instability. Here we have investigated the AURKA-PLK1 cell cycle checkpoint recovery pathway that is responsible for exit from the G2 phase cell cycle checkpoint arrest. We demonstrate that dysregulation of PP6 and AURKA maintained elevated PLK1 activation to promote premature exit from only ATM, and not ATR-dependent checkpoint arrest. Surprisingly, depletion of the B55α subunit of PP2A that negatively regulates PLK1 was capable of overcoming ATM and ATR checkpoint arrests. Dysregulation of the checkpoint recovery pathway reduced S/G2 phase DNA repair efficiency and increased genomic instability. We found a strong correlation between dysregulation of the PP6-AURKA-PLK1-B55α checkpoint recovery pathway with signatures of defective homologous recombination and increased chromosomal instability in several cancer types. This work has identified an unrealised source of G2 phase DNA repair defects and chromosomal instability that are likely to be sensitive to treatments targeting defective repair.

AIMS OF THE STUDY: To assess whether the COVID-19 pandemic caused by SARS-CoV-2 had an impact on incidence, treatment or major adverse short-term outcome of preterm-born infants in Switzerland. METHODS: Retrospective cohort study of preterm infants born in 2020 based on two independent data sources from the Swiss Federal Statistics Office (FSO) and SwissNeoNet. Based on FSO data, we calculated the odds ratios for extremely preterm (22–27 weeks gestation), very preterm (28–31 weeks gestation), and late preterm (32–36 weeks gestation) births during the pandemic. Based on SwissNeoNet data of infants born between 22 and 31 weeks gestation, we compared infants born during the Swiss lockdown period in 2020 with infants born during the same period between 2015 and 2019, all infants of 2020 with all infants between 2015 and 2019 and infants born to mothers tested SARS-CoV-2 positive and negative. Possible associations with the pandemic were tested using logistic regression adjusted for case-mix. As a control, we compared births of 2019 with those of 2015–2018. RESULTS: The FSO data revealed equivalent odds for extremely preterm births in 2020 (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.89–1.14), as well as somewhat lower odds ratios for very preterm (OR 0.9, 95% CI 0.82–1.00) and late preterm (OR 0.91, 95% CI 0.88–0.93) births in 2020. A comparison between 2019 and 2015–2018, however, revealed matching odds ratios rendering an association to the pandemic unlikely. In the SwissNeoNet data, 137 infants were born during lockdown in 2020 compared with 134 births per year during 2015–2019. When including all infants, 744 infants were compared to 845 births, respectively. The only difference observed in treatments and short term outcomes between 2020 and the reference years were a higher odds for respiratory distress syndrome (OR 1.6, 95% CI 1.08–2.37) and provision of continuous positive airway pressure (CPAP) (OR 1.39, 95% CI 1.05–1.84). CONCLUSIONS: Our Swiss population-based analysis did not identify the elsewhere reported association between the COVID-19 pandemic and a reduced preterm birth rate. However, we can confirm a possible link between the COVID-19 pandemic and higher odds of respiratory distress syndrome, possibly coupled with CPAP requirements. Further observation of potential effects of the pandemic on health and health care provision to newborns may however be indicated based on the literature available so far and that our data only covers the first 9 months of the current pandemic.

Odorant cues play a critical role in premating isolation among many species. In mammals, they have been most well-studied in rodents, but only in a handful of species. The genus Rattus is one of the most species-rich genera of mammals, with a natural distribution from Asia to Australia and a nearly global distribution for a few species that spread through human commensalism. More than one-third of Rattus species are the result of a recent and rapid radiation on continental Australia (Sahul) centred on the island of New Guinea. The two most widespread species resulting from this radiation, Rattus fuscipes and Rattus leucopus, occur sympatrically in the Wet Tropics region of Queensland, Australia. Despite their recent divergence, morphological similarity, and ability to produce fertile offspring in captivity, hybrids of the two species have not been reported in the wild, suggesting that premating isolation mechanisms maintain the species’ boundaries. Odorant cues are a plausible mechanism that these species could use to identify mates of the same species, but the chemical composition of their odours has not been characterized. With allozyme data from 166 specimens of the two species we confirmed the absence of gene flow between the species in sympatry. From chemical analysis of preputial glands of 32 males from sympatric and allopatric populations of the two species we identified 120 volatile organic compounds of which 80 were reliably quantitated for statistical analysis. Some of these chemicals have been indicated as signalling compounds in other species of mammals, including seven thiazolines. Among them two (2-sec-butylthiazoline and 2-isopropythiazoline) have been previously detected in a rodent, the House Mouse, Mus musculus, and are involved in social interactions including attracting females. We demonstrate that R. fuscipes and R. leucopus are quantitatively and qualitatively distinguishable by the chemical composition of their preputial gland secretions. In comparison to allopatric subspecies, sympatric species contained more unique chemical compounds and a higher abundance of compounds overall, suggesting that sympatric populations have more complex and concentrated odours. Together these results indicate that odorant chemistry has evolved rapidly in these two species, with substantial differences among species and subspecies, especially in sympatry. Ultimately, the rapid evolution of chemical signals involved in mate recognition may help to explain the exceptional diversity of species in the genus Rattus.

AIMS OF THE STUDY To investigate and compare the centre-specific short-term outcome indicators seizures, arterial hypotension, infection and mortality during therapeutic hypothermia until discharge from the neonatal/paediatric intensive care unit in term and near-term neonates with hypoxic-ischaemic encephalopathy (HIE) registered in the Swiss National Asphyxia and Cooling Register between 2011 and 2018. METHODS Retrospective analysis of prospectively collected national register data between 1 January 2011 and 31 December 2018. Pregnancy, maternal, delivery and neonatal characteristics were compared between the centres. Four short-term outcomes were defined: seizures, arterial hypotension, infection and mortality. The outcome indicators were defined as stated in the protocol of the Swiss National Asphyxia and Cooling Register. Descriptive analyses of the de-identified centre to centre analysis were performed, and standardised observed-to-expected values (risk adjusted for male sex, small for gestational age, Sarnat score on admission, pregnancy/delivery complications) of each centre were compared using with the entire network indirectly standardised mortality/morbidity ratio charts. RESULTS 570 cooled neonates with HIE receiving therapeutic hypothermia in 10 different centres were included. Clinical or subclinical seizures were reported in a median of 32% (range 17–49%). Arterial hypotension occurred in a median of 62% (range 30–90%). Median infection rate was 10% (range 0–31%). Median mortality rate until discharge was 14% (range 0–25%). CONCLUSIONS Short-term outcome indicators of seizures, arterial hypotension, infection and mortality showed significant differences in incidence between the centres. These data will help to establish benchmarks for the assessed outcome measures. Benchmarking is a continuous need with the ultimate goal of improving modifiable short-term outcomes in neonates with HIE.

Amoebic gill disease (AGD) is a significant health issue for Atlantic salmon farmed in a marine environment. While the disease is currently managed using freshwater or hydrogen peroxide baths, there is a need to develop other treatments. The aims of this study were to examine the effect of salinity (0 ppt and 35 ppt) and temperature (3 °C and 15 °C) on attachment and survival of Neoparamoeba perurans in vitro over short exposure times (15 min and 2 h) and to assess the efficacy of reduced temperature (3 °C) as treatment for Atlantic salmon affected by AGD. In vitro freshwater 3 °C was at least as effective as freshwater 15 °C and the attachment was significantly lower after 2 h in freshwater 3 °C than freshwater 15 °C. In vivo there was no difference between the fish treated with freshwater 15 °C for 2 h or freshwater 3 °C. This study showed that despite exposure to low temperature reducing attachment of N. perurans to their substrate in vitro, 15 min cold-water bath treatment was not more effective at reducing AGD in Atlantic salmon than current commercial 2 h freshwater bath.

The severe consequences of human disruptions to the global carbon cycle have prompted intense interest in strategies to reduce atmospheric CO2 concentrations. Because growing forests capture CO2 in their biomass and soils, large-scale tree planting efforts have been advertised as a viable way to counteract anthropogenic emissions as part of net-zero emission strategies. Here, we assess the potential impact of reforestation and afforestation on the global climate system, and identify ecological, economic, and societal implications of such efforts.

BackgroundUK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.AimsDescribe the development, implementation and results of this questionnaire.MethodAn expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.ResultsA total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.ConclusionsThe UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects (CHDs) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007–2015 at 24 to 31 weeks’ gestation with birth weights

Background Programs targeting the standard modifiable cardiovascular risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, smoking) are critical to tackling coronary heart disease at a community level. However, myocardial infarction in SMuRF‐less individuals is not uncommon. This study uses 2 sequential large, multicenter registries to examine the proportion and outcomes of SMuRF‐less ST‐segment–elevation myocardial infarction (STEMI) patients. Methods and Results We identified 3081 STEMI patients without a prior history of cardiovascular disease in the Australian GRACE (Global Registry of Acute Coronary Events) and CONCORDANCE (Cooperative National Registry of Acute Coronary Syndrome Care) registries, encompassing 42 hospitals, between 1999 and 2017. We examined the proportion that were SMuRF‐less as well as outcomes. The primary outcome was in‐hospital mortality, and the secondary outcome was major adverse cardiovascular events (death, myocardial infarction, or heart failure, during the index admission). Multivariate regression models were used to identify predictors of major adverse cardiovascular events. Of STEMI patients without a prior history of cardiovascular disease 19% also had no history of SMuRFs. This proportion increased from 14% to 23% during the study period (P=0.0067). SMuRF‐less individuals had a higher in‐hospital mortality rate than individuals with 1 or more SMuRFs. There were no clinically significant differences in major adverse cardiovascular events at 6 months between the 2 groups. Conclusions A substantial and increasing proportion of STEMI presentations occur independently of SMuRFs. Discovery of new markers and mechanisms of disease beyond standard risk factors may facilitate novel preventative strategies. Studies to assess longer‐term outcomes of SMuRF‐less STEMI patients are warranted.

BackgroundUK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors.AimsAn online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders.MethodAn expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders.Results157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.ConclusionsThe questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.Declaration of interestG.B. received grants from the National Institute for Health Research during the study; and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work.

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) β-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-β-lactamases (MBLs) producers.

Abstract Background Quality improvement in health care requires identification of areas in need of improvement by comparing processes and patient outcomes within and between health care providers. It is critical to adjust for different case-mix and outcome risks of patient populations but it is currently unclear which approach has higher validity and how limitations need to be dealt with. Our aim was to compare 3 approaches towards risk adjustment for 7 different major quality indicators in neonatal intensive care (21 models). Methods We compared an indirect standardization, logistic regression and multilevel approach. Parameters for risk adjustment were chosen according to literature and the condition that they may not depend on processes performed by treating clinics. Predictive validity was tested using the mean Brier Score and by comparing area under curve (AUC) using high quality population based data separated into training and validation sets. Changes in attributional validity were analysed by comparing the effect of the models on the observed-to-expected ratios of the clinics in standardized mortality/morbidity ratio charts. Results Risk adjustment based on indirect standardization revealed inferior c-statistics but superior Brier scores for 3 of 7 outcomes. Logistic regression and multilevel modelling were equivalent to one another. C-statistics revealed that predictive validity was high for 8 and acceptable for 11 of the 21 models. Yet, the effect of all forms of risk adjustment on any clinic’s comparison with the standard was small, even though there was clear risk heterogeneity between clinics. Conclusions All three approaches to risk adjustment revealed comparable results. The limited effect of risk adjustment on clinic comparisons indicates a small case-mix influence on observed outcomes, but also a limited ability to isolate quality improvement potential based on risk-adjustment models. Rather than relying on methodological approaches, we instead recommend that clinics build small collaboratives and compare their indicators both in risk-adjusted and unadjusted form together. This allows qualitatively investigating and discussing the residual risk-differences within networks. The predictive validity should be quantified and reported and stratification into risk groups should be more widely used to correct for confounding.

Molecular typing using repetitive sequenced-based PCR (rep-PCR) and hsp60 sequencing were applied to a collection of diverse Enterobacter cloacae complex isolates. To determine the most practical method for reference laboratories, we analyzed 71 E. cloacae complex isolates from sporadic and outbreak occurrences originating from 4 geographic areas. While rep-PCR was more discriminating, hsp60 sequencing provided a broader and a more objective geographical tracking method similar to multilocus sequence typing (MLST). In addition, we suggest that MLST may have higher discriminative power compared to hsp60 sequencing, although rep-PCR remains the most discriminative method for local outbreak investigations. In addition, rep-PCR can be an effective and inexpensive method for local outbreak investigation.

BACKGROUND Infants born very preterm are at higher risk of long-term neurodevelopmental problems than children born at term. Although there are increasing numbers of reports on outcomes from international cohorts of premature infants, a Swiss national report on infants after 2 years of age is lacking. AIMS OF THE STUDY To describe neurodevelopmental outcomes at early school age of preterm children born in Switzerland with a special focus on the cognitive abilities. METHODS This prospective national cohort study included children born alive before 30 weeks of gestation in 2006. At 5 years of age, children underwent a neurological examination and intelligence testing with the Kaufman Assessment Battery for Children first edition (K-ABC). We assessed the mental processing composite score (MPC) and its subscales to explore specific cognitive deficits. The primary outcome was cognitive impairment (MPC score

Amoebic gill disease (AGD), caused by the amoeba Neoparamoeba perurans, has led to considerable economic losses in every major Atlantic salmon producing country, and is increasing in frequency. The most serious infections occur during summer and autumn, when temperatures are high and poor dissolved oxygen (DO) conditions are most common. Here, we tested if exposure to cyclic hypoxia at DO saturations of 40–60% altered the course of infection with N. perurans compared to normoxic controls maintained at ≥90% DO saturation. Although hypoxia exposure did not increase initial susceptibility to N. perurans, it accelerated progression of the disease. By 7 days post-inoculation, amoeba counts estimated from qPCR analysis were 1.7 times higher in the hypoxic treatment than in normoxic controls, and cumulative mortalities were twice as high (16 ± 4% and 8 ± 2%), respectively. At 10 days post-inoculation, however, there were no differences between amoeba counts in the hypoxic and normoxic treatments, nor in the percentage of filaments with AGD lesions (control = 74 ± 2.8%, hypoxic = 69 ± 3.3%), or number of lamellae per lesion (control = 30 ± 0.9%, hypoxic = 27.9 ± 0.9%) as determined by histological examination. Cumulative mortalities at the termination of the experiment were similarly high in both treatments (hypoxic = 60 ± 2%, normoxic = 53 ± 11%). These results reveal that exposure to cyclic hypoxia in a diel pattern, equivalent to what salmon are exposed to in marine aquaculture cages, accelerated the progression of AGD in post-smolts.

Background Little is known about the prognostic implications of frailty, a state of susceptibility to stressors and poor recovery to homeostasis in older people, after myocardial infarction (MI). Methods and Results We studied 3944 MI patients aged ≥65 years treated at 41 Australian hospitals from 2009 to 2016 in the CONCORDANCE (Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events) registry. Frailty index (FI) was determined using the health deficit accumulation method. All‐cause and cardiac‐specific mortality at 6 months were compared between frail (FI >0.25) and nonfrail (FI ≤0.25) patients. Among 1275 patients with ST‐segment–elevation MI (STEMI), 192 (15%) were frail, and among 2669 non‐STEMI (NSTEMI) patients, 902 (34%) were frail. Compared with nonfrail counterparts, frail STEMI patients received 30% less reperfusion therapy and 22% less revascularization during index hospitalization; frail NSTEMI patients received 30% less diagnostic angiography and 39% less revascularization. Unadjusted 6‐month all‐cause mortality (STEMI: 13% versus 3%; NSTEMI: 13% versus 4%) and cardiac‐specific mortality (STEMI: 6% versus 1.4%, NSTEMI: 3.2% versus 1.2%) were higher among frail patients. After adjustment for known prognosticators, FI was significantly associated with higher 6‐month all‐cause (STEMI: odds ratio: 1.74 per 0.1 FI [95% confidence interval, 1.37–2.22], P

The Common HOL project aims to facilitate porting source code and proofs between members of the HOL family of theorem provers. At the heart of the project is the Common HOL Platform, which defines a standard HOL theory and API that aims to be compatible with all HOL systems. So far, HOL Light and hol90 have been adapted for conformance, and HOL Zero was originally developed to conform. In this paper we provide motivation for a platform, give an overview of the Common HOL Platform's theory and API components, and show how to adapt legacy systems. We also report on the platform's successful application in the hand-translation of a few thousand lines of source code from HOL Light to HOL Zero.

This article describes a formal proof of the Kepler conjecture on dense sphere packings in a combination of the HOL Light and Isabelle proof assistants. This paper constitutes the official published account of the now completed Flyspeck project.

ENSCO, Inc. is developing an innovative atmospheric observing system known as Global Environmental Micro Sensors (GEMS). The GEMS concept features an integrated system of miniaturized in situ, airborne probes measuring temperature, relative humidity, pressure, and vector wind velocity. In order for the probes to remain airborne for long periods of time, their design is based on a helium-filled super-pressure balloon. The GEMS probes are neutrally buoyant and carried passively by the wind at predetermined levels. Each probe contains on-board satellite communication, power generation, processing, and geolocation capabilities. ENSCO has partnered with the National Aeronautics and Space Administration’s Kennedy Space Center (KSC) Weather Office for a project called GEMS Test Operations in the Natural Environment (GEMSTONE). The goal of the GEMSTONE project was to build and field-test a small system of prototype probes in the Earth’s atmosphere. This paper summarizes the 9-month GEMSTONE project (Sep 2006 – May 2007) including probe and system engineering as well as experiment design and data analysis from laboratory and field tests. These tests revealed issues with reliability, sensor accuracy, electronics miniaturization, and sub-system optimization. Nevertheless, the success of the third and final free flight test provides a solid foundation to move forward in follow on projects addressing these issues as highlighted in the technology roadmap for future GEMS development.

Habitat fragmentation caused by human activities alters metapopulation dynamics and decreases biological connectivity through reduced migration and gene flow, leading to lowered levels of population genetic diversity and to local extinctions. The threatened Yarra pygmy perch, Nannoperca obscura, is a poor disperser found in small, isolated populations in wetlands and streams of southeastern Australia. Modifications to natural flow regimes in anthropogenically-impacted river systems have recently reduced the amount of habitat for this species and likely further limited its opportunity to disperse. We employed highly resolving microsatellite DNA markers to assess genetic variation, population structure and the spatial scale that dispersal takes place across the distribution of this freshwater fish and used this information to identify conservation units for management. The levels of genetic variation found for N. obscura are amongst the lowest reported for a fish species (mean heterozygosity of 0.318 and mean allelic richness of 1.92). We identified very strong population genetic structure, nil to little evidence of recent migration among demes and a minimum of 11 units for conservation management, hierarchically nested within four major genetic lineages. A combination of spatial analytical methods revealed hierarchical genetic structure corresponding with catchment boundaries and also demonstrated significant isolation by riverine distance. Our findings have implications for the national recovery plan of this species by demonstrating that N. obscura populations should be managed at a catchment level and highlighting the need to restore habitat and avoid further alteration of the natural hydrology.

Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925).The ADVANCE trial was a multicentre, 2 × 2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (-1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6).The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment.

The freshwater fauna of Southern Australia is primarily restricted to the southwestern and southeastern corners of the continent, and is separated by a large, arid region that is inhospitable to this biota. This geographic phenomenon has attracted considerable interest from biogeographers looking to explain evolutionary diversification in this region. Here, we employed phylogenetic and phylogeographic approaches to evaluate the effect of this barrier on a group of four galaxiid fish species (Galaxiella) endemic to temperate Southern Australia. We also tested if continental shelf width has influenced connectivity among populations during low sea levels when rivers, now isolated, could have been connected. We addressed these questions by sampling each species across its range using multiple molecular markers (mitochondrial cytochrome b sequences, nuclear S7 intron sequences, and 49 allozyme loci). These data also allowed us to assess species boundaries, to refine phylogenetic affinities, and to estimate species ages. Interestingly, we found compelling evidence for cryptic species in G. pusilla, manifesting as allopatric eastern and western taxa. Our combined phylogeny and dating analysis point to an origin for the genus dating to the early Cenozoic, with three of the four species originating during the Oligocene-Miocene. Each Galaxiella species showed high levels of genetic divergences between all but the most proximate populations. Despite extensive drainage connections during recent low sea levels in southeastern Australia, populations of both species within G. pusilla maintained high levels of genetic structure. All populations experienced Late Pleistocene-Holocene population growth, possibly in response to the relaxation of arid conditions after the last glacial maximum. High levels of genetic divergence and the discovery of new cryptic species have important implications for the conservation of this already threatened group of freshwater species.