Plant genome evolution in the genus Eucalyptus is driven by structural rearrangements that promote sequence divergence.

Genomes have a highly organized architecture (nonrandom organization of functional and nonfunctional genetic elements within chromosomes) that is essential for many biological functions, particularly gene expression and reproduction. Despite the need to conserve genome architecture, a high level of structural variation has been observed within species. As species separate and diverge, genome architecture also diverges, becoming increasingly poorly conserved as divergence time increases. However, within plant genomes, the processes of genome architecture divergence are not well described. Here we use long-read sequencing and de novo assembly of 33 phylogenetically diverse, wild and naturally evolving Eucalyptus species, covering 1-50 million years of diverging genome evolution to measure genome architectural conservation and describe architectural divergence. The investigation of these genomes revealed that following lineage divergence, genome architecture is highly fragmented by rearrangements. As genomes continue to diverge, the accumulation of mutations and the subsequent divergence beyond recognition of rearrangements become the primary driver of genome divergence. The loss of syntenic regions also contribute to genome divergence but at a slower pace than that of rearrangements. We hypothesize that duplications and translocations are potentially the greatest contributors to Eucalyptus genome divergence.

Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils.

The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans. Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.

Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.

Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

Associations Between Flavonoid Intake and Subclinical Atherosclerosis: The MESA.

BACKGROUND: Flavonoids may play a role in mitigating atherosclerotic cardiovascular diseases, with evidence suggesting effects may differ between vascular beds. Studies examining associations with subclinical markers of atherosclerosis between subpopulations with different underlying risks of atherosclerosis are lacking. METHODS: Among 5599 participants from the MESA (Multi-Ethnic Study of Atherosclerosis), associations between dietary flavonoid intakes (estimated from a food frequency questionnaire) and subclinical measures of atherosclerosis (ankle-brachial index, carotid plaques and intima-media thickness, and coronary artery calcification) were examined using repeated measures models. Exposures and outcomes were measured at exam 1 (2000-2002) and exam 5 (2010-2011). Stratified analyses and interaction terms were used to explore effect modification by time, sex, race/ethnicity, and smoking status. RESULTS: In the analytic population, at baseline, ≈46% were males with a median age of 62 (interquartile range, 53-70) years and total flavonoid intakes of 182 (interquartile range, 98-308) mg/d. After multivariable adjustments, participants with the highest (quartile 4) versus lowest (quartile 1) total flavonoid intakes had 26% lower odds of having an ankle-brachial index <1 (odds ratio, 0.74 [95% CI, 0.60-0.92]) and 18% lower odds of having a carotid plaque (odds ratio, 0.82 [95% CI, 0.69-0.99]), averaged over exams 1 and 5. Moderate (quartile 3) to high (quartile 4) intakes of flavonols, flavanol monomers, and anthocyanins were associated with 19% to 34% lower odds of having an ankle-brachial index <1 and 18% to 20% lower odds of having carotid plaque. Participants with the highest intakes of anthocyanins (quartile 4) at baseline had a marginally slower rate of carotid plaque progression than those with moderate intakes (quartiles 2 and 3). There were no significant associations with intima-media thickness or coronary artery calcification. Observed associations did not differ by sex, race/ethnicity, or smoking status. CONCLUSIONS: In this multi-ethnic population, higher dietary flavonoid intakes were associated with lower odds of peripheral and carotid artery atherosclerosis. Increasing intakes of healthy, flavonoid-rich foods may protect against atherosclerosis in the peripheral and carotid arteries.

Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

BACKGROUND: Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K1 are associated with a lower incidence of aortic stenosis. METHODS: In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K1 were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease-related mortality; secondary outcome). RESULTS: In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K1 intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63-0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56-0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. CONCLUSIONS: In this study, a high intake of vitamin K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

De novo designed protein inhibitors of amyloid aggregation and seeding.

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-ß (Aß) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aß, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Genomic determinants, architecture, and constraints in drought-related traits in Corymbia calophylla.

BACKGROUND: Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla. RESULTS: We found 273 genomic variants determining traits with moderate heritability (h2SNP = 0.26-0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions. CONCLUSIONS: Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change.

Excess Deaths Associated with Rheumatic Heart Disease, Australia, 2013-2017.

During 2013-2017, the mortality rate ratio for rheumatic heart disease among Indigenous versus non-Indigenous persons in Australia was 15.9, reflecting health inequity. Using excess mortality methods, we found that deaths associated with rheumatic heart disease among Indigenous Australians were probably substantially undercounted, affecting accuracy of calculations based solely on Australian Bureau of Statistics data.

Vitamin D status and cognitive performance in community-dwelling adults: A dose-response meta-analysis of observational studies.

Low vitamin D status is linked with poorer cognition in adults while findings in relation to high levels are mixed.We performed a systematic review and meta-analyses to examine dose-response associations between 25-hydroxyvitamin D (25OHD) levelsand cognitive performance in community-dwelling adults. Thirty-eight observational studies were included in dose-response meta-analyses. Positive, nonlinear associations were identified between baseline25OHD levels and global cognition incross-sectional and longitudinal analyses, and for performance in memory and executive function in longitudinal analyses. When restricted to studies involving older adults, thepattern emerged forspecific domains in cross-sectional analyses. Poorer performance was associated with low 25OHD levels, while a sharp improvement was associated withlevels up to 60-70 nM/L. Further improvement was observed only for longitudinal global cognition. Our findings support the association between low vitamin D and poorer cognition and suggest levels of at least 60 nM/L are associated with better cognition during ageing.

Exertional heat stroke causes long-term skeletal muscle epigenetic reprogramming, altered gene expression, and impaired satellite cell function in mice.

The effect of exertional heat stroke (EHS) exposure on skeletal muscles is incompletely understood. Muscle weakness is an early symptom of EHS but is not considered a major target of multiorgan injury. Previously, in a preclinical mouse model of EHS, we observed the vulnerability of limb muscles to a second EHS exposure, suggesting hidden processes contributing to declines in muscle resilience. Here, we evaluated the possible molecular origins of EHS-induced declines in muscle resilience. Female C57BL/6 mice [total n = 56; 28/condition, i.e., EHS and exercise control (EXC)] underwent forced wheel running at 37.5°C/40% relative humidity until symptom limitation (unconsciousness). EXC mice exercised identically at room temperature (22-23°C). After 1 mo of recovery, the following were assessed: 1) specific force and caffeine-induced contracture in soleus (SOL) and extensor digitorum longus (EDL) muscles; 2) transcriptome and DNA methylome responses in gastrocnemius (GAST); and 3) primary satellite cell function (proliferation and differentiation). There were no differences in specific force in either SOL or EDL from EXC. Only EHS solei exhibited lower caffeine sensitivity. EHS GAST exhibited higher RNA expression of genes encoding structural proteins of slow fibers, heat shock proteins, and myogenesis. A total of ∼2,500 differentially methylated regions of DNA that could potentially affect many cell functions were identified. Primary satellite cells exhibited suppressed proliferation rates but normal differentiation responses. Results demonstrate long-term changes in skeletal muscles 1 mo after EHS that could contribute to declines in muscle resilience. Skeletal muscle may join other, more recognized tissues considered vulnerable to long-term effects of EHS.NEW & NOTEWORTHY Exertional heat stroke (EHS) in mice induces long-term molecular and functional changes in limb muscle that could reflect a loss of "resilience" to further stress. The phenotype was characterized by altered caffeine sensitivity and suppressed satellite cell proliferative potential. This was accompanied by changes in gene expression and DNA methylation consistent with ongoing muscle remodeling and stress adaptation. We propose that EHS may induce a prolonged vulnerability of skeletal muscle to further stress or injury.

A further update on mortality and morbidity in patients with very low hemoglobin levels who decline blood transfusion.

BACKGROUND: In the past two decades, researchers have published mortality and morbidity rates in patients with very low hemoglobin levels declining blood transfusion. The clinical knowledge and tools available for the management of patients who decline transfusions have grown since these publications. The aim of our study was to provide a further update on outcomes associated with severe anemia in these patients. STUDY DESIGN AND METHODS: A retrospective observational study of patients declining allogeneic blood transfusions with nadir hemoglobin levels ≤8 g/dL treated at The Institute for Blood Management, HELIOS Klinikum Gotha, Germany. Outcomes were in-hospital mortality within 30 days and composite morbidity or mortality, with morbidity events defined as acute myocardial infarction, cardiac failure, wound infection, arrhythmia, and pneumonia. RESULTS: Between June 2008 and June 2021, The Institute for Blood Management treated 2841 admissions of which 159 (5.6%) recorded nadir hemoglobin levels ≤8 g/dL. Of these, five (3.1%) patients died in hospital within 30 days, including four (4.8%) patients admitted for surgical procedures and one (1.4%) medical admission. There was a significant increase in the unadjusted proportion of composite morbidity or mortality events with severity of nadir hemoglobin, with each gram decrease in hemoglobin associated with a 1.48 (95% confidence interval = 1.05-2.09; p = .025) times increase. CONCLUSION: Our comparatively lower proportion of patients reaching hemoglobin levels ≤8 g/dL and lower mortality rates suggest outcomes in patients with severe anemia is modifiable with the application of current patient blood management and bloodless medicine and surgery strategies.

Longitudinal effects of dog ownership, dog acquisition, and dog loss on children's movement behaviours: findings from the PLAYCE cohort study.

INTRODUCTION: Regular physical activity is important for children's physical and mental health, yet many children do not achieve recommended amounts of physical activity. Dog ownership has been associated with increased physical activity in children, however, there have been no longitudinal studies examining this relationship. This study used data from the Play Spaces and Environments for Children's Physical Activity (PLAYCE) cohort study to examine the longitudinal effects of dog ownership status on children's movement behaviours. METHODS: Change in dog ownership from preschool (wave 1, age 2-5) to fulltime school (wave 2, age 5-7) was used as a natural experiment with four distinct dog ownership groups: continuing non-dog owners (n = 307), continuing dog owners (n = 204), dog acquired (n = 58), and dog loss (n = 31; total n = 600). Daily movement behaviours, including physical activity, sedentary time, sleep, and screen time, were measured using accelerometry and parent-report surveys. Differences between groups over time and by sex were tested using linear mixed effects regression models. RESULTS: Girls who acquired a dog increased their light intensity activities and games by 52.0 min/day (95%CI 7.9, 96.0) and girls who lost a dog decreased their light intensity activities and games by 62.1 min/day (95%CI -119.3, -4.9) compared to no change among non-dog owners. Girls and boys who acquired a dog increased their unstructured physical activity by 6.8 (95%CI 3.2, 10.3) and 7.1 (95%CI 3.9, 10.3) occasions/week, compared to no changes among non-dog owners. Girls and boys who lost a dog reduced their unstructured physical activity by 10.2 (95%CI -15.0, -5.3) and 7.7 (95%CI -12.0, -3.5) occasions/week. Girls who lost a dog decreased their total physical activity by 46.3 min/day (95%CI -107.5, 14.8) compared to no change among non-dog owners. Continuing dog ownership was typically not associated with movement behaviours. Dog ownership group was not associated with changes in sleep and had mixed associations with screen time. CONCLUSION: The positive influence of dog ownership on children's physical activity begins in early childhood and differs by child sex. Further research should examine the specific contributions dog-facilitated physical activity makes to children's overall physical activity, including the intensity and duration of dog walking and play.

Developmental trends in young children's device-measured physical activity and sedentary behaviour.

BACKGROUND: Knowledge of developmental trends in meeting age-specific 24-hour movement behaviour guidelines is lacking. This study describes developmental trends in device-measured physical activity and sedentary time over a three-year period among Western Australian children aged two to seven years, including differences between boys and girls. The proportion of children meeting age-specific physical activity guidelines before and after they transition to full-time school was also examined. METHODS: Data from waves 1 and 2 of the Play Spaces and Environments for Children's Physical Activity (PLAYCE) cohort study were used (analysis n = 1217). Physical activity and sedentary time were measured by accelerometry at ages two to five (preschool, wave 1) and ages five to seven (commenced full-time school, wave 2). Accelerometer data were processed using a validated machine-learning physical activity classification model. Daily time spent in sedentary behaviour, energetic play (moderate-to-vigorous physical activity (MVPA)), total physical activity, and meeting physical activity guidelines were analysed using linear and generalised linear mixed-effects models with age by sex interaction terms. RESULTS: All movement behaviours changed significantly with increasing age, and trends were similar in boys and girls. Total daily physical activity increased from age two to five then declined to age seven. Mean daily total physical activity exceeded 180 min/day from ages two to five. Daily energetic play increased significantly from age two to seven, however, was below 60 min/day at all ages except for seven-year-old boys. Daily sedentary time decreased to age five then increased to age seven but remained lower than at age two. All two-year-olds met their age-specific physical activity guideline, decreasing to 5% of girls and 6% of boys at age four. At age seven, 46% of boys and 35% of girls met their age-specific physical activity guideline. CONCLUSIONS: Young children's energetic play and total physical activity increased with age, but few children aged three to seven met the energetic play (MVPA) guideline. Interventions should focus on increasing children's energetic play in early childhood. Clearer guidance and strategies are needed to support young children as they change developmentally and as they transition from one age-specific movement guideline to the next.

Current use, training, and barriers in point-of-care ultrasound in nephrology: A national survey of VA medical centers.

BACKGROUND: Point-of-care ultrasound (POCUS) can improve diagnostic accuracy, reduce procedural complications and enhance physician-patient interactions in nephrology. Currently, there is limited knowledge about how practicing nephrologists are using POCUS. OBJECTIVE: This study aimed to characterize current POCUS use, training needs, and barriers to use among nephrology groups. MATERIALS AND METHODS: A prospective observational study of all Veterans Affairs (VA) medical centers was conducted between August 2019 and March 2020 using a web-based survey sent to all chiefs of staff and nephrology specialty chiefs. RESULTS: Chiefs of staff (n = 130) and nephrology chiefs (n = 79) completed surveys on facility- and service-level POCUS use (response rates of 100% and 77%, respectively). Current diagnostic or procedural POCUS use was reported by 41% of nephrology groups, and the most common POCUS applications were central line insertion (28%) and assessment of urinary retention (23%), hydronephrosis (18%), volume status (15%), and bladder (14%). Lack of training was the most common barrier (72%), and most nephrology groups (65%) desired POCUS training. Limited access to ultrasound equipment and POCUS training were barriers reported by 54% and 18% of groups, respectively. CONCLUSION: A minority of nephrology groups currently use common POCUS applications including evaluation of urinary retention, hydronephrosis, and volume status. The most common barriers to POCUS use in nephrology were lack of trained providers and ultrasound equipment. Investment in POCUS training and infrastructure is needed to expand and standardize POCUS use in nephrology.

Longitudinal associations of DXA-measured visceral adipose tissue and cardiometabolic risk in middle-to-older aged adults.

BACKGROUND AND AIMS: DXA-measured visceral adipose tissue (VATDXA) is associated with adverse cardiometabolic risk profiles in cross-sectional studies, but longitudinal associations have not been investigated. We examined the longitudinal associations of baseline and change in VATDXA with future cardiometabolic risk in Australian participants of the Busselton Healthy Ageing study. METHODS AND RESULTS: We studied 3569 participants (54.7% female, aged 46-70 years) with data on VATDXA (GE Lunar Prodigy) and cardiometabolic risk factors at baseline and 6 years follow-up. The associations were examined using logistic and linear regression models, adjusting for baseline age and lifestyle factors. Mean baseline VATDXA mass was 1653 ± 880 g and 855 ± 580 g, and mean change in VATDXA +99 ± 500 g and +58 ± 312 g in males and females, respectively. Among all participants, 182 males (11.3%) and 197 females (10.1%) developed incident metabolic syndrome (MetS). Baseline VATDXA was associated with incident MetS with an adjusted odds ratio of 2.53 (95% CI: 2.03, 3.15) in males and 2.78 (2.30, 3.36) in females per SD increment. There was a graded positive association between longitudinal change in VATDXA and MetS severity z score in both sexes adjusted for baseline VAT (P < 0.001). All the above associations remained significant after further adjustment for baseline or change in BMI, waist circumference or waist-to-hip ratio in respective models (all P < 0.001). CONCLUSIONS: Higher baseline and greater longitudinal increase in VATDXA are independently associated with raised cardiometabolic risk over time, and may serve as useful markers for identifying middle-aged individuals at increased cardiometabolic risk.

The Safety of Methoxyflurane for Emergency Pain Relief in Children and Adolescents: A Retrospective Cohort Study.

OBJECTIVES: The use of methoxyflurane is becoming increasingly popular in the treatment of pain in an emergency setting, in part due to its ease of administration. However, little is known about the risk of serious adverse events in children and adolescents. The aim of this study was to examine the safety of methoxyflurane in a pediatric population. METHODS: The study was a retrospective cohort study of pediatric prehospital events using probabilistic linked health data. All ambulance transfers in Western Australia between 1990 and 2016 involving children and adolescent patients were identified. Patients were categorized based on administered analgesia: methoxyflurane, an opioid analgesic, both methoxyflurane and an opioid analgesic, or no analgesic. Hospital and mortality data were linked to transferred patients to identify deaths, adverse drug reactions, liver and kidney toxicity, and re-admissions to hospital following ambulance transfer. Generalized linear models, adjusting for sociodemographic and ambulance transfer characteristics, were used to compare outcomes between children exposed to methoxyflurane and the other three groups. RESULTS: The study cohort consisted of 37,211 children, including 9,472 patients (25.5%) treated with methoxyflurane alone, 2,764 (7.4%) treated with an opioid analgesic, 1,235 (3.3%) treated with both methoxyflurane and an opioid analgesic, and 23,740 (63.8%) treated with no analgesic. Death in children and adolescents was uncommon, with less than five deaths (<0.1%) observed in the 12 months following treatment with methoxyflurane and no deaths in those treated with both methoxyflurane and an opioid analgesic. Adverse drug reaction was rare (<0.1%) in patients treated with methoxyflurane, as was liver and kidney toxicity with no case observed. At 90-days follow-up, there was no significant difference in hospitalization in patients treated with methoxyflurane and those treated with methoxyflurane and an opioid analgesic (adjusted OR:1.01, 95%CI:0.85-1.21). Compared with methoxyflurane treated patients, patients treated with an opioid analgesic were more likely to be hospitalized (aOR:1.23, 95%CI:1.09-1.39), while patients treated with no analgesic were less likely to be hospitalized (aOR:0.85, 95%CI:0.79-0.92). CONCLUSIONS: In children and adolescents transported by ambulance, the use of methoxyflurane was not associated with an increased risk of hospitalization, death, serious adverse drug reactions or liver and kidney toxicity.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Young children's use of blue spaces and the impact on their health, development and environmental awareness: A qualitative study from parents' perspectives.

ISSUE ADDRESSED: This study examined how families with young children access and use different types of blue spaces and the health and development benefits, and potential negative effects. METHODS: Parents(n = 25) of young children across four coastal communities in Western Australia were recruited via purposive sampling to participate in interviews. A generic qualitative study design grounded in the pragmatism paradigm was utilised. RESULTS: Beaches were the most frequently used blue space for families all year around, however families did not necessarily attend their closest beach. This appears due to certain beach features making them more or less attractive for use regardless of the distance from home. Parents perceived blue spaces as health promoting due to the increased physical activity children did in and around these spaces. They also reported blue spaces could be positive for child development, contributing to the development of identity. Blue spaces were also perceived to promote children's environmental awareness and environmentally friendly behaviours. However, blue spaces could also be potentially risky environments for families with young children. CONCLUSIONS: The findings highlight blue spaces are an important setting for supporting children's health, development and environmental consciousness. SO WHAT?: It is important to protect natural outdoor environments such as blue spaces for future generations. The findings can be used by governments and policy makers to improve the quality (features and amenities) of blue spaces and positively impact how often families (including those with dogs) use blue spaces and the benefits they experience.