Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (P=1.95×10-3). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.

Landscape fire smoke airway exposure impairs respiratory and cardiac function and worsens experimental asthma.

BACKGROUND: Millions of people are exposed to landscape fire smoke (LFS) globally, and inhalation of LFS particulate matter (PM) is associated with poor respiratory and cardiovascular outcomes. However, how LFS affects respiratory and cardiovascular function is less well understood. OBJECTIVE: We aimed to characterize the pathophysiologic effects of representative LFS airway exposure on respiratory and cardiac function and on asthma outcomes. METHODS: LFS was generated using a customized combustion chamber. In 8-week-old female BALB/c mice, low (25 µg/m3, 24-hour equivalent) or moderate (100 µg/m3, 24-hour equivalent) concentrations of LFS PM (10 µm and below [PM10]) were administered daily for 3 (short-term) and 14 (long-term) days in the presence and absence of experimental asthma. Lung inflammation, gene expression, structural changes, and lung function were assessed. In 8-week-old male C57BL/6 mice, low concentrations of LFS PM10 were administered for 3 days. Cardiac function and gene expression were assessed. RESULTS: Short- and long-term LFS PM10 airway exposure increased airway hyperresponsiveness and induced steroid insensitivity in experimental asthma, independent of significant changes in airway inflammation. Long-term LFS PM10 airway exposure also decreased gas diffusion. Short-term LFS PM10 airway exposure decreased cardiac function and expression of gene changes relating to oxidative stress and cardiovascular pathologies. CONCLUSIONS: We characterized significant detrimental effects of physiologically relevant concentrations and durations of LFS PM10 airway exposure on lung and heart function. Our study provides a platform for assessment of mechanisms that underpin LFS PM10 airway exposure on respiratory and cardiovascular disease outcomes.

Effect of fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy versus usual care on infant development, temperament, sensory function and autism signs.

Asthma during pregnancy is associated with a range of adverse perinatal outcomes. It is also linked to increased rates of neurodevelopmental conditions in the offspring. We aimed to assess whether fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy improves child developmental and behavioural outcomes compared to usual care. The Breathing for Life Trial was a randomised controlled trial that compared FENO-based asthma management during pregnancy to usual care. Participants were invited to the developmental follow-up, the Breathing for Life Trial - Infant Development study, which followed up infants at 6 weeks, 6 months and 12 months. The primary outcomes were measured in infants at 12 months using the Bayley-III: Cognitive, Language and Motor composite scores. Secondary outcomes included Bayley-III social-emotional and adaptive behaviour scores, autism likelihood and sensory and temperament outcomes. The exposure of interest was the randomised intervention group. Two hundred and twenty-two infants and their 217 participating mothers were recruited to the follow-up; 107 mothers were in the intervention group and 113 were in the control group. There was no evidence of an intervention effect for the primary outcomes: Bayley-III cognitive (mean = 108.9 control, 108.5 intervention, p = 0.93), language (mean = 95.9 control, 95.6 intervention, p = 0.87) and motor composite scores (mean = 97.2 control, 97.9 intervention, p = 0.25). Mean scores for secondary outcomes were also similar among infants born to control and FENO group mothers, with few results reaching p < 0.05. CONCLUSION:  In this sample, FENO-guided asthma treatment during pregnancy did not improve infant developmental outcomes in the first year of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12613000202763. WHAT IS KNOWN: • Maternal asthma during pregnancy has been associated with increased rates of neurodevelopmental conditions in offspring, including intellectual disability and autism. WHAT IS NEW: • This is the first study to examine how managing asthma during pregnancy via a FENO-guided algorithm or usual care affects infant developmental and behavioural outcomes. While the results of the study showed no impact of the intervention, and therefore do not support the integration of FENO-based management of asthma in antenatal settings for optimal infant development, they do send a positive message about the implications of active asthma management during pregnancy on infant developmental outcomes.

Characterization and inhibition of inflammasome responses in severe and non-severe asthma.

BACKGROUND: Increased airway NLRP3 inflammasome-mediated IL-1ß responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown. OBJECTIVE: To investigate the activation and inhibition of inflammasome-mediated IL-1ß responses in immune cells from patients with asthma. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1ß release were assessed. RESULTS: PBMCs from patients with non-severe or severe asthma produced more IL-1ß in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1ß in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1ß release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1ß release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1ß release from PBMCs from all groups. CONCLUSION: An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Effect of asthma management with exhaled nitric oxide versus usual care on perinatal outcomes.

INTRODUCTION: Asthma exacerbations in pregnancy are associated with adverse perinatal outcomes. We aimed to determine whether fractional exhaled nitric oxide (F ENO)-based asthma management improves perinatal outcomes compared to usual care. METHODS: The Breathing for Life Trial was a multicentre, parallel-group, randomised controlled trial conducted in six hospital antenatal clinics, which compared asthma management guided by F ENO (adjustment of asthma treatment according to exhaled nitric oxide and symptoms each 6-12 weeks) to usual care (no treatment adjustment as part of the trial). The primary outcome was a composite of adverse perinatal events (preterm birth, small for gestational age (SGA), perinatal mortality or neonatal hospitalisation) assessed using hospital records. Secondary outcomes included maternal asthma exacerbations. Concealed random allocation, stratified by study site and self-reported smoking status was used, with blinded outcome assessment and statistical analysis (intention to treat). RESULTS: Pregnant women with current asthma were recruited; 599 to the control group (608 infants) and 601 to the intervention (615 infants). There were no significant group differences for the primary composite perinatal outcome (152 (25.6%) out of 594 control, 177 (29.4%) out of 603 intervention; OR 1.21, 95% CI 0.94-1.56; p=0.15), preterm birth (OR 1.14, 95% CI 0.78-1.68), SGA (OR 1.06, 95% CI 0.78-1.68), perinatal mortality (OR 3.62, 95% CI 0.80-16.5), neonatal hospitalisation (OR 1.24, 95% CI 0.89-1.72) or maternal asthma exacerbations requiring hospital admission or emergency department presentation (OR 1.19, 95% CI 0.69-2.05). CONCLUSION: F ENO-guided asthma pharmacotherapy delivered by a nurse or midwife in the antenatal clinic setting did not improve perinatal outcomes.

The impact of prolonged landscape fire smoke exposure on women with asthma in Australia.

BACKGROUND: Little is known about the physical and mental health impact of exposure to landscape fire smoke in women with asthma. This study examined the health impacts and information-seeking behaviours of women with asthma exposed to the 2019/2020 Australian fires, including women who were pregnant. METHODS: Women with asthma were recruited from the Breathing for Life Trial in Australia. Following the landscape fire exposure period, self-reported data were collected regarding symptoms (respiratory and non-respiratory), asthma exacerbations, wellbeing, quality of life, information seeking, and landscape fire smoke exposure mitigation strategies. Participants' primary residential location and fixed site monitoring was used to geolocate and estimate exposure to landscape fire-related fine Particulate Matter (PM2.5). RESULTS: The survey was completed by 81 pregnant, 70 breastfeeding and 232 non-pregnant and non-breastfeeding women with asthma. Participants had a median daily average of 17 µg/m3 PM2.5 and 105 µg/m3 peak PM2.5 exposure over the fire period (October 2019 to February 2020). Over 80% of participants reported non-respiratory and respiratory symptoms during the fire period and 41% reported persistent symptoms. Over 82% reported asthma symptoms and exacerbations of asthma during the fire period. Half the participants sought advice from a health professional for their symptoms. Most (97%) kept windows/doors shut when inside and 94% stayed indoors to minimise exposure to landscape fire smoke. Over two in five (43%) participants reported that their capacity to participate in usual activities was reduced due to prolonged smoke exposure during the fire period. Participants reported greater anxiety during the fire period than after the fire period (mean (SD) = 53(13) versus 39 (13); p < 0.001). Two in five (38%) pregnant participants reported having concerns about the effect of fire events on their pregnancy. CONCLUSION: Prolonged landscape fire smoke exposure during the 2019/2020 Australian fire period had a significant impact on the health and wellbeing of women with asthma, including pregnant women with asthma. This was despite most women taking actions to minimise exposure to landscape fire smoke. Effective and consistent public health messaging is needed during landscape fire events to guard the health of women with asthma.

Maternal anemia and baby birth size mediate the association between short birth interval and under-five undernutrition in Ethiopia: a generalized structural equation modeling approach.

BACKGROUND: Studies assessing the association between short birth interval, a birth-to-birth interval of less than 33 months, and under-five undernutrition have produced inconclusive results. This study aimed to assess the relationship between short birth interval and outcomes of stunting, underweight, and wasting among children aged under-five in Ethiopia, and potential mediation of any associations by maternal anemia and baby birth size. METHOD: Data from the 2016 Ethiopia Demographic and Health Survey (EDHS) was used. Stunting, wasting, and underweight among children aged under-five were outcome variables. Generalized Structural Equation Modeling (GSEM) was used to examine associations between short birth interval and outcomes, and to assess hypothesized mediation by maternal anemia and baby birth size. RESULTS: Significant associations between short birth interval and stunting (AOR = 1.49; 95% CI = 1.35, 1.66) and underweight (AOR = 1.43; 95% CI = 1.28, 1.61) were found. There was no observed association between short birth interval and wasting (AOR = 1.05; 95% CI = 0.90, 1.23). Maternal anemia and baby birth size had a significant partial mediation effect on the association between short birth interval and stunting (the coefficient reduced from ß = 0.337, p < 0.001 to ß = 0.286, p < 0.001) and underweight (the coefficient reduced from ß = 0.449, p < 0.001 to ß = 0.338, p < 0.001). Maternal anemia and baby birth size mediated 4.2% and 4.6% of the total effect of short birth interval on stunting and underweight, respectively. CONCLUSION: Maternal anemia and baby birth size were identified as mediators of the association between short birth interval and under-five undernutrition status. Policies and programs targeting the reduction of under-five undernutrition should integrate strategies to reduce maternal anemia and small baby birth size in addition to short birth interval.

Socioeconomic status of practice location and Australian GP registrars' training: a cross-sectional analysis.

BACKGROUND: Socioeconomic status (SES) is a major determinant of health. In Australia, areas of socioeconomic disadvantage are characterised by complex health needs and inequity in primary health care provision. General Practice (GP) registrars play an important role in addressing workforce needs, including equitable health care provision in areas of greater socioeconomic disadvantage. We aimed to characterize GP registrars' practice location by level of socioeconomic disadvantage, and establish associations (of registrar, practice, patient characteristics, and registrars' clinical behaviours) with GP registrars training being undertaken in areas of greater socioeconomic disadvantage. METHODS: A cross-sectional analysis from the Registrars' Clinical Encounters in Training (ReCEnT) study. ReCEnT is an ongoing, multi-centre, cohort study that documents 60 consecutive consultations by each GP registrar once in each of their three six-monthly training terms. The outcome factor was the practice location's level of socioeconomic disadvantage, defined using the Index of Relative Socio-economic Disadvantage (SEIFA-IRSD). The odds of being in the lowest quintile was compared to the other four quintiles. Independent variables related to the registrar, patient, practice, and consultation. RESULTS: A total of 1,736 registrars contributed 241,945 consultations. Significant associations of training being in areas of most disadvantage included: the registrar being full-time, being in training term 1, being in the rural training pathway; patients being Aboriginal or Torres Strait Islander, or from a non-English-speaking background; and measures of continuity of care. CONCLUSIONS: Training in areas of greater social disadvantage, as well as addressing community need, may provide GP registrars with richer learning opportunities.

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

Effect of a physical activity and sleep m-health intervention on a composite activity-sleep behaviour score and mental health: a mediation analysis of two randomised controlled trials.

BACKGROUND: To examine if a composite activity-sleep behaviour index (ASI) mediates the effects of a combined physical activity and sleep intervention on symptoms of depression, anxiety, or stress, quality of life (QOL), energy and fatigue in adults. METHODS: This analysis used data pooled from two studies: Synergy and Refresh. Synergy: Physically inactive adults (18-65 years) who reported poor sleep quality were recruited for a two-arm Randomised Controlled Trial (RCT) (Physical Activity and Sleep Health (PAS; n = 80), or Wait-list Control (CON; n = 80) groups). Refresh: Physically inactive adults (40-65 years) who reported poor sleep quality were recruited for a three-arm RCT (PAS (n = 110), Sleep Health-Only (SO; n = 110) or CON (n = 55) groups). The SO group was omitted from this study. The PAS groups received a pedometer, and accessed a smartphone/tablet "app" using behaviour change strategies (e.g., self-monitoring, goal setting, action planning), with additional email/SMS support. The ASI score comprised self-reported moderate-to-vigorous-intensity physical activity, resistance training, sitting time, sleep duration, efficiency, quality and timing. Outcomes were assessed using DASS-21 (depression, anxiety, stress), SF-12 (QOL-physical, QOL-mental) and SF-36 (Energy & Fatigue). Assessments were conducted at baseline, 3 months (primary time-point), and 6 months. Mediation effects were examined using Structural Equation Modelling and the product of coefficients approach (AB), with significance set at 0.05. RESULTS: At 3 months there were no direct intervention effects on mental health, QOL or energy and fatigue (all p > 0.05), and the intervention significantly improved the ASI (all p < 0.05). A more favourable ASI score was associated with improved symptoms of depression, anxiety, stress, QOL-mental and of energy and fatigue (all p < 0.05). The intervention effects on symptoms of depression ([AB; 95%CI] -0.31; - 0.60,-0.11), anxiety (- 0.11; - 0.27,-0.01), stress (- 0.37; - 0.65,-0.174), QOL-mental (0.53; 0.22, 1.01) and ratings of energy and fatigue (0.85; 0.33, 1.63) were mediated by ASI. At 6 months the magnitude of association was larger although the overall pattern of results remained similar. CONCLUSIONS: Improvements in the overall physical activity and sleep behaviours of adults partially mediated the intervention effects on mental health and quality of life outcomes. This highlights the potential benefit of improving the overall pattern of physical activity and sleep on these outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN12617000680369 ; ACTRN12617000376347 . Universal Trial number: U1111-1194-2680; U1111-1186-6588. Human Research Ethics Committee Approval: H-2016-0267; H-2016-0181.

Behavioural mediators of reduced energy intake in a physical activity, diet, and sleep behaviour weight loss intervention in adults.

Reduced energy intake is a major driver of weight loss and evidence suggests that physical activity, dietary, and sleep behaviours interact to influence energy intake. Energy restriction can be challenging to sustain. Therefore to improve intervention efficacy, evaluation of how changes in physical activity, diet, and sleep behaviours mediate reduced energy intake in adults with overweight/obesity who participated in a six-month multiple-behaviour-change weight loss intervention was undertaken. This was a secondary analysis of a 3-arm randomised controlled trial. Adults with body mass index (BMI) 25-40 kg/m2 were randomised to either: a physical activity and diet intervention; physical activity, diet, and sleep intervention; or wait-list control. Physical activity, dietary intake, and sleep was measured at baseline and six-months using validated measures. The two intervention groups were pooled and compared to the control. Structural equation modelling was used to estimate the mediated effects (AB Coefficient) of the intervention on total energy intake. One hundred and sixteen adults (70% female, 44.5y, BMI 31.7 kg/m2) were enrolled and 70% (n = 81) completed the six-month assessment. The significant intervention effect on energy intake at six-months (-1011 kJ/day, 95% CI -1922, -101) was partially mediated by reduced fat intake (AB = -761.12, 95% CI -1564.25, -53.74) and reduced consumption of energy-dense, nutrient-poor foods (AB = -576.19, 95% CI -1189.23, -97.26). In this study, reducing fat intake and consumption of energy-dense, nutrient-poor foods was an effective strategy for reducing daily energy intake in adults with overweight/obesity at six-months. These strategies should be explicitly targeted in future weight loss interventions.

Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Efficacy of an m-Health Physical Activity and Sleep Intervention to Improve Sleep Quality in Middle-Aged Adults: The Refresh Study Randomized Controlled Trial.

BACKGROUND: Poor sleep health is highly prevalent. Physical activity is known to improve sleep quality but not specifically targeted in sleep interventions. PURPOSE: To compare the efficacy of a combined physical activity and sleep intervention with a sleep-only intervention and a wait-list control, for improving sleep quality in middle-aged adults without a diagnosed sleep disorder. METHODS: Three-arm randomized controlled trial (Physical Activity and Sleep Health (PAS), Sleep Health Only (SO), Wait-list Control (CON) groups; 3-month primary time-point, 6-month follow-up) of 275 (PAS = 110, SO = 110, CON = 55) inactive adults (40-65 years) reporting poor sleep quality. The main intervention component was a smartphone/tablet "app" to aid goal setting and self-monitoring physical activity and/or sleep hygiene behaviors (including stress management), and a pedometer for PAS group. Primary outcome was Pittsburgh Sleep Quality Index (PSQI) global score. Secondary outcomes included several self-reported physical activity measures and PSQI subcomponents. Group differences were examined stepwise, first between pooled intervention (PI = PAS + SO) and CON groups, then between PAS and SO groups. RESULTS: Compared with CON, PI groups significantly improved PSQI global and subcomponents scores at 3 and 6 months. There were no differences in sleep quality between PAS and SO groups. The PAS group reported significantly less daily sitting time at 3 months and was significantly more likely to report ≥2 days/week resistance training and meeting physical activity guidelines at 6 months than the SO group. CONCLUSIONS: PIs had statistically significantly improved sleep quality among middle-aged adults with poor sleep quality without a diagnosed sleep disorder. The adjunctive physical activity intervention did not additionally improve sleep quality. CLINICAL TRIAL INFORMATION: Australian New Zealand Clinical Trial Registry: ACTRN12617000680369; Universal Trial number: U1111-1194-2680; Human Research Ethics Committee, Blinded by request of journal: H-2016-0267.

Socioeconomic inequality in short birth interval in Ethiopia: a decomposition analysis.

BACKGROUND: Short birth interval, defined as a birth-to-birth interval less than 33 months, is associated with adverse maternal and child outcomes. Evidence regarding the association of maternal socioeconomic status and short birth interval is inconclusive. Factors contributing to the socioeconomic inequality of short birth interval have also not been investigated. The current study assessed socioeconomic inequality in short birth interval and its contributing factors in Ethiopia. METHODS: Data from 8448 women collected in the 2016 Ethiopia Demographic and Health survey were included in the study. Socioeconomic inequality in short birth interval was the outcome variable. Erreygers normalized concentration index (ECI) and concentration curves were used to measure and illustrate socioeconomic-related inequality in short birth interval, respectively. Decomposition analysis was performed to identify factors explaining the socioeconomic-related inequality in short birth interval. RESULTS: The Erreygers normalized concentration index for short birth interval was - 0.0478 (SE = 0.0062) and differed significantly from zero (P < 0.0001); indicating that short birth interval was more concentrated among the poor. Decomposition analysis indicated that wealth quintiles (74.2%), administrative regions (26.4%), and not listening to the radio (5.6%) were the major contributors to the pro-poor socioeconomic inequalities in short birth interval. CONCLUSION: There was a pro-poor inequality of short birth interval in Ethiopia. Strengthening the implementation of poverty alleviation programs may improve the population's socioeconomic status and reduce the associated inequality in short birth interval.

Common coding variant in SERPINA1 increases the risk for large artery stroke.

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.

Time-efficient intervention to improve older adolescents' cardiorespiratory fitness: findings from the 'Burn 2 Learn' cluster randomised controlled trial.

BACKGROUND: Cardiorespiratory fitness (CRF) is an important marker of current and future health status. The primary aim of our study was to evaluate the impact of a time-efficient school-based intervention on older adolescents' CRF. METHODS: Two-arm cluster randomised controlled trial conducted in two cohorts (February 2018 to February 2019 and February 2019 to February 2020) in New South Wales, Australia. Participants (N=670, 44.6% women, 16.0±0.43 years) from 20 secondary schools: 10 schools (337 participants) were randomised to the Burn 2 Learn (B2L) intervention and 10 schools (333 participants) to the control. Teachers in schools allocated to the B2L intervention were provided with training, resources, and support to facilitate the delivery of high-intensity interval training (HIIT) activity breaks during curriculum time. Teachers and students in the control group continued their usual practice. The primary outcome was CRF (20 m multi-stage fitness test). Secondary outcomes were muscular fitness, physical activity, hair cortisol concentrations, mental health and cognitive function. Outcomes were assessed at baseline, 6 months (primary end-point) and 12 months. Effects were estimated using mixed models accounting for clustering. RESULTS: We observed a group-by-time effect for CRF (difference=4.1 laps, 95% CI 1.8 to 6.4) at the primary end-point (6 months), but not at 12 months. At 6 months, group-by-time effects were found for muscular fitness, steps during school hours and cortisol. CONCLUSIONS: Implementing HIIT during curricular time improved adolescents' CRF and several secondary outcomes. Our findings suggest B2L is unlikely to be an effective approach unless teachers embed sessions within the school day. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618000293268).

Configurations for obtaining in-consultation assistance from supervisors in general practice training, and patient-related barriers to trainee help-seeking: a survey study.

BACKGROUND: General practice (GP) trainees may seek supervisor assistance to complete their patient consultations. This in-consultation assistance plays a key role in the supervisory oversight of trainees and in trainee learning. It may be obtained face-to-face, or using phone or messaging systems, and either in front of patients or outside their hearing. Trainee concerns about decreased patient impressions of their competence, and discomfort presenting patients within their hearing, act as barriers to seeking help during consultations. Little is known about the frequency and associations of trainee concerns about these patient-related barriers, or the various trainee-supervisor-patient configurations used to obtain in-consultation assistance. METHODS: Australian GP trainees rated their frequency of use of five specific configurations for obtaining in-consultation assistance, perceived change in patient impressions of their competence after this assistance, and relative trainee comfort presenting patients outside, compared to within, patients' hearing. Statistical analyses included descriptive statistics and multivariable logistic regression. RESULTS: Responses were received from 778 Australian GP trainees (response rate 89%). Help-seeking configurations did not differ between trainees at different training stages, except for greater use of electronic messaging in later stages. In-consultation assistance was most commonly provided by phone between trainee and supervisor consulting rooms, or outside the trainee's patient's hearing. Supervisor assistance in the trainee's room face-to-face with the patient was reported as either never or rarely obtained by 12% of respondents. More trainees (25%) perceived that patient impressions of their competence increased after help-seeking than perceived that these impressions decreased (19%). Most trainees (55%) preferred to present patients outside their hearing. Trainee age was the only variable associated with both patient-related barriers. CONCLUSION: Supervisors appear to have considerable influence over trainee help-seeking, including which configurations are used and trainee perceptions of patient-related barriers. In-consultation supervision may actually increase trainee perceptions of patient impressions of their competence. Many supervisors and trainees may benefit from additional educational and workplace interventions to facilitate comfortable and effective trainee help-seeking in front of patients. More work is required to understand the clinical and educational implications of different help-seeking configurations when trainees require 'just in time' supervisor assistance.

Australian general practice registrars and their experience with postpartum consultations: A cross-sectional analysis of prevalence and associations.

BACKGROUND: In Australia, general practitioners (GPs) are recognised as an essential source of postpartum care. However, there remains a paucity of research pertaining to this, and in particular, to that of GP trainees (in Australia, termed 'registrars'). Previous post-graduate experience in obstetrics and gynaecology (O&G) is not a prerequisite for GP training, and thus, it is imperative that vocational training provides adequate exposure to postpartum consultations. AIM: To investigate the prevalence and associations of Australian GP registrars' (trainees') experience in postpartum care. MATERIALS AND METHODS: A cross-sectional study employing data from the Registrar Clinical Encounters in Training (ReCEnT) project. ReCEnT is an ongoing cohort study where GP registrars record 60 consecutive consultations mid-way through each training term. The outcome variable was postpartum problem/diagnosis (compared to all other problems/diagnoses). The independent variables included registrar, practice, patient, consultation, clinical and educational factors. Analyses employed univariate and multivariable regression. RESULTS: Analysis included 2234 registrars (response rate 96.1%), 289 594 consultations, and 453 786 problems/diagnoses. Postpartum care (897) comprised 0.2% (95% CI: 0.19-0.21) of all problems/diagnoses in 0.3% (95% CI: 0.27-0.31) of all consultations. Significant multivariable associations included registrar's gender (female) and obtainment of post-graduate O&G qualifications. Postpartum consultations were longer and resulted in more learning goals being generated. DISCUSSION: An overall low prevalence was established. Both male registrars, and those without pre-existing O&G qualifications, may have particularly limited experience. These findings should inform educational policy and practice regarding postpartum care experience in general practice training.

General practice registrars' experiences of antenatal care: A cross-sectional analysis.

BACKGROUND: General practitioners play an important role in diagnosis and ongoing management of pregnancies. Some GP registrars entering GP training may have had no post-graduate experience in obstetrics and gynaecology. GP registrars' involvement in antenatal care is under-researched. AIMS: This study aimed to determine the prevalence and associations of Australian GP registrars' clinical consultations involving antenatal care. MATERIALS AND METHODS: A cross-sectional analysis from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. GP registrars record details of 60 consecutive consultations during each of three six-month training terms. Associations of managing pregnancy-related problems (compared to all other problems) were analysed using univariate and multivariable logistic regression. Independent variables included registrar, practice, patient, consultation and educational factors. RESULTS: Antenatal care comprised 3277 (1.1%) of registrar problems/diagnoses. Consultations involving pregnancy-related problems were significantly associated with registrars being female, in term three, younger, and having post-graduate qualifications in obstetrics/gynaecology. Patients were significantly more likely to be from a non-English speaking background. Pregnancy-related problems/diagnoses were more likely to be seen in lower socioeconomic areas. Consultation factors significantly associated with a pregnancy-related problem/diagnosis included ordering imaging, ordering pathology, arranging referrals, and a longer duration of consultation. Registrars were less likely to prescribe medication or generate learning goals. CONCLUSIONS: GP registrars see fewer antenatal problems compared to established GPs. Male registrars, especially, have significantly less exposure to antenatal care, suggesting potential limitation of opportunity to gain skills and experience in antenatal care.