National Health Council Research Articles

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial

The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Is there an optimal window of time for transferring single frozen-thawed euploid blastocysts? A cohort study of 1170 embryo transfers.

Is there an optimal window of time when the transfer of single frozen-thawed euploid blastocysts is associated with a maximal live birth rate (LBR)? Performing a single frozen-thawed euploid blastocyst transfer at 160 ± 4 h post-hCG trigger in modified-natural frozen-thawed embryo transfer (FET) cycles was independently associated with a higher LBR as compared to transfers outside this window; however, in natural FET cycles, LBRs were comparable across a wider range of time intervals. There is compelling evidence for maintaining embryo-endometrial synchrony to optimize clinical outcomes following FETs, which could potentially be achieved by matching the transfer time of an embryo post-ovulation to its developmental age post-oocyte retrieval. For modified-natural cycles, ovulation is widely accepted to occur ∼40 h following the hCG trigger, whilst ovulation following spontaneous LH surge onset is thought to vary from 24 to 56 h. This is a multicentered retrospective cohort study analyzing 1170 single frozen-thawed euploid blastocyst transfers following trophectoderm biopsy and preimplantation genetic testing (PGT) between May 2015 and February 2019. Limiting the analysis to single euploid embryo transfers allowed for a more accurate estimation of the endometrial synchrony factor by controlling for the developmental stage of the embryo (full blastocyst or more advanced) and its genetic composition. LBR per FET was the primary outcome measure. Patients underwent natural or gonadotrophin-induced preparation of the endometrium, with serial serum oestradiol, LH and progesterone measurements. Optimally timed transfers were predefined as those conducted 120 ± 4 h post-ovulation since biopsy and subsequent cryopreservation of full blastocysts which is usually performed at 116-124 h post-oocyte retrieval. This was considered the equivalent of 160 ± 4 h post-hCG trigger in modified-natural cycles (n = 253), as ovulation was assumed to occur ∼40 h after the hCG trigger. For natural cycles (n = 917), this was also considered to be, on average, 160 ± 4 h post the spontaneous LH surge. Thus, study groups were determined as those with optimal timing or not, and additional exploratory and subgroup analyses were performed, varying the time window in terms of onset and width, both overall and per endometrial preparation protocol. Statistical analysis was performed using the generalized estimating equations (GEE) framework to control for the clustered nature of the data while adjusting for potential confounders. Overall, LBRs were significantly higher when the transfer had been performed at 160 ± 4 h post-hCG trigger or LH surge onset compared to when it had been performed outside this window (44.7% vs 36.0%; P = 0.008). A multivariable regression GEE model including the cycle type (natural versus modified-natural), previtrification embryo quality (top versus good quality), embryo stage (fully hatched versus hatching or earlier blastocyst), vitrification day (D5 versus D6) and survival rate (>90% versus <90%) as covariates, confirmed that, overall, embryo transfers conducted 160 ± 4 h post-hCG trigger or LH surge onset (the assumed equivalent of 120 ± 4 h post-ovulation) were associated with a significantly higher LBR (relative risk (RR) 1.21, 95% CI 1.04-1.41). Subgroup exploratory analyses per endometrial preparation protocol demonstrated that these findings were primarily present in the modified-natural cycle group (RR 1.52, 95% CI 1.15-1.99), whilst the natural cycle group showed comparable LBRs across a wider range of time intervals. Moreover, the overall LBR for the natural group (36.8%; 95% CI 33.7-39.9%) was lower than that of the modified-natural group (41.3%; 95% CI 35.4-47.1%), suggesting that there likely remains a greater potential to further optimize the timing of natural cycle embryo transfers. As with all retrospective studies, the presence of residual unknown bias cannot be excluded. Additionally, patients included in this study were a selected group who underwent PGT for specific reasons and hence the results obtained might not be directly applicable to the general population or embryos that have not undergone embryo biopsy. Furthermore, the criteria utilized to interpret hormonal data from natural cycles were specifically adopted for the present study and need to be validated in further studies. The results of this study highlight the significance of embryo-endometrial synchrony for the optimization of frozen embryo transfer outcome. However, it also clearly supports that the implantation window is in most cases wide and the achievement of live birth is possible with relatively high success rates even outside the optimal window of 160 ± 4 h post-trigger for modified-natural cycles and across a range of time intervals for natural cycles. Additionally, this study suggests that implantation rates could be further optimized in natural cycles by improving methods of assessing embryo-endometrial synchrony. C. V. is supported by a National Health and Medical Research Council Early Career Fellowship (GNT1147154). No other funding was received for this study and there are no competing interests. N/A.

Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years

BackgroundDocosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks’ gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood.MethodsWe assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks’ gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI.ResultsA total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available — 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P=0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups.ConclusionsIn infants born before 29 weeks’ gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.)

The 2022 report of the MJA-Lancet Countdown on health and climate change: Australia unprepared and paying the price.

The MJA-Lancet Countdown on health and climate change in Australia was established in 2017 and produced its first national assessment in 2018 and annual updates in 2019, 2020 and 2021. It examines five broad domains: climate change impacts, exposures and vulnerability; adaptation, planning and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. In this, the fifth year of the MJA-Lancet Countdown, we track progress on an extensive suite of indicators across these five domains, accessing and presenting the latest data and further refining and developing our analyses. Within just two years, Australia has experienced two unprecedented national catastrophes - the 2019-2020 summer heatwaves and bushfires and the 2021-2022 torrential rains and flooding. Such events are costing lives and displacing tens of thousands of people. Further, our analysis shows that there are clear signs that Australia's health emergency management capacity substantially decreased in 2021. We find some signs of progress with respect to health and climate change. The states continue to lead the way in health and climate change adaptation planning, with the Victorian plan being published in early 2022. At the national level, we note progress in health and climate change research funding by the National Health and Medical Research Council. We now also see an acceleration in the uptake of electric vehicles and continued uptake of and employment in renewable energy. However, we also find Australia's transition to renewables and zero carbon remains unacceptably slow, and the Australian Government's continuing failure to produce a national climate change and health adaptation plan places the health and lives of Australians at unnecessary risk today, which does not bode well for the future.

Vitamin D Deficiency Increases Mortality Risk in the UK Biobank : A Nonlinear Mendelian Randomization Study.

Low vitamin D status is associated with increased mortality, but randomized trials on severely deficient participants are lacking. To assess genetic evidence for the causal role of low vitamin D status in mortality. Nonlinear Mendelian randomization analyses. UK Biobank, a large-scale, prospective cohort from England, Scotland, and Wales with participants recruited between March 2006 and July 2010. 307 601 unrelated UK Biobank participants of White European ancestry (aged 37 to 73 years at recruitment) with available measurements of 25-hydroxyvitamin D (25-(OH)D) and genetic data. Genetically predicted 25-(OH)D was estimated using 35 confirmed variants of 25-(OH)D. All-cause and cause-specific mortality (cardiovascular disease [CVD], cancer, and respiratory) were recorded up to June 2020. There were 18 700 deaths during the 14 years of follow-up. The association of genetically predicted 25-(OH)D with all-cause mortality was L-shaped (P for nonlinearity < 0.001), and risk for death decreased steeply with increasing concentrations until 50 nmol/L. Evidence for an association was also seen in analyses of mortality from cancer, CVD, and respiratory diseases (P ≤ 0.033 for all outcomes). Odds of all-cause mortality in the genetic analysis were estimated to increase by 25% (odds ratio, 1.25 [95% CI, 1.16 to 1.35]) for participants with a measured 25-(OH)D concentration of 25 nmol/L compared with 50 nmol/L. Analyses were restricted to a White European population. A genetic approach is best suited to providing proof of principle on causality, whereas the strength of the association is approximate. Our study supports a causal relationship between vitamin D deficiency and mortality. Additional research needs to identify strategies that meet the National Academy of Medicine's guideline of greater than 50 nmol/L and that reduce the premature risk for death associated with low vitamin D levels. National Health and Medical Research Council.

Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

SummaryBackgroundWell tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes.MethodsPeople with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety.FindingsBetween 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms.InterpretationFavipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection.FundingThe study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Associations between social connections and cognition: a global collaborative individual participant data meta-analysis

Poor social connections (eg, small networks, infrequent interactions, and loneliness) are modifiable risk factors for cognitive decline. Existing meta-analyses are limited by reporting aggregate responses, a focus on global cognition, and combining social measures into single constructs. We aimed to investigate the association between social connection markers and the rate of annual change in cognition (ie, global and domain-specific), as well as sex differences, using an individual participant data meta-analysis. We harmonised data from 13 longitudinal cohort studies of ageing in North America, South America, Europe, Africa, Asia, and Australia. Studies were eligible for inclusion if they had baseline data for social connection markers and at least two waves of cognitive scores. Follow-up periods ranged from 0 years to 15 years across cohorts. We included participants with cognitive data for at least two waves and social connection data for at least one wave. We then identified and excluded people with dementia at baseline. Primary outcomes were annual rates of change in global cognition and cognitive domain scores over time until final follow-up within each cohort study analysed by use of an individual participant data meta-analysis. Linear mixed models within cohorts used baseline social connection markers as predictors of the primary outcomes. Effects were pooled in two stages using random-effects meta-analyses. We assessed the primary outcomes in the main (partially adjusted) and fully adjusted models. Partially adjusted models controlled for age, sex, and education; fully adjusted models additionally controlled for diabetes, hypertension, smoking, cardiovascular risk, and depression. Of the 40 006 participants in the 13 cohort studies, we excluded 1392 people with dementia at baseline. 38 614 individual participants were included in our analyses. For the main models, being in a relationship or married predicted slower global cognitive decline (b=0·010, 95% CI 0·000-0·019) than did being single or never married; living with others predicted slower global cognitive (b=0·007, 0·002-0·012), memory (b=0·017, 0·006-0·028), and language (b=0·008, 0·000-0·015) decline than did living alone; and weekly interactions with family and friends (b=0·016, 0·006-0·026) and weekly community group engagement (b=0·030, 0·007-0·052) predicted slower memory decline than did no interactions and no engagement. Never feeling lonely predicted slower global cognitive (b=0·047, 95% CI 0·018-0·075) and executive function (b=0·047, 0·017-0·077) decline than did often feeling lonely. Degree of social support, having a confidante, and relationship satisfaction did not predict cognitive decline across global cognition or cognitive domains. Heterogeneity was low (I2=0·00-15·11%) for all but two of the significant findings (association between slower memory decline and living with others [I2=58·33%] and community group engagement, I2=37·54-72·19%), suggesting robust results across studies. Good social connections (ie, living with others, weekly community group engagement, interacting weekly with family and friends, and never feeling lonely) are associated with slower cognitive decline. EU Joint Programme-Neurodegenerative Disease Research grant, funded by the National Health and Medical Research Council Australia, and the US National Institute on Aging of the US National Institutes of Health.

Interventions to prevent obesity in school-aged children 6-18 years: An update of a Cochrane systematic review and meta-analysis including studies from 2015-2021.

BackgroundChildhood obesity remains a global public health priority due to the enormous burden it generates. Recent surveillance data suggests there has been a sharp increase in the prevalence of childhood obesity during the COVID-19 pandemic. The Cochrane review of childhood obesity prevention interventions (0–18 years) updated to 2015 is the most rigorous and comprehensive review of randomised controlled trials (RCTs) on this topic. A burgeoning number of high quality studies have been published since that are yet to be synthesised.MethodsAn update of the Cochrane systematic review was conducted to include RCT studies in school-aged children (6-18 years) published to 30 June 2021 that assessed effectiveness on child weight (PROSPERO registration: CRD42020218928). Available cost-effectiveness and adverse effect data were extracted. Intervention effects on body mass index (BMI) were synthesised in random effects meta-analyses by setting (school, after-school program, community, home), and meta-regression examined the association of study characteristics with intervention effect.FindingsMeta-analysis of 140 of 195 included studies (183,063 participants) found a very small positive effect on body mass index for school-based studies (SMD –0·03, 95%CI –0·06,–0·01; trials = 93; participants = 131,443; moderate certainty evidence) but not after-school programs, community or home-based studies. Subgroup analysis by age (6–12 years; 13–18 years) found no differential effects in any setting. Meta-regression found no associations between study characteristics (including setting, income level) and intervention effect. Ten of 53 studies assessing adverse effects reported presence of an adverse event. Insufficient data was available to draw conclusions on cost-effectiveness.InterpretationThis updated synthesis of obesity prevention interventions for children aged 6–18 years, found a small beneficial impact on child BMI for school-based obesity prevention interventions. A more comprehensive assessment of interventions is required to identify mechanisms of effective interventions to inform future obesity prevention public health policy, which may be particularly salient in for COVID-19 recovery planning.FundingThis research was funded by the National Health and Medical Research Council (NHMRC), Australia (Application No APP1153479).

Lifetime spirometry patterns of obstruction and restriction, and their risk factors and outcomes: a prospective cohort study

Interest in lifetime lung function trajectories has increased in the context of emerging evidence that chronic obstructive pulmonary disease (COPD) can arise from multiple disadvantaged lung function pathways, including those that stem from poor lung function in childhood. To our knowledge, no previous study has investigated both obstructive and restrictive lifetime patterns concurrently, while accounting for potential overlaps between them. We aimed to investigate lifetime trajectories of the FEV1/forced vital capacity (FVC) ratio, FVC, and their combinations, relate these combined trajectory groups to static lung volume and gas transfer measurements, and investigate both risk factors for and consequences of these combined trajectory groups. Using z scores from spirometry measured at ages 7, 13, 18, 45, 50, and 53 years in the Tasmanian Longitudinal Health Study (n=2422), we identified six FEV1/FVC ratio trajectories and five FVC trajectories via group-based trajectory modelling. Based on whether trajectories of the FEV1/FVC ratio and FVC were low (ie, low from childhood or adulthood) or normal, four patterns of lifetime spirometry obstruction or restriction were identified and compared against static lung volumes and gas transfer. Childhood and adulthood characteristics and morbidities of these patterns were investigated. The prevalence of the four lifetime spirometry patterns was as follows: low FEV1/FVC ratio only, labelled as obstructive-only, 25·8%; low FVC only, labelled as restrictive-only, 10·5%; both low FEV1/FVC ratio and low FVC, labelled as mixed, 3·5%; and neither low FEV1/FVC ratio nor low FVC, labelled as reference, 60·2%. The prevalence of COPD at age 53 years was highest in the mixed pattern (31 [37%] of 84 individuals) followed by the obstructive-only pattern (135 [22%] of 626 individuals). Individuals with the mixed pattern also had the highest prevalence of parental asthma, childhood respiratory illnesses, adult asthma, and depression. Individuals with the restrictive-only pattern had lower total lung capacity and residual volume, and had the highest prevalence of childhood underweight, adult obesity, diabetes, cardiovascular conditions, hypertension, and obstructive sleep apnoea. To our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEV1/FVC ratio and FVC from childhood to middle age. Mixed and obstructive-only patterns indicate those who might benefit from early COPD interventions. Those with the restrictive-only pattern had evidence of true lung restriction and were at increased risk of multimorbidity by middle age. National Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.

Evaluation of premenstrual syndrome and its relationship with changes in food consumption during the luteal phase in a university center in northwest paulista: a prospective observational cross-sectional study

Introduction: The menstrual cycle is a natural phenomenon that occurs in two phases: follicular and luteal. Several hormonal, physical and psychological changes occur during this period, which influence the female diet. These changes and consequences are felt mainly in the luteal phase, that is between 1 to 5 days before the menstrual flow, characterizing the premenstrual syndrome (PMS) or premenstrual tension (PMS). Objective: This article aims to evaluate food intake and dietary changes in adult women of reproductive age during the luteal phase of the menstrual cycle. Methods: Quali-quantitative descriptive exploratory study, carried out with 207 female students, between 18 and 41 years of age, from all courses at a University Center in northwestern São Paulo. An online questionnaire was applied via Google Forms with closed and open questions that characterized the sample regarding the participants' personal and dietary aspects in the luteal phase. The work complied with Resolution 466/12 of the National Health Council and was approved by the Ethics Committee and all participants signed the Informed Consent Term. Results: It was observed that there was a predominance of women aged between 19 and 22 years (64.25%). With regard to physical symptoms in the luteal phase, 95.65% of women reported having at least one symptom, such as swollen and/or painful breasts (67.7%) and colic (55.1%). Regarding the intensity of food craving, 5.3% of the women reported no changes, 10.6% had low intensity (mild), 50.7% had moderate intensity, 27.5% had high intensity (high) and 5, 8% very high intensity (severe). According to the change in dietary pattern, among the foods presented, 85% of the participants claimed to have a higher consumption of sugars and sweets during this period and 38.6% higher consumption of carbohydrates, representing most of the responses collected. It was found that food cravings among the participants occurred with high frequency in 91.78% of the cases, with emphasis on the high craving for sweets (87%) and fast food (33.8%). The increase in food consumption in the luteal phase was significant, as it was present in 70.5% of women. Conclusion: The luteal phase interferes with the pattern and intensity of food craving, as well as with the increased intake of macronutrients, especially carbohydrates, sugars and sweets.

Serum lipid traits and the risk of dementia: A cohort study of 254,575 women and 214,891 men in the UK Biobank.

SummaryBackgroundSerum lipid traits are associated with cardiovascular disease, but uncertainty remains regarding their associations with dementia.MethodsFrom 2006 to 2010, 254,575 women and 214,891 men were included from the UK Biobank. Cox regression estimated overall and sex-specific hazard ratios (HRs) for apolipoprotein A (ApoA), apolipoprotein B (ApoB), HDL, LDL, total cholesterol, triglycerides, lipoprotein A, and various lipid ratios, by quarters and standard deviation (SD) higher, associated with all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD). Subgroup analyses by age and social deprivation were conducted.FindingsOver 11·8 years (median), 3734 all-cause dementia (1,716 women), 1231 AD and 929 VaD were recorded. Compared to respective lowest quarters, highest quarter of ApoA was associated with lower dementia risk (HR, [95% confidence interval (95% CI)]: 0·77 [0·69, 0·86]) while the highest quarter of ApoB was associated with greater risk (HR, 1·12 [1·01, 1·24]). Higher HDL/ApoA and ApoB/ApoA, were associated with greater risk of dementia (HR, 1·12 [1·00, 1·25], per standard deviation (SD), 1.23 [1·11, 1·37], per SD, respectively), LDL/ApoB was inversely associated (HR, 0·85 [0·76, 0·94], per SD. Higher triglycerides was associated with higher dementia risk in <60 years, but the inverse was observed for ≥60 years. Similar associations were observed for VaD and AD.InterpretationApolipoproteins, and their ratios, were associated with the risk of dementia. It may be prudent to consider apolipoproteins, along with circulating cholesterol, when assessing dementia risk.FundingUniversity of New South Wales, UK Medical Research Council, and the Australian National Health and Medical Research Council.

Systematic review of the effect of additional doses of oral rotavirus vaccine on immunogenicity and reduction in diarrhoeal disease among young children.

SummaryBackgroundOral rotavirus vaccines have lower effectiveness in high child mortality settings. We evaluated the impact of additional dose(s) schedules of rotavirus vaccine on vaccine immunogenicity and reduction in episodes of gastroenteritis.MethodsWe searched Medline (via PubMed), Cochrane databases and ClinicalTrials.gov for randomised controlled trials from 1973 to February 2022, evaluating the immunological and clinical impact of additional dose vs standard dose oral rotavirus vaccine schedules. We extracted immunogenicity – proportion of children with evidence of anti-rotavirus IgA seroresponse, and clinical – proportion of children with at least one episode of severe rotavirus gastroenteritis, outcome data and used random effects meta-analysis where appropriate. We assessed the methodological quality of the studies using the Cochrane risk of bias tool. The study protocol was registered in PROSPERO (CRD42021261058).FindingsWe screened 536 items and included 7 clinical trials. Our results suggest moderate to high level evidence that an additional dose rotavirus vaccine schedule improves IgA vaccine immune response, including additional doses administered as a booster dose schedule >6 months old; IgA vaccine seroresponse 74·3% additional dose schedule vs 56·1% standard dose schedule RR 1·3 (95%CI, 1·15 – 1·48), and when administered to children who were seronegative at baseline; IgA vaccine seroresponse 48.2% additional dose schedule vs 29.6% standard dose schedule RR 1.86 (95%CI 1.27 to 2.72). Only one study evaluated reduction in gastroenteritis episodes and found little benefit in first year of life, 1·8% vs 2·0% RR 0·88 (95% CI, 0·52 to 1·48), or second year of life, 1·7% vs 2·9% RR 0·62 (95%CI, 0·31 – 1·23).InterpretationAdministering an additional dose of oral rotavirus vaccines is likely to result in an improved vaccine immune response, including when administered as a booster dose to older children. Evidence of an impact on diarrhoeal disease is needed before additional dose rotavirus vaccine schedules can be recommended as vaccine policy.FundingBM was funded by the National Health and Medical Research Council, the Royal Australasian College of Physicians Paediatrics and Child Health Division, and the Australian Academy of Science.

Phenotyping patients with aortic stenosis using cluster analysis to determine mortality and suitability for transcatheter aortic valve replacement

Abstract Background Current classification of aortic stenosis (AS) is based on guideline-recommended echocardiographic criteria. Heterogeneity of patients with AS is increasingly recognised. Clinical and demographic factors in addition to echocardiographic parameters can determine those who may derive the greatest benefit from transcatheter aortic valvular replacement (TAVR) and influence patient outcomes. Purpose Our study aims to define distinct AS echocardiographic and clinical phenotypes and to accurately identify patients most likely to die or benefit from TAVR. Methods Patients diagnosed with at least mild AS between 2009 and 2021 (pre-TAVR) from a multicentre echocardiographic database at a quaternary referral centre included. Unsupervised clustering analysis was performed using K-means, partitioning around medoids, density-based spatial clustering, hierarchical clustering algorithms on 56 demographic, echocardiographic and clinical variables. Associations between AS clusters and clinical outcomes (all-cause mortality, cardiovascular death, AS-related death), and effect of TAVR on clinical outcomes were assessed using Cox proportional hazards models. Results Four AS clusters were identified amongst 2,456 patients with median follow up of 4.7 years (median age: 77 years, male: 66%). Cluster 1 (n=542) had the lowest aortic valvular area (AVA, mean 0.89 cm2), highest peak velocity (Vmax) (4.3 m/s), mean gradient (45 mmHg), and the most bicuspid valves (12.7%). Cluster 2 (n=827) had 50% women, mostly in sinus rhythm and less severe echo findings. Cluster 3 (n=592) had predominantly males (85%) with a mean AVA of 1.65 cm2 and the most cardiovascular risk factors (hypertension, diabetes, hyperlipidaemia, stable angina, acute coronary syndrome, and atherosclerosis). Cluster 4 (n=495) had the highest left atrial size (mean 32 cm2), the most atrial fibrillation (82%), heart failure (80%), rheumatic heart disease (26%) and chronic kidney disease (55.8%), but only moderate AS (AVA 1.3 cm2, Vmax 3 m/s). All-cause mortality was highest in Cluster 4 (Hazard ratio (HR) 1.57, 95% CI: 1.33–1.85) and AS-related death was highest in Cluster 1 (HR 3.96, 95% CI: 2.61–5.99, Figure 1A). TAVR reduced AS-related death in only Cluster 1 (HR 0.22, 95% CI: 0.05–0.88, p=0.033, Figure 1B). Conclusions We demonstrated that phenotypic classification via a combination of demographics, echocardiography and comorbidities can significantly improve management of AS. This personalised approach can be implemented to identify patients most likely to die and most likely to benefit from TAVR. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of Australia (ID: 102578)National Health and Medical Research Council of Australia (ID: 1191044)

Stakeholder perception of pharmaceutical value: A multicriteria decision analysis pilot case study for value assessment in the United States.

BACKGROUND: Recent attention to value frameworks has highlighted limitations of current conventional value and health technology assessment (V/HTA) methods (eg, cost-effectiveness). Multicriteria decision analysis (MCDA) has potential as a supplemental tool to incorporate additional value criteria into conventional value assessment. OBJECTIVE: To conduct a pilot study to illustrate the impact of an MCDA approach on the value perceptions of hypothetical treatment profiles from a multistakeholder panel. METHODS: Participants voted on value perceptions of 2 hypothetical treatments with similar cost-effectiveness evidence: Treatment A for aggressive B-cell non-Hodgkin lymphoma in adults and treatment B for episodic migraine in adults. Participants voted treatments A and B as low, intermediate, or high value before and after a weighting exercise on prespecified, additional value criteria. Weights from participants were used to calculate treatment-specific MCDA scores from 0 (least favorable) to 100 (most favorable) and were presented to participants for a second value-perception vote. Analyses compared changes in value perceptions within treatments A and B post-MCDA exercise. RESULTS: Before considering MCDA scores for treatment A, 0% of participants considered it to be low, 52% intermediate, and 48% high value. After considering MCDA scores for treatment A, 4% considered it low, 29% intermediate, and 67% high value. Both before and after considering MCDA scores for treatment B, 13%, considered it low, 57% intermediate, and 30% high value. Mean MCDA scores for treatments A and B were 67 and 63, respectively. Of all stakeholders, 41% altered their perception of value for treatment A (9% negatively and 32% positively) and, separately, 45% for treatment B (23% both negatively and positively) after considering MCDA scores. CONCLUSIONS: With nearly half of participants altering their perception of value after consideration of additional value criteria, findings support the need for a more inclusive and flexible value assessment process. DISCLOSURES: This study was funded by The National Pharmaceutical Council. Dr Perfetto was employed by the National Health Council (NHC) at the time this work was completed, and all honoraria and consulting and travel fees were paid to the NHC. The NHC is a not-for-profit, membership organization. It is supported through membership dues and sponsorship funds. The complete list of members and sponsors is located on the NHC's website at www.nationalhealthcouncil.org. She is also an advisor for the Brain Injury Association of America, Dan Lewis Foundation, and Canter for Medical Technology Policy.

Healthy Environments and Lives (HEAL): Australian research network in human health and environmental change

BackgroundThe HEAL Network aims to strengthen the Australian health system and community resilience to climate change, extreme events, and environmental degradation. This resilience is achieved by stimulating collaborative research that will improve our understanding of the interactions between climate, the natural and built environment, public health, and the benefits and trade-offs of adaptation and mitigation action aiming to reduce the health impacts of environmental change. HEAL is embedding systematic codesign processes with First Nations people on environmental change preparedness, capacity and capability building, and mitigation and adaptation solutions. MethodsHEAL is addressing capacity and capability gaps in human health, climate and environmental change, and credibility gaps in interactions between policy makers, practitioners, industry, and communities. The HEAL Network is regionally distributed and includes multiple communities of practice, comprising researchers, environmental and health practitioners, community organisations, and policy makers. On the basis of initial gap analyses and stakeholder consultations, we have established ten interdisciplinary research themes (Indigenous knowledge systems; data and decision support systems; science communication; health system resilience; bushfires and extreme events; food, soil, and water security; biosecurity and emerging infectious diseases; urban health; rural and remote health; and at-risk populations and life course solutions) and a range of research capacity and capability strengthening activities that will support investigators, local services and communities. FindingsThe HEAL Network is developing the skills needed to formulate priorities, codesign projects, and translate and implement research findings into policy and practice. New interdisciplinary collaborations emerging from HEAL have led to development of participatory action research, such as facilitating Aboriginal community-led climate adaptation plans based on traditional knowledge and environmental, climate, and health data. InterpretationHEAL identifies evidence gaps and prioritises research capacity and capability needs and local action with community-led codesign of environmental change adaptation and mitigation solutions. This network and related programme of work will lead to more effective national, regional, and local policies to protect and improve planetary health and reduce inequities within and across communities and generations. FundingThe HEAL National Research Network has been awarded funding from the Australian Government National Health and Medical Research Council Special Initiative in Human Health and Environmental Change.

Is the Australian primary healthcare system ready for the Rheumatic Heart Disease Endgame strategy? Data synthesis and recommendations

Is the Australian primary healthcare system ready for the Rheumatic Heart Disease Endgame strategy? Data synthesis and recommendations

The metabolic health of young men conceived using intracytoplasmic sperm injection.

Is the metabolic health of men conceived using ICSI different to that of IVF and spontaneously conceived (SC) men? ICSI-conceived men aged 18-24 years, compared with SC controls, showed differences in some metabolic parameters including higher resting diastolic blood pressure (BP) and homeostasis model assessment for insulin resistance (HOMA-IR) scores, although the metabolic parameters of ICSI- and IVF-conceived singleton men were more comparable. Some studies suggest that IVF-conceived offspring may have poorer cardiovascular and metabolic profiles than SC children. Few studies have examined the metabolic health of ICSI-conceived offspring. This cohort study compared the metabolic health of ICSI-conceived men to IVF-conceived and SC controls who were derived from prior cohorts. Participants included 121 ICSI-conceived men (including 100 singletons), 74 IVF-conceived controls (all singletons) and 688 SC controls (including 662 singletons). Resting systolic and diastolic BP (measured using an automated sphygmomanometer), height, weight, BMI, body surface area and fasting serum metabolic markers including fasting insulin, glucose, total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, triglycerides, highly sensitive C-reactive protein (hsCRP) and HOMA-IR were compared between groups. Data were analysed using multivariable linear regression adjusted for various covariates including age and education level. After adjusting for covariates, compared to 688 SC controls, 121 ICSI-conceived men had higher diastolic BP (β 4.9, 95% CI 1.1-8.7), lower fasting glucose (β -0.7, 95% CI -0.9 to -0.5), higher fasting insulin (ratio 2.2, 95% CI 1.6-3.0), higher HOMA-IR (ratio 1.9, 95% CI 1.4-2.6), higher HDLC (β 0.2, 95% CI 0.07-0.3) and lower hsCRP (ratio 0.4, 95% CI 0.2-0.7) levels. Compared to 74 IVF-conceived singletons, only glucose differed in the ICSI-conceived singleton men (β -0.4, 95% CI -0.7 to -0.1). No differences were seen in the paternal infertility subgroups. The recruitment rate of ICSI-conceived men in this study was low and potential for recruitment bias exists. The ICSI-conceived men, the IVF-conceived men and SC controls were from different cohorts with different birth years and different geographical locations. Assessment of study groups and controls was not contemporaneous, and the measurements differed for some outcomes (BP, insulin, glucose, lipids and hsCRP). These observations require confirmation in a larger study with a focus on potential mechanisms. Further efforts to identify whether health differences are due to parental characteristics and/or factors related to the ICSI procedure are also necessary. This study was funded by an Australian National Health and Medical Research Council Partnership Grant (NHMRC APP1140706) and was partially funded by the Monash IVF Research and Education Foundation. S.R.C. was supported through an Australian Government Research Training Program Scholarship. R.J.H. is supported by an NHMRC project grant (634457), and J.H. and R.I.M. have been supported by the NHMRC as Senior and Principal Research Fellows respectively (J.H. fellowship number: 1021252; R.I.M. fellowship number: 1022327). L.R. is a minority shareholder and the Group Medical Director for Monash IVF Group, and reports personal fees from Monash IVF Group and Ferring Australia, honoraria from Ferring Australia and travel fees from Merck Serono and MSD and Guerbet; R.J.H. is the Medical Director of Fertility Specialists of Western Australia and has equity in Western IVF; R.I.M. is a consultant for and shareholder of Monash IVF Group and S.R.C. reports personal fees from Besins Healthcare and nonfinancial support from Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare. N/A.

Incidence of death or disability at 6 months after extracorporeal membrane oxygenation in Australia: a prospective, multicentre, registry-embedded cohort study

Extracorporeal membrane oxygenation (ECMO) is an invasive procedure used to support critically ill patients with the most severe forms of cardiac or respiratory failure in the short term, but long-term effects on incidence of death and disability are unknown. We aimed to assess incidence of death or disability associated with ECMO up to 6 months (180 days) after treatment. This prospective, multicentre, registry-embedded cohort study was done at 23 hospitals in Australia from Feb 15, 2019, to Dec 31, 2020. The EXCEL registry included all adults (≥18 years) in Australia who were admitted to an intensive care unit (ICU) in a participating centre at the time of the study and who underwent ECMO. All patients who received ECMO support for respiratory failure, cardiac failure, or cardiac arrest during their ICU stay were eligible for this study. The primary outcome was death or moderate-to-severe disability (defined using the WHO Disability Assessment Schedule 2.0, 12-item survey) at 6 months after ECMO initiation. We used Fisher's exact test to compare categorical variables. This study is registered with ClinicalTrials.gov, NCT03793257. Outcome data were available for 391 (88%) of 442 enrolled patients. The primary outcome of death or moderate-to-severe disability at 6 months was reported in 260 (66%) of 391 patients: 136 (67%) of 202 who received veno-arterial (VA)-ECMO, 60 (54%) of 111 who received veno-venous (VV)-ECMO, and 64 (82%) of 78 who received extracorporeal cardiopulmonary resuscitation (eCPR). After adjustment for age, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) IV score, days between ICU admission and ECMO start, and use of vasopressors before ECMO, death or moderate-to-severe disability was higher in patients who received eCPR than in those who received VV-ECMO (VV-ECMO vs eCPR: risk difference [RD] -32% [95% CI -49 to -15]; p&lt;0·001) but not VA-ECMO (VA-ECMO vs eCPR -8% [-22 to 6]; p=0·27). In our study, only a third of patients were alive without moderate-to-severe disability at 6 months after initiation of ECMO. The finding that disability was common across all areas of functioning points to the need for long-term, multidisciplinary care and support for surviving patients who have had ECMO. Further studies are needed to understand the 180-day and longer-term prognosis of patients with different diagnoses receiving different modes of ECMO, which could have important implications for the selection of patients for ECMO and management strategies in the ICU. The National Health and Medical Research Council of Australia.

HIV prevalence ratio of international migrants compared to their native-born counterparts: A systematic review and meta-analysis.

SummaryBackgroundPeople on the move, including international migrants, may face health inequities that expose them to a higher risk for HIV than native-born populations. We conducted a systematic review to calculate the HIV prevalence ratio of international migrants compared with native-born populations.MethodsWe searched five databases between January 2010 and March 2022. Using random-effects meta-analysis, we calculated the pooled HIV prevalence ratios (PR) by comparing the HIV prevalence of migrants with native-born populations. Our research protocol is registered in the International prospective register of systematic reviews (PROSPERO, CRD42021250867).FindingsIn total, 5,121 studies were screened, and 38 were included in the final analysis: 7,121,699 migrants and more than 270 million natives were included in the analysis. The pooled PR for any foreign-born migrants was 1·70 (95% CI 1·11 – 2·61, I2=99·67%, n = 33 studies), refugees was 2·37 (95% CI 0·33–16·99, I2=99·5%, n = 5), undocumented people was 3·98 (95% CI 0·11–143·01, I2=94·6%, n = 3), whilst asylum seekers was 54·79 (95% CI 17·23–174·23, I2=90·2%, n = 2). Meta-regression revealed that population type (adjusted R-squared 11.5%), region of origin (11.3%) and migrant type (10.8%) accounted for heterogeneity more than country-income (2.4%) and study setting (2.3%).InterpretationAlthough it was not possible to assess if HIV infection occurred in the country of origin or destination, the HIV prevalence ratio was higher among migrants than in native-born populations. Inclusive health policies and strategies for delivering HIV testing, prevention and treatment services for migrant populations tailored to their needs are urgently needed.FundingJ.J.O. and E.P.F.C. are supported by the Australian National Health and Medical Research Council (NHMRC) Emerging Leader Fellowship (GNT1193955 and GNT1172873, respectively).

Natural and hybrid immunity following four COVID-19 waves: A prospective cohort study of mothers in South Africa.

BackgroundMore than half the global population has been exposed to SARS-CoV-2. Naturally induced immunity influences the outcome of subsequent exposure to variants and vaccine responses. We measured anti-spike IgG responses to explore the basis for this enhanced immunity.MethodsA prospective cohort study of mothers in a South African community through ancestral/beta/delta/omicron SARS-CoV-2 waves (March 2020-February 2022). Health seeking behaviour/illness were recorded and post-wave serum samples probed for IgG to Spike (CoV2-S-IgG) by ECLISA. To estimate protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter for unvaccinated and vaccinated adults.FindingsDespite little disease, 176/339 (51·9%) participants were seropositive following wave 1, rising to 74%, 89·8% and 97·3% after waves 2, 3 and 4 respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection with the greatest protection for beta and least for omicron. Vaccination induced higher CoV2-S-IgG in seropositive compared to naïve vaccinees. Amongst seropositive participants, proportions above the 50% protection against infection threshold were 69% (95% CrI: 62, 72) following 1 vaccine dose, 63% (95% CrI: 63, 75) following 2 doses and only 11% (95% CrI: 7, 14) in unvaccinated during the omicron wave.InterpretationNaturally induced CoV2-S-IgG do not achieve high enough levels to prevent omicron infection in most exposed individuals but are substantially boosted by vaccination leading to significant protection. A single vaccination in those with prior immunity is more immunogenic than 2 doses in a naïve vaccinee and may provide adequate protection.FundingUK NIH GECO award (GEC111), Wellcome Trust Centre for Infectious Disease Research in Africa (CIDRI), Bill & Melinda Gates Foundation, USA (OPP1017641, OPP1017579) and NIH H3 Africa (U54HG009824, U01AI110466]. HZ is supported by the SA-MRC. MPN is supported by an Australian National Health and Medical Research Council Investigator Grant (APP1174455). BJQ is supported by a grant from the Bill and Melinda Gates Foundation (OPP1139859). Stefan Flasche is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant number 208812/Z/17/Z).