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Background: Decisions about hypertension management are substantially influenced by blood pressure (BP) levels measured before and soon after starting BP lowering drugs. We aimed to assess the utility of short-term BP changes in individuals in terms of long-term treatment response. Methods: Post hoc analyses of 2 randomized trials with 4-to-6 weeks active run-in for all participants, followed by randomization to active BP lowering treatment (combination perindopril±indapamide) or placebo. We categorized individuals by degree of systolic BP (SBP) change during active run-in treatment and assessed associations with subsequent postrandomization placebo-corrected BP reduction, cardiovascular events, and tolerability. We included individuals with baseline BP ≥140/90 mm Hg from the PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study; 4275 individuals with cerebrovascular disease) and ADVANCE trial (The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; 6610 individuals with diabetes). Results: During the active run-in period, the proportion of participants with initial SBP changes in 4 categories (SBP increase, 0–9.9 mm Hg decrease, 10–19.9 mm Hg decrease, and ≥20 mm Hg decrease) were 17%, 27%, 28%, and 28% in PROGRESS and 21%, 22%, 24%, and 33% in ADVANCE. Randomization to active therapy achieved similar placebo-corrected long-term BP reductions across the 4 initial SBP change groups in both trials ( P -values for heterogeneity >0.1). There was no significant difference in achieving BP P -values >0.1). Conclusions: An individual’s apparent BP change immediately after commencing therapy has limited clinical utility. Therefore, more emphasis should be given to use of evidence-based regimens and measures over the long-term to ensure sustained BP control. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00145925.

Peer mentoring is a learning process wherein a more experienced student provides advice and support to a less experienced student during their academic career. At the graduate level, peer mentoring has been shown to increase social support, career readiness, retention, and graduation rates among first-year students. In spring 2021, the Exercise Science graduate program at Texas State University initiated a peer mentoring program. The participants reported that they felt more integrated in the graduate program. Meeting and socializing with mentor/mentee have enhanced their sense of belonging and relatedness, especially during COVID, when students felt more isolated. The professional relationship made them more prone to return and strive for academic success. This article describes a peer mentoring program that has been successfully implemented in a kinesiology graduate program and makes recommendations for universities to study the impact of peer mentoring on marginalized student well-being, retention, career readiness, and academic success in future research.

Aims Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. Methods and results Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. Conclusion The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. Classification of evidence Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.

Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time.The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes.A post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models.Over a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes.Cumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286).

Background: Early diagnosis through symptom recognition is vital in the management of acute stroke. However, women who experience stroke are more likely than men to be initially given a nonstroke diagnosis and it is unclear if potential sex differences in presenting symptoms increase the risk of delayed or missed stroke diagnosis. Aims: To quantify sex differences in the symptom presentation of stroke and assess whether these differences are associated with a delayed or missed diagnosis. Methods: PubMed, EMBASE, and the Cochrane Library were systematically searched up to January 2021. Studies were included if they reported presenting symptoms of adult women and men with diagnosed stroke (ischemic or hemorrhagic) or transient ischemic attack (TIA) and were published in English. Mean percentages with 95% confidence intervals (CIs) of each symptom were calculated for women and men. The crude relative risks (RRs) with 95% CI of symptoms being present in women, relative to men, were also calculated and pooled. Any data on the delayed or missed diagnosis of stroke for women compared to men based on symptom presentation were also extracted. Results: Pooled results from 21 eligible articles showed that women and men presented with a similar mean percentage of motor deficit (56% in women vs 56% in men) and speech deficit (41% in women vs 40% in men). Despite this, women more commonly presented with nonfocal symptoms than men: generalized nonspecific weakness (49% vs 36%), mental status change (31% vs 21%), and confusion (37% vs 28%), whereas men more commonly presented with ataxia (44% vs 30%) and dysarthria (32% vs 27%). Women also had a higher risk of presenting with some nonfocal symptoms: generalized weakness (RR 1.49, 95% CI 1.09–2.03), mental status change (RR 1.44, 95% CI 1.22–1.71), fatigue (RR 1.42, 95% CI 1.05–1.92), and loss of consciousness (RR 1.30, 95% CI 1.12–1.51). In contrast, women had a lower risk of presenting with dysarthria (RR 0.89, 95% CI 0.82–0.95), dizziness (RR 0.87, 95% CI 0.80–0.95), gait disturbance (RR 0.79, 95% CI 0.65–0.97), and imbalance (RR 0.68, 95% CI 0.57–0.81). Only one study linking symptoms to definite stroke/TIA diagnosis found that pain and unilateral sensory loss are associated with lower odds of a definite diagnosis in women compared to men. Conclusion: Although women showed a higher prevalence of some nonfocal symptoms, the prevalence of focal neurological symptoms, such as motor weakness and speech deficit, was similar for both sexes. Awareness of sex differences in symptoms in acute stroke evaluation, careful consideration of the full constellation of presenting symptoms, and further studies linking symptoms to diagnostic outcomes can be helpful in improving early diagnosis and management in both sexes.

Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9–17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4–14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10–1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05–1.32]), per unit increase log e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09–1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04–1.21], per unit increase log e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04–1.21]; hsCRP, RR, 1.09 [95% CI, 1.04–1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00–1.19]; hsCRP, RR, 1.05 [95% CI, 1.00–1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09–1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07–1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08–1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93–1.43]). Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

STUDY QUESTION In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION This is a novel population-based birth cohort study of 898 084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks’ gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included a total of 898 084 births (606 488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009–2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent’s age, parity, socio-economic status, maternal country of birth, remoteness of mother’s dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother’s age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81–0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74–0.77]). LIMITATIONS, REASONS FOR CAUTION The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S) This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women’s and Children’s Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Objective: To quantitate the changes in stress urinary incontinence (SUI) outcome measures after 12 weeks of vaginal estriol cream in women with stress incontinence. Methods: A prospective multicentre observational study conducted in tertiary urogynaecology centers. Postmenopausal women with pure SUI or stress predominant mixed urinary incontinence (MUI), not receiving any other treatment for their incontinence were given written instructions regarding digital application of a standard dose of vaginal estriol cream. Outcomes were measured at baseline and 12 weeks. The primary objective outcome was vaginal pH. The primary subjective outcome was the stress domain of the Urogenital Distress Inventory-6 (UDI-6). The secondary objective outcome used was the erect cough stress test. Two quality of life questionnaires and two patient reported outcomes were also included. Results: The 46 postmenopausal recruits had a median age of 62.1 interquartile range (IQR 56.2–65.4). At follow up, the primary subjective outcome SUI domain [UDI-6] significantly improved from 83.3 (IQR 50–100) to 33.3 (33.3–66.7, p ≤ 0.001) as did vaginal pH [from 5.1 (4.9–5.9) to 4.9 (4.6–5.0] p ≤ 0.001; 18/43 patients (42%) were dry on cough stress test. Conclusions: Twelve weeks of vaginal estriol cream significantly reduced symptoms of stress urinary incontinence in this sample of postmenopausal women.

Background Stroke and transient ischemic attack confer greater risk of cognitive decline and dementia. Aims We used data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a blood pressure-lowering randomized controlled trial in stroke/transient ischemic attack. We evaluated overall and sex-specific differences in treatment effects for cognitive decline/dementia, as well as associations with vascular and stroke-specific predictors,considering death as a competing risk. Methods Multinomial logistic regression was used to estimate overall and sex-specific odds ratios (OR) (95% confidence intervals (CI)) for treatment effects and predictors associated with the risk of cognitive decline/dementia, and the women-to-men ratio of odds ratio (RORs). Results Over a median four years, 763 cognitive decline/dementia (30.9% women) were recorded in 5888 participants. Women had lower odds of cognitive decline/dementia than men (OR 0.78, 95%CI 0.63–0.95). Active treatment was associated with lower odds of cognitive decline/dementia (0.84, 0.72–0.98), with no evidence of sex difference. Higher education (0.96,0.94–0.98 (per year)) and baseline Mini-Mental State Examination (MMSE)) were associated with lower odds of cognitive decline/dementia (0.84,0.82–0.86 (per point higher)). Higher diastolic blood pressure (1.11,1.02–1.20 (per 10 mmHg)), low estimated glomerular filtration rate (eGFR) 2 (1.27,1.03–1.58), and peripheral arterial disease (1.78,1.26–2.52) were associated with higher odds of cognitive decline/dementia. APOE ɛ4 was not associated with cognitive decline/dementia (1.05 (0.85–1.30)). Low eGFR was more strongly associated with cognitive decline/dementia in women than men (RORs, 1.60 (1.03–2.48)). Diabetes was more strongly associated with men than women. Conclusions Several risk factors were associated with cognitive decline/dementia in people with prior stroke/transient ischemic attack, with notable sex differences. Long-term cognitive sequelae of stroke should be considered to strengthen joint prevention strategies for stroke, cognitive decline, and dementia. Trial Registration: This trial was not registered because enrolment began before 1 July 2005.

Over the past decade, there has been a notable increase in interest in master’s education in the United States. However, not much attention has been paid to recruiting and retaining master’s students in the field of kinesiology. This article describes recruitment and retention strategies that have been successfully implemented in a kinesiology graduate program at a Hispanic-serving institution. Recruiting from undergraduate programs, removing use of the Graduate Record Examination (GRE) in graduate admissions, awarding graduate teaching assistantships, creating new programs that flow with the evolving workforce, actively promoting the program at other universities and conferences, and building partnership with other universities are described for recruiting quality master’s students. Establishing a peer/faculty mentorship program and building a strong student network/organization have been shown to have a positive impact on retention. Readers may pick and choose the strategies that work best with the student population, faculty, and other resources available in the program.

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81–0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71–0.74), trials with a mean age of participants p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials.

This study aimed to investigate the association between individual and combinations of macronutrients with premature death, CVD and dementia. Sex differences were investigated. Data were utilised from a prospective cohort of 120 963 individuals (57 % women) within the UK Biobank, who completed ≥ two 24-h diet recalls. The associations of macronutrients, as percentages of total energy intake, with outcomes were investigated. Combinations of macronutrients were defined using k-means cluster analysis, with clusters explored in association with outcomes. There was a higher risk of death with high carbohydrate intake (hazard ratios (HR), 95 % CI upper v. lowest third 1·13 (1·03, 1·23)), yet a lower risk with higher intakes of protein (upper v. lowest third 0·82 (0·76, 0·89)). There was a lower risk of CVD with moderate intakes (middle v. lowest third) of energy and protein (sub distribution HR (SHR), 0·87 (0·79, 0·97) and 0·87 (0·79, 0·96), respectively). There was a lower risk of dementia with moderate energy intake (SHR 0·71 (0·52, 0·96)). Sex differences were identified. The dietary cluster characterised by low carbohydrate, low fat and high protein was associated with a lower risk of death (HR 0·84 (0·76, 0·93)) compared with the reference cluster and a lower risk of CVD for men (SHR 0·83 (0·71, 0·97)). Given that associations were evident, both as single macronutrients and for combinations with other macronutrients for death, and for CVD in men, we suggest that the biggest benefit from diet-related policy and interventions will be when combinations of macronutrients are targeted.

OBJECTIVE To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.

OBJECTIVE: Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. METHODS: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization. RESULTS: Among the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:−4.9,8.2) or NT-proBNP (−10.3%; 95%CI: −20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (−2.9%; 95%CI: −8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI: −30.2%,−11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95). CONCLUSIONS: In adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes. This trial is registered at clinicaltrials.gov, number: NCT00145925.

Background: Early diagnosis through symptom recognition is vital in acute stroke management. However, women who experience stroke are more likely than men to receive a missed or delayed diagnosis. Aims: To assess sex differences in the symptom presentation of stroke and whether these differences are associated with a delayed or missed diagnosis. Methods: PubMed, EMBASE and the Cochrane Library were systematically searched up to January 2021 for all studies that reported on symptoms in both adult women and men with diagnosed stroke (ischaemic or haemorrhagic) and transient ischaemic attack and were published in English. Sex-stratified proportions for each symptom were extracted and pooled. The relative risk (RR) of a symptom being present in women relative to men with 95% confidence intervals (CI) was also calculated and pooled, as well as the RR of a delayed or missed stroke diagnosis. Results: Pooled results from 21 eligible articles showed that the top three symptoms were similar between women and men - limb weakness (72% vs. 66%), hemiparesis (56% vs. 55%), and weakness of the face, arm or leg (55% vs. 55%). However, the top 4th and 5th symptoms found in women were generalised non-specific weakness (49%) and motor deficit (46%), whereas in men these were motor deficit (46%) and ataxia (44%). In addition, crude RR showed that women were more likely to have higher risk than men of presenting with confusion (RR 1.16, CI 1.01-1.32), dysphagia (RR 1.29, CI 1.13-1.48), dysphasia (RR 1.11, CI 1.00-1.24), fatigue (RR 1.42, CI 1.05-1.92), generalised weakness (RR 1.56 CI 1.23-1.98), headache (RR 1.14, CI 1.01-1.30), urinary incontinence (RR 1.25, CI 1.17-1.33), loss of consciousness (RR 1.30, CI 1.12-1.51), and mental status change (RR 1.37, CI 1.18-1.58), and lower risk of presenting with dizziness (RR 0.87, CI 0.80-0.95), dysarthria (RR 0.89, CI 0.82-0.95), imbalance (RR 0.68, CI 0.57-0.81), paraesthesia (RR 0.74, CI 0.58-0.93), and trouble walking (RR 0.83, CI 0.70-0.99). Finally, pooled RR of delayed or missed diagnosis for women compared to men was not statistically significant (RR 1.19, CI 0.94-1.49). Conclusion: Though women and men commonly presented with similar symptoms, some sex differences were present which needs consideration in stroke evaluation.

Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear.Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median).During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00;Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium.Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

AimsAssociations of plasma viscosity and plasma Ig levels (a determinant of viscosity) with incident coronary heart disease (CHD) events; and with CHD, cardiovascular disease (CVD: CHD and stroke) and all-cause mortalities.MethodsMeta-analysis of plasma viscosity levels from the MONitoring of trends and determinants of CArdiovascular (MONICA)/Cooperative Health Research in the Region of Augsburg, MONICA Glasgow and Speedwell Studies; and five other published studies. Meta-analysis of IgA, IgG and IgM levels from the Augsburg, Glasgow and Speedwell studies; and one other published study.ResultsOver median follow-up periods of 14–26 years, there were 2270 CHD events, and 4220 all cause deaths in 28 605 participants with baseline plasma viscosity measurements. After adjustment for major risk factors, (HRs; 95% CIs) for a 1 SD increase in viscosity were 1.14 (1.09 to 1.20) for CHD events; and 1.21 (1.17 to 1.25) for all-cause mortality. 821 CHD events and 2085 all-cause deaths occurred in 8218 participants with baseline Ig levels. For CHD events, adjusted HRs for 1 SD increases in IgA, IgG and IgM were, respectively, 0.97 (0.89 to 1.05); 0.95(0.76 to 1.17) and 0.90 (0.79 to 1.03). Corresponding adjusted HRs for all-cause mortality were 1.08 (95% CI 1.02 to 1.13), 1.03 (95% CI 0.94 to 1.14) and 1.01 (95% CI 0.96 to 1.06).ConclusionsAfter risk factor adjustment, plasma viscosity was significantly associated with risks of CHD events; and with CHD, CVD and all-cause mortalities. We found no significant association of IgA, IgG or IgM levels with incident CHD events or mortality, except for a borderline association of IgA with all-cause mortality.

BackgroundLack of progress in finding disease-modifying treatments for dementia may be due to heterogeneity in treatment effects among subgroups, such as by sex. Therefore, we investigated the characteristics of dementia trials completed in the last decade, with a focus on women’s representation and sex-disaggregated outcomes.MethodsClinical trials on dementia completed since 2010 were identified from ClinicalTrials.gov. Randomised, phase III/IV trials with ≥100 participants were selected to quantify women’s representation among participants, by computing the participation to prevalence ratio (PPR) and investigate whether sex-disaggregated analyses had been performed.ResultsA total of 1351 trials were identified between January 2010 and August 2021 (429 520 participants), of which 118 were eligible for analysis of women’s representation and sex-stratified analysis. Only 113 reported the sex of participants and were included in the analysis of women’s representation. Of the 110 469 participants in these 113 trials, 58% were women, lower than their estimated representation in the global dementia population of 64%. The mean PPR was 0.90 (95% CI 0.86 to 0.94). Women’s participation tended to be higher when the first or last authors of the trial report were women. Eight out of the 118 trials reported sex-disaggregated outcomes, and three of those found significant sex differences in efficacy outcomes. None of the trials reported screening failures or adverse events stratified by sex.ConclusionsOverall, women and men were equally represented in dementia trials carried out over the past decade, but women’s representation was lower than in the underlying dementia population. Sex-disaggregated efficacy and safety outcomes were rarely reported.

STUDY QUESTION What is the number of oocytes where the maximum cumulative live birth rate per aspiration (CLBR) is observed during ART in women of different ages? SUMMARY ANSWER The maximum CLBR was observed when around 25 oocytes were retrieved in women between 18–35 years of age, around 9 oocytes in women more than 45 years of age and continued to increase beyond 30 oocytes in women between 36–44 years of age. WHAT IS KNOWN ALREADY The live birth rate per fresh or frozen/thaw embryo transfer (FET) procedure has traditionally been the main measure of ART success. However, with the introduction of highly efficient embryo cryopreservation methods, CLBR encompassing live delivery outcomes from the fresh and all subsequent FET following a single ovarian stimulation and oocyte collection is increasingly viewed as a more meaningful measure of treatment success. There is evidence suggesting that larger oocyte yields are associated with increased likelihood of cumulative live birth per aspiration. Whether this association is the same across female ages has not yet been properly investigated. STUDY DESIGN, SIZE, DURATION This is a large retrospective population-based cohort study using data from the Australian and New Zealand Assisted Reproduction Database (ANZARD). ANZARD contains information from all ART treatment cycles carried out in all fertility centres in Australia and New Zealand. Overall, 221 221 autologous oocyte aspiration cycles carried out between January 2009 to December 2015 were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Cumulative live birth per aspiration was defined as at least one liveborn baby at ≥20 weeks gestation resulting from an ART aspiration cycle, including all fresh and FET resulting from the associated ovarian stimulation, until one live birth occurred or all embryos were used. Cycles where no oocytes were retrieved were excluded from analysis as there is no possibility of live birth. Analyses of data were performed using generalized estimating equations to account for the clustered nature of data (multiple cycles undertaken by a woman). Univariate and multivariable regression analysis was performed to identify and adjust for factors known to independently affect cumulative live birth per aspiration. An interaction term between female age and the number of oocytes retrieved was included to assess whether the age of the women was associated with a different optimal number of oocytes to achieve at least one live birth from an aspiration cycle (i.e. the effect-modifying role of female age). The likelihood of cumulative live birth per aspiration was calculated as odds ratios (ORs) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE The median number of oocytes retrieved was 7 (interquartile range, 4–12) and median age of patients was 36 (interquartile range, 33–40). The overall CLBR was 32.2%. The results from the multivariable regression analysis showed that the number of oocytes retrieved remained a significant predictor (P LIMITATIONS, REASONS FOR CAUTION As with all large retrospective database studies, there are potential confounders that cannot be accounted for. Despite the current study being based on complete ascertainment of ART cycles across two countries, ovarian stimulation protocols, oocyte quality parameters and a number of important patient characteristics are not collected by ANZARD. Additionally, a small number of cycles were available for women over 45 years yielding more than 15 oocytes, making these estimates unreliable. WIDER IMPLICATIONS OF THE FINDINGS The results from this study demonstrate that the number of oocytes retrieved where the maximum CLBR is observed during ART is dependent on female age. This provides information for clinicians and patients to understand the modifying effect of age on the number of oocytes retrieved and the likelihood of success with ART. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this study. The Fertility Society of Australia funds the National Perinatal Epidemiology and Statistics Unit to manage ANZARD and conduct national reporting of ART in Australia and New Zealand. Associate Professor Georgina Chambers (G.C.) is employed by the University of New South Wales (UNSW) and is director of the National Perinatal Epidemiology and Statistics Unit at UNSW. G.C. was also a paid member of the Australian governments Medicare Benefits Scheme taskforce on assisted reproductive technologies in 2017.

IntroductionAssisted reproductive technologies (ART), such as in-vitro fertilisation (IVF), have revolutionised the treatment of infertility, with an estimated 8 million babies born worldwide. However, the long-term health outcomes for women and their offspring remain an area of concern. Linking IVF treatment data to long-term health data is the most efficient method for assessing such outcomes. ObjectivesTo describe the creation and performance of a bespoke population-based data linkage of an ART clinical quality registry to state-based and national administrative datasets. MethodsThe linked dataset was created by deterministically and probabilistically linking the Australia and New Zealand Assisted Reproduction Database (ANZARD) to New South Wales (NSW) and Australian Capital Territory (ACT) administrative datasets (performed by NSW Centre for Health Record Linkage (CHeReL)) and to national claims datasets (performed by Australian Institute of Health and Welfare (AIHW)). The CHeReL's Master Linkage Key (MLK) was used as a bridge between ANZARD's partially identifiable patient data (statistical linkage key) and NSW and ACT administrative datasets. CHeReL then provided personal identifiers to the AIHW to obtain national content data. The results of the linkage were reported, and concordance between births recorded in ANZARD and perinatal data collections (PDCs) was evaluated. ResultsOf the 62,833 women who had ART treatment in NSW or ACT, 60,419 could be linked to the CHeReL MLK (linkage rate: 96.2%). A reconciliation of ANZARD-recorded births among NSW residents found that 94.2% (95% CI: 93.9--94.4%) of births were also recorded in state/territory-based PDCs. A high concordance was found in plurality status and birth outcome (≥99% agreement rate, Cohen's kappa ranged: 0.78--0.98) between ANZARD and PDCs. ConclusionThe data linkage resource demonstrates that high linkage rates can be achieved with partially identifiable data and that a population spine, such as the CHeReL's MLK, can be successfully used as a bridge between clinical registries and administrative datasets.

Clinical practice guidelines for patients with diabetes recommend using blood pressure (BP) and atherosclerotic cardiovascular disease (ASCVD) risk to guide antihypertensive treatment. While this approach directs treatment to patients who should receive a large ASCVD risk reduction, its effect on other outcomes is uncertain. The aim of this study was to assess the contributions of systolic blood pressure level (SBP) and predicted 10-year ASCVD risk using Pooled Cohort risk equations to the prediction of major macrovascular disease, death and major microvascular disease in patients with diabetes. Data came from 7426 individuals with type 2 diabetes (T2D) without macrovascular disease at baseline in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The risk for major macrovascular events and death increased progressively across ASCVD risk categories. Compared to participants with 10-year predicted ASCVD risk20% and SBP130 mmHg, the hazard ratios (HRs) (95% confidence intervals (CIs)) associated with SBP ≥150 mmHg and 10-year predicted ASCVD risk20%, 20-34% and ≥35% were 1.01 (0.58, 1.77), 1.90 (1.28, 2.84) and 2.82 (1.98, 4.01) for major macrovascular disease, respectively, and 0.83 (0.42, 1.62), 1.79 (1.13, 2.82) and 3.29 (2.22, 4.88) for death, respectively. The risk for major microvascular disease increased with BP regardless of ASCVD risk; HRs for SBP ≥150 mmHg and 10-year predicted ASCVD risk20%, 20-34% and ≥35% vs. ASCVD risk20% and SBP130 mmHg were 1.52 (1.08,2.13), 1.47 (1.10, 1.96) and 1.23 (0.94, 1.60), respectively. ASCVD risk in addition to SBP improved the estimation of major macrovascular events and death but not major microvascular events among individuals with T2D.