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Background: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. Methods: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). Results: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). Conclusion: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. Research design and methods We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. Results HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m 2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. Study Design: Secondary analysis of a randomized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models. Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed. Limitations: This was a post hoc analysis with multiple comparisons. Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the

Background: The Victorian Salt Reduction Partnership (VSRP) implemented a media advocacy strategy (intervention) to stimulate food manufacturers to reduce sodium levels across targeted Australian packaged foods between 2017 and 2019. This study assessed changes in sodium levels of targeted and non-targeted packaged foods during the intervention (2017 to 2019) compared to before the intervention (2014 to 2016) in Australia. Methods: Annually collected branded-food composition data from 2014 to 2019 were used. Interrupted time series analyses was conducted to compare the trend in sodium levels in packaged foods during the intervention (2017–2019) to the trend in the pre-intervention period (2014–2016). The difference between these trends was derived to estimate the effect of the intervention. Results: A total of 90,807 products were included in the analysis, of which 14,743 were targeted by the intervention. The difference in before and during intervention trends between targeted and non-targeted food categories was 2.59 mg/100 g (95% CI: -13.88 to 19.06). There was a difference in the pre-intervention slope (2014, 2015, 2016) and intervention slope (2017, 2018, 2019) for four of 17 targeted food categories. There was a decrease in sodium levels (mg/100 g) in one food category: frozen ready meals (-13.47; 95% CI: -25.40 to -1.53), and an increase in three categories: flat bread (20.46; 95% CI: 9.11 to 31.81), plain dry biscuits (24.53; 95% CI: 5.87 to 43.19), and bacon (44.54; 95% CI: 6.36 to 82.72). For the other 13 targeted categories, the difference in slopes crossed the line of null effect. Conclusions: The VSRP’s media advocacy strategy did not result in a meaningful reduction in sodium levels of targeted packaged food products during the intervention years compared to trends in sodium levels before the intervention. Our study suggests media advocacy activities highlighting the differences in sodium levels in packaged food products and industry meetings alone are

Background: ‘Food is medicine’ strategies aim to integrate food-based nutrition interventions into healthcare systems and are of growing interest to healthcare providers and policy makers. ‘Medically Tailored Meals’ (MTM) is one such intervention, which involves the ‘prescription’ by healthcare providers of subsidized, pre-prepared meals for individuals to prevent or manage chronic conditions, combined with nutrition education. Objective: This study will test the efficacy of an MTM program in Australia among participants with type 2 diabetes (T2D) and hyperglycemia, who experience difficulties accessing and eating nutritious food. Methods: This study will be a two-arm parallel trial (goal n = 212) with individuals randomized in a 1:1 ratio to a MTM intervention group or a control group (106 per arm). Over 26 weeks, the intervention group will be prescribed 20 MTM per fortnight and up to 3 sessions with an accredited dietitian. Controls will continue with their usual care. The primary outcome is glycated hemoglobin (HbA1c, %) and secondary outcomes include differences in blood pressure, blood lipids and weight, all measured at 26 weeks. Process and economic data will be analyzed to assess the feasibility, acceptability, scalability, and cost-effectiveness of the intervention. Recruitment commenced in the first quarter of 2023, with analyses and results anticipated to be available by March 2025. Discussion: Few randomized controlled trials have assessed the impact of MTM on clinical outcomes. This Australian-first trial will generate robust data to inform the case for sustained, large-scale implementation of MTM to improve the management of T2D among vulnerable populations. ANZCTR: ACTRN12622000852752. Protocol version: Version 1.1, July 2023.

Uncertainties about the efficacy of influenza vaccination for populations with heart failure (HF) in preventing cardiovascular outcomes, as well as lack of effective vaccination strategies, may contribute to low vaccine coverage rate (VCR) in China and globally. We assessed the feasibility of a strategy to promote influenza vaccines in patients hospitalized with acute HF in China and to inform the design of a hybrid effectiveness-implementation cluster randomized trial to evaluate this strategy on mortality and hospital re-admission. We conducted a cluster randomized pilot trial involving 11 hospitals in Henan Province in China, with mixed-methods evaluation between December 2020 and April 2021. A process evaluation involved interviews with 51 key informants (patients, health professionals, policy makers). The intervention included education about influenza vaccination and availability of free vaccines administered prior to hospital discharge for HF patients, while usual care included attending community-based points of vaccination (PoV) for screening and vaccination. Implementation outcomes focused on reach, fidelity, adoption, and acceptability. Recruitment rates were assessed for trial feasibility. Effectiveness outcomes were influenza VCR, HF-specific rehospitalizations and mortality at 90 days. A total of 518 HF patients were recruited from 7 intervention and 4 usual care hospitals (mean of 45 participants per hospital per month). VCR was 89.9% (311/346, 86.1–92.8%) in the intervention group and 0.6% (1/ 172, 0.0–3.7%) in the control group. The process evaluation demonstrated reach to patients with lower socioeconomic and education status. There was good fidelity of the intervention components, with education and PoV set up processes being adapted to local hospital work-flow and workforce capacity. Intervention was acceptable and adopted by patients and health professionals. However, outside of a trial setting, concerns were raised around vaccination reimbursem

BACKGROUND: As healthcare is responsible for 7% of Australia's carbon emissions, it was recognised that a policy implemented at St George Hospital, Sydney, to reduce non-urgent pathology testing to 2 days per week and, on other days only if essential, would also result in a reduction in carbon emissions. The aim of the study was to measure the impact of this intervention on pathology collections and associated carbon emissions and pathology costs. AIMS: To measure the impact of an intervention to reduce unnecessary testing on pathology collections and associated carbon emissions and pathology costs. METHODS: The difference in the number of pathology collections, carbon dioxide equivalents (CO2 e) for five common blood tests and pathology cost per admission were compared between a 6-month reference period and 6-month intervention period. CO2 e were estimated from published pathology CO2 e impacts. Cost was derived from pathology billing records. Outcomes were modelled using multivariable negative binomial, generalised linear and logistic regression. RESULTS: In total, 24 585 pathology collections in 5695 patients were identified. In adjusted analysis, the rate of collections was lower during the intervention period (rate ratio 0.90; 95% confidence interval (CI), 0.86-0.95; P < 0.001). This resulted in a reduction of 53 g CO2 e (95% CI, 24-83 g; P < 0.001) and $22 (95% CI, $9-$34; P = 0.001) in pathology fees per admission. The intervention was estimated to have saved 132 kg CO2 e (95% CI, 59-205 kg) and $53 573 (95% CI, 22 076-85 096). CONCLUSIONS: Reduction in unnecessary hospital pathology collections was associated with both carbon emission and cost savings. Pathology stewardship warrants further study as a potentially scalable, cost-effective and incentivising pathway to lowering healthcare associated greenhouse gas emissions.

Background: Monitoring salt consumption in children is essential for informing and implementing public health interventions to reduce children’s salt intake. However, collection of 24-hour urines, considered as the most reliable approach, can be especially challenging to school children. This study aimed to assess the agreement between 24-hour urine (24hrU) and 24-hour food recall (24hrFR) in: (1) estimating salt intake in children; (2) classifying salt intakes above the recommended upper level set for children, and; (3) estimating change in mean salt intake over time. Methods: This study utilised data from two cross-sectional surveys of school children aged 8 to 12 years living in the state of Victoria, Australia. A single 24hrU and 24hrFR were collected from each participant. Suspected inaccurate urine collections and implausible energy intakes were excluded based on pre-defined criteria. The agreement between the two methods was assessed using Bland-Altman methodology, the intraclass correlation coefficient (ICC), and the kappa statistic. The difference between the measured change in salt intake over time using 24hrU and 24hrFR was derived using mixed effects linear regression analysis. Results: A total of 588 participants provided a 24hrU and 24hrFR. Overall, there was no meaningful difference in mean estimated salt intake between the two methods (− 0.2 g/day, 95% CI − 0.5 to 0.1). The Bland-Altman plot showed wide 95% limits of agreement (− 7.2 to 6.8). The ICC between the two methods was 0.13 (95% CI 0.05 to 0.21). There was poor interrater reliability in terms of classifying salt intake above the recommended upper level for children, with an observed agreement of 63% and kappa statistic of 0.11. The change in mean salt intake over time was 0.2 g/day (− 0.4 to 0.7) based on 24hrU, and 0.5 g/day (− 0.0 to 1.1) based on 24hrFR, with a difference-in-differences of 0.4 g/day (− 0.3 to 1.1). Conclusions: 24hrFR appears to provide a reasonable estimate of mean salt

Aim: Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy. Methods: The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events. Results: Almost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. Conclusion: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy.

Background: High dietary sodium intake is a leading cause of hypertension. A major source of dietary sodium is salt added to processed food products available in retail food environments. The fast-growing online grocery shopping setting provides new opportunities for salt reduction interventions that support consumers in choosing healthier options. Methods: The SaltSwitch Online Grocery Shopping randomized controlled trial is investigating the feasibility, acceptability, and effectiveness of a novel intervention for lowering salt consumption and blood pressure amongst people with hypertension who shop for groceries online. The intervention is based on a bespoke web browser extension that interfaces with a major retailer's online store to highlight and interpret product sodium content and suggest similar but lower-sodium alternatives. The primary outcome of interest is change in mean systolic blood pressure between individuals randomized (1:1) to the intervention and control (usual online shopping) arms at 12 weeks. Secondary outcomes are diastolic blood pressure, spot urinary sodium and sodium:potassium ratio, sodium purchases, and dietary intake. Intervention implementation and lessons for future uptake will be assessed using a mixed methods process evaluation. Participants with hypertension who shop online for groceries and exhibit high sodium purchasing behavior are being recruited across Australia. A target sample size of 1,966 provides 80% power (2-sided alpha = 0.05) to detect a 2 mm Hg difference in systolic blood pressure between groups, assuming a 15 mm Hg standard deviation, after allowing for a 10% dropout rate. Discussion: This trial will provide evidence on an innovative intervention to potentially reduce salt intake and blood pressure in people with hypertension. The intervention caters to individual preferences by encouraging sustainable switches to similar but lower-salt products. If effective, the intervention will be readily scalable at low cost by

This article details a correction to: Li J-W, Guo Y-T, Di Tanna GL, Neal B, Chen Y-D, Schutte AE. Vital Signs During the COVID-19 Outbreak: A Retrospective Analysis of 19,960 Participants in Wuhan and Four Nearby Capital Cities in China. Global Heart. 2021;16(1):47. DOI: http://doi.org/10.5334/gh.913. CORRECTION The original article was published without complete funding details. It listed one funder, the National Natural Science Foundation of China (H2501), National Key Research and Development Project of China (2018YFC2001200). There was another funder missing from the original article, the Chinese Military Health Care (20BJZ26). The originally listed funder covered expenses for enrolment and follow-up of patients, and the purchase and maintenance of necessary equipment. The second funder covered the costs of publication. COMPETING INTERESTS J.L. held an International Postdoctoral Exchange Fellowship Program China (20170103) during the course of this work. G. Tao has no disclosures. A.E. Schutte received speaker honoraria from Omron Healthcare, Takeda Pharmaceuticals, Novartis, Servier, and serves on research advisory board for Abbott. She is President of the International Society of Hypertension, 2018-2020. G.L. Di Tanna has no disclosures. B. Neal is supported by an Australian National Health and Medical Research Council Principal Research Fellowship; holds a research grant for this study from Janssen; and has held research grants for other large-scale cardiovascular outcome trials from Roche, Servier, and Merck Schering Plough; and his institution has received consultancy, honoraria, or travel support for contributions he has made to advisory boards and/or the continuing medical education programs of Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. Y. Chen has no disclosures.

Background: SSaSS (Salt Substitute and Stroke Study), a 5-year cluster randomized controlled trial, demonstrated that replacing regular salt with a reduced-sodium, added-potassium salt substitute reduced the risks of stroke, major adverse cardiovascular events, and premature death among individuals with previous stroke or uncontrolled high blood pressure living in rural China. This study assessed the cost-effectiveness profile of the intervention. Methods: A within-trial economic evaluation of SSaSS was conducted from the perspective of the health care system and consumers. The primary health outcome assessed was stroke. We also quantified the effect on quality-adjusted life-years (QALYs). Health care costs were identified from participant health insurance records and the literature. All costs (in Chinese yuan [¥]) and QALYs were discounted at 5% per annum. Incremental costs, stroke events averted, and QALYs gained were estimated using bivariate multilevel models. Results: Mean follow-up of the 20 995 participants was 4.7 years. Over this period, replacing regular salt with salt substitute reduced the risk of stroke by 14% (rate ratio, 0.86 [95% CI, 0.77-0.96]; P=0.006), and the salt substitute group had on average 0.054 more QALYs per person. The average costs (¥1538 for the intervention group and ¥1649 for the control group) were lower in the salt substitute group (¥110 less). The intervention was dominant (better outcomes at lower cost) for prevention of stroke as well as for QALYs gained. Sensitivity analyses showed that these conclusions were robust, except when the price of salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95.0% probability of being cost-saving and a >99.9% probability of being cost-effective. Conclusions: Replacing regular salt with salt substitute was a cost-saving intervention for the prevention of stroke and improvement of quality of life among SSaSS participan

Background: Consumption of ultra-processed foods is associated with increased risk of obesity and non-communicable diseases. Little is known about current patterns of ultra-processed foods intake in Australia. The aim of this study was to examine the amount and type of ultra-processed foods purchased by Australian households in 2019 and determine whether purchases differed by socio-economic status (SES). We also assessed whether purchases of ultra-processed foods changed between 2015 and 2019. Methods: We used grocery purchase data from a nationally representative consumer panel in Australia to assess packaged and unpackaged grocery purchases that were brought home between 2015 to 2019. Ultra-processed foods were identified according to the NOVA system, which classifies foods according to the nature, extent and purpose of industrial food processing. Purchases of ultra-processed foods were calculated per capita, using two outcomes: grams/day and percent of total energy. The top food categories contributing to purchases of ultra-processed foods in 2019 were identified, and differences in ultra-processed food purchases by SES (Index of Relative Social Advantage and Disadvantage) were assessed using survey-weighted linear regression. Changes in purchases of ultra-processed foods between 2015 to 2019 were examined overall and by SES using mixed linear models. Results: In 2019, the mean ± SD total grocery purchases made by Australian households was 881.1 ± 511.9 g/d per capita. Of this, 424.2 ± 319.0 g/d per capita was attributable to purchases of ultra-processed foods, which represented 56.4% of total energy purchased. The largest food categories contributing to total energy purchased included mass-produced, packaged breads (8.2% of total energy purchased), chocolate and sweets (5.7%), biscuits and crackers (5.7%) and ice-cream and edible ices (4.3%). In 2019, purchases of ultra-processed foods were significantly higher for the lowest SES households compared to all other

Background: There is growing interest in Food is Medicine programs that incorporate food-based interventions into health care for patients with diet-related conditions. Objectives: We aimed to test the feasibility of a “produce prescription” program and its impact on diet quality for people with type 2 diabetes (T2D) experiencing food insecurity in Australia. Methods: We conducted a pre–post intervention study in n = 50 adults experiencing food insecurity with T2D and glycated hemoglobin (HbA1c) ≥8%. Once enrolled, participants received healthy food boxes weekly free of charge, with the contents sufficient to create 2 meals/d, 5 d/wk for the entire household, over 12 wk. Participants were also provided with tailored recipes and behavioral change support. The primary outcome was change in diet quality assessed by 24-h diet recalls. Secondary outcomes included differences in cardiovascular disease risk factors; blood micronutrients; and feasibility indicators. Differences in the baseline and 12-wk mean primary and secondary outcomes were assessed by paired t tests. Results: Participants were older adults with mean ± SD age 63 ± 9 y (range: 40–87 y), HbA1c 9.8% ± 1.5%, and 46% were female. Overall, 92% completed the final study follow-up for the primary outcome. Compared with baseline, diet quality improved at week 12, with an increase in the mean overall diet quality (Alternate Healthy Eating Index score) of 12.9 (95% CI: 8.7, 17.1; P < 0.001), driven by significant improvements in vegetables, fruits, whole grains, red/processed meat, trans fat, sodium, and alcohol consumption. Blood lipids also improved (total:HDL cholesterol: −0.48; 95% CI: −0.72, −0.24; P < 0.001), and there was significant weight loss (−1.74 kg; 95% CI: −2.80, −0.68 kg, P = 0.002), but no changes in other clinical outcomes. Participants reported high levels of satisfaction with the program. Conclusions: These findings provide strong support for an adequately powered randomized trial to assess effe

Objectives The Salt Substitute and Stroke Study (SSaSS) recently reported blood pressure-mediated benefits of a potassium-enriched salt substitute on cardiovascular outcomes and death. This study assessed the effects of salt substitutes on a breadth of outcomes to quantify the consistency of the findings and understand the likely generalisability of the SSaSS results. Methods We searched PubMed, Embase and the Cochrane Library up to 31 August 2021. Parallel group, step-wedge or cluster randomised controlled trials reporting the effect of salt substitute on blood pressure or clinical outcomes were included. Meta-analyses and metaregressions were used to define the consistency of findings across trials, geographies and patient groups. Results There were 21 trials and 31 949 participants included, with 19 reporting effects on blood pressure and 5 reporting effects on clinical outcomes. Overall reduction of systolic blood pressure (SBP) was-4.61 mm Hg (95% CI-6.07 to-3.14) and of diastolic blood pressure (DBP) was-1.61 mm Hg (95% CI-2.42 to-0.79). Reductions in blood pressure appeared to be consistent across geographical regions and population subgroups defined by age, sex, history of hypertension, body mass index, baseline blood pressure, baseline 24-hour urinary sodium and baseline 24-hour urinary potassium (all p homogeneity >0.05). Metaregression showed that each 10% lower proportion of sodium choloride in the salt substitute was associated with a-1.53 mm Hg (95% CI-3.02 to-0.03, p=0.045) greater reduction in SBP and a-0.95 mm Hg (95% CI-1.78 to-0.12, p=0.025) greater reduction in DBP. There were clear protective effects of salt substitute on total mortality (risk ratio (RR) 0.89, 95% CI 0.85 to 0.94), cardiovascular mortality (RR 0.87, 95% CI 0. 81 to 0.94) and cardiovascular events (RR 0.89, 95% CI 0.85 to 0.94). Conclusions The beneficial effects of salt substitutes on blood pressure across geographies and populations were consistent. Blood pressure-mediated prot

Rationale & Objective: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs). Study Design: A randomized, double-blind, placebo-controlled, multicenter international trial. Setting & Participants: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g. Interventions: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. Outcomes: Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m2). Results: Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.61-0.82]; P < 0.001), with consistent results for serious kidney-related AEs (HR, 0.72 [95% CI, 0.51-1.00]; P = 0.05) and acute kidney injury (AKI; HR, 0.85 [95% CI, 0.64-1.13]; P = 0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73 m2, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio, 2.2 [95% CI, 1.0-4.7]; P = 0.04). Limitations: Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured, and creatinine data after an AKI ev

BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence

BACKGROUND: The fracture pathophysiology associated with type 2 diabetes and chronic kidney disease (CKD) is incompletely understood. We examined individual fracture predictors and prediction sets based on different pathophysiological hypotheses, testing whether any of the sets improved prediction beyond that based on traditional osteoporotic risk factors. METHODS: Within the CREDENCE cohort with adjudicated fracture outcomes, we assessed the association of individual factors with fracture using Cox regression models. We used the Akaike information criteria (AIC) and Schwartz Bayes Criterion (SBC) to assess six separate variable sets based on hypothesized associations with fracture, namely, traditional osteoporosis, exploratory general population findings, cardiovascular risk, CKD-mineral and bone disorder, diabetic osteodystrophy, and an all-inclusive set containing all variables. RESULTS: Fracture occurred in 135 (3.1%) participants over a median 2.35 [1.88-2.93] years. Independent fracture predictors were older age (hazard ratio [HR] 1.04, confidence interval [CI] 1.01-1.06), female sex (HR 2.49, CI 1.70-3.65), previous fracture (HR 2.30, CI 1.58-3.34), Asian race (HR 1.74, CI 1.09-2.78), vitamin D therapy requirement (HR 2.05, CI 1.31-3.21), HbA1c (HR 1.14, CI 1.00-1.32), prior cardiovascular event (HR 1.60, CI 1.10-2.33), and serum albumin (HR 0.41, CI 0.23-0.74) (lower albumin associated with greater risk). The goodness of fit of the various hypothesis sets was similar (AIC range 1870.92-1849.51, SBC range 1875.60-1948.04). CONCLUSION: Independent predictors of fracture were identified in the CREDENCE participants with type 2 diabetes and CKD. Fracture prediction was not improved by models built on alternative pathophysiology hypotheses compared with traditional osteoporosis predictors.

BACKGROUND: Individual case series and cohort studies have reported conflicting results in people with asthma on the vulnerability to and risk of mortality from coronavirus disease 2019 (COVID-19). RESEARCH QUESTION: Are people with asthma at a higher risk of being infected or hospitalised or poorer clinical outcomes from COVID-19? METHODS: A systematic review and meta-analysis based on five main databases including the World Health Organization COVID-19 database between 1 December 2019 and 11 July 2021 on studies with a control (non-asthma) group was conducted. Prevalence and risk ratios were pooled using Sidik-Jonkman random-effects meta-analyses. FINDINGS: 51 studies with an 8.08% (95% CI 6.87-9.30%) pooled prevalence of people with asthma among COVID-19 positive cases. The risk ratios were 0.83 (95% CI 0.73-0.95, p=0.01) for acquiring COVID-19; 1.18 (95% CI 0.98-1.42, p=0.08) for hospitalisation; 1.21 (95% CI 0.97-1.51, p=0.09) for intensive care unit (ICU) admission; 1.06 (95% CI 0.82-1.36, p=0.65) for ventilator use; and 0.94 (95% CI 0.76-1.17, p=0.58) for mortality for people with asthma. Subgroup analyses by continent revealed a significant difference in risk of acquiring COVID-19, ICU admission, ventilator use and death between the continents. INTERPRETATION: The risk of being infected with severe acute respiratory syndrome coronavirus 2 was reduced compared to the non-asthma group. No statistically significant differences in hospitalisation, ICU admission and ventilator use were found between groups. Subgroup analyses showed significant differences in outcomes from COVID-19 between America, Europe and Asia. Additional studies are required to confirm this risk profile, particularly in Africa and South America, where few studies originate.

Background: The implications of city lockdown on vital signs during the COVID-19 outbreak are unknown. Objective: We longitudinally tracked vital signs using data from wearable sensors and determined associations with anxiety and depression. Methods: We selected all participants in the HUAWEI Heart Study from Wuhan and four nearby large provincial capital cities (Guangzhou, Chongqing, Hangzhou, Zhengzhou) and extracted all data from 26 December 2019 (one month before city lockdown) to 21 February 2020. Sleep duration and quality, daily steps, oxygen saturation and heart rate were collected on a daily basis. We compared the vital signs before and after the lockdown using segmented regression analysis of the interrupted time series. The depression and anxiety cases were defined as scores ≥8 on the Hospital Anxiety and Depression Scale depression and anxiety subscales [HADS-D and HADS-A] in 727 participants who finished the survey. Results: We included 19,960 participants (mean age 36 yrs, 90% men). Compared with pre-lockdown, resting heart rate dropped immediately by 1.1 bpm after city lockdown (95% confidence interval [CI]: –1.8, –0.4). Sleep duration increased by 0.5 hour (95% CI: 0.3, 0.8) but deep sleep ratio decreased by 0.9% (95% CI: –1.2, –0.6). Daily steps decreased by 3352 steps (95% CI: –4333, –2370). Anxiety and depression existed in 26% and 17% among 727 available participants, respectively, and associated with longer sleep duration (0.2 and 0.1 hour, both p < 0.001). Conclusions: Lockdown of Wuhan in China was associated with an adverse vital signs profile (reduced physical activity, heart rate, and sleep quality, but increased sleep duration). Wearable devices in combination with mobile-based apps may be useful to monitor both physical and mental health.

Objectives: To determine whether a multifaceted primary health care intervention better controlled cardiovascular disease (CVD) risk factors in patients with high risk of CVD than usual care. Design, setting: Parallel arm, cluster randomised trial in 71 Australian general practices, 5 December 2016 – 13 September 2019. Participants: General practices that predominantly used an electronic medical record system compatible with the HealthTracker electronic decision support tool, and willing to implement all components of the INTEGRATE intervention. Intervention: Electronic point-of-care decision support for general practices; combination cardiovascular medications (polypills); and a pharmacy-based medication adherence program. Main outcome measures: Proportion of patients with high CVD risk not on an optimal preventive medication regimen at baseline who had achieved both blood pressure and low-density lipoprotein (LDL) cholesterol goals at study end. Results: After a median 15 months’ follow-up, primary outcome data were available for 4477 of 7165 patients in the primary outcome cohort (62%). The proportion of patients who achieved both treatment targets was similar in the intervention (423 of 2156; 19.6%) and control groups (466 of 2321; 20.1%; relative risk, 1.06; 95% CI, 0.85–1.32). Further, no statistically significant differences were found for a number of secondary outcomes, including risk factor screening, preventive medication prescribing, and risk factor levels. Use of intervention components was low; it was highest for HealthTracker, used at least once for 347 of 3236 undertreated patients with high CVD risk (10.7%). Conclusions: Despite evidence for the efficacy of its individual components, the INTEGRATE intervention was not broadly implemented and did not improve CVD risk management in participating Australian general practices. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12616000233426 (prospective).

OBJECTIVES: To investigate the association between plasma sodium concentrations and 6-month neurologic outcome in critically ill patients with aneurysmal subarachnoid hemorrhage. DESIGN: Prospective cohort study. SETTING: Eleven ICUs in Australia and New Zealand. PARTICIPANTS: Three-hundred fifty-six aneurysmal subarachnoid hemorrhage patients admitted to ICU between March 2016 and June 2018. The exposure variable was daily measured plasma sodium. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six-month neurologic outcome as measured by the modified Rankin Scale. A poor outcome was defined as a modified Rankin Scale greater than or equal to 4. The mean age was 57 years (± 12.6 yr), 68% were female, and 32% (n = 113) had a poor outcome. In multivariable analysis, including age, illness severity, and process of care measures as covariates, higher mean sodium concentrations (odds ratio, 1.17; 95% CI, 1.05-1.29), and greater overall variability-as measured by the sd (odds ratio, 1.53; 95% CI, 1.17-1.99)-were associated with a greater likelihood of a poor outcome. Multivariable generalized additive modeling demonstrated, specifically, that a high initial sodium concentration, followed by a gradual decline from day 3 onwards, was also associated with a poor outcome. Finally, greater variability in sodium concentrations was associated with a longer ICU and hospital length of stay: mean ICU length of stay ratio (1.13; 95% CI, 1.07-1.20) and mean hospital length of stay ratio (1.08; 95% CI, 1.01-1.15). CONCLUSIONS: In critically ill aneurysmal subarachnoid hemorrhage patients, higher mean sodium concentrations and greater variability were associated with worse neurologic outcomes at 6 months, despite adjustment for known confounders. Interventional studies would be required to demonstrate a causal relationship.

Objectives To determine whether a multifaceted primary health care intervention better controlled cardiovascular disease (CVD) risk factors in patients with high risk of CVD than usual care. Design, setting Parallel arm, cluster randomised trial in 71 Australian general practices, 5 December 2016 – 13 September 2019. Participants General practices that predominantly used an electronic medical record system compatible with the HealthTracker electronic decision support tool, and willing to implement all components of the INTEGRATE intervention. Intervention Electronic point-of-care decision support for general practices; combination cardiovascular medications (polypills); and a pharmacy-based medication adherence program. Main outcome measures Proportion of patients with high CVD risk not on an optimal preventive medication regimen at baseline who had achieved both blood pressure and low-density lipoprotein (LDL) cholesterol goals at study end. Results After a median 15 months’ follow-up, primary outcome data were available for 4477 of 7165 patients in the primary outcome cohort (62%). The proportion of patients who achieved both treatment targets was similar in the intervention (423 of 2156; 19.6%) and control groups (466 of 2321; 20.1%; relative risk, 1.06; 95% CI, 0.85–1.32). Further, no statistically significant differences were found for a number of secondary outcomes, including risk factor screening, preventive medication prescribing, and risk factor levels. Use of intervention components was low; it was highest for HealthTracker, used at least once for 347 of 3236 undertreated patients with high CVD risk (10.7%). Conclusions Despite evidence for the efficacy of its individual components, the INTEGRATE intervention was not broadly implemented and did not improve CVD risk management in participating Australian general practices.

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Data sources and study selection

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Conclusion

Private-label products, products owned by supermarkets, are a growing area of the food supply. The aim of this study was to assess the effect of an intervention that provided an Australian supermarket (‘intervention supermarket’) with comparative nutrition data to improve the healthiness of their private-label range. Between 2015 and 2016, the intervention supermarket received reports that ranked the nutritional quality of their products against competitors. Changes in the nutrient content (sodium, sugar, saturated fat, energy and Health Star Rating) of products from the intervention supermarket between 2015 and 2018 were compared against changes achieved for three comparators (private-label products from two other supermarkets and branded products). The intervention supermarket achieved a significantly greater reduction in the sodium content of their products relative to all three comparators, which ranged between −104 and −52 mg/100 g (all p < 0.05). Conversely, the three comparators each achieved a greater relative reduction in the sugar content of their products by between −3.5 and −1.6 g/100 g (all p < 0.05). One of the comparators also had a greater relative reduction in the saturated fat and energy content of their products compared to the intervention supermarket (both p < 0.05). There were negligible differences in the Health Star Rating of products between the intervention supermarket and comparators (all p > 0.05). Providing comparative nutrition information to a supermarket may be ineffective in improving the healthiness of their private-label products, likely due to competing factors that play a role in the decision-making process behind product reformulation and product discontinuation/innovation.

Background: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). Methods: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. Results: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). Conclusions: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

BACKGROUND: Physical manipulation of the manufactured dose form is a common practice, with almost a quarter of all drugs administered in primary care having their dose altered. Splitting a tablet can be advantageous as it facilitates swallowing, allows for dose flexibility and provides cost reductions. However, there are concerns these physical changes can lead to inaccurate portions resulting in significant variations from the prescribed dose. Thus, the review described in this protocol aims to summarise the literature assessing the effect of tablet splitting on dose accuracy. METHODS: Relevant studies will be identified through electronic searches in databases including EMBASE, MEDLINE, CINAHL, and the Cochrane Library, from the beginning of databases until January 2020. Studies investigating any drug, where the tablet was split, will be potentially eligible. Two reviewers will independently screen studies and extract data using standardised forms. Data extracted will include general study information, characteristics of the study, intervention characteristics and outcomes. Primary outcome is to assess dose accuracy of a split tablet measured by drug content or weight variability. Assessment of risk of bias will be dependent upon study design. If deemed feasible, meta-analysis will be performed. RESULTS: The study described within this protocol will provide a synthesis of current evidence assessing the effect of tablet splitting on dose accuracy. CONCLUSION: The conclusion of our study will provide evidence to judge whether splitting a tablet results in an accurate half dose. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. The results of the systematic review described will be published in a peer-reviewed journal. REGISTRATION DETAILS: PROSPERO CRD42018106252.