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Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m 2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m 2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly become a global health pandemic. Among the viral proteins, RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as a promising target against SARS-CoV-2 infection. Dietary bioactive compounds represent an important source of evolutionarily optimized molecules with antiviral properties against SARS-CoV-2 RdRp. We investigated the inhibitory potential effects of different phytochemicals against SARS-CoV-2 RdRp, including andrographolide, kaempferol, resveratrol, and silibinin. Unlike the other investigated compounds, kaempferol exhibited a significant dose-dependent in vitro inhibition of SARS-CoV-2 RdRp activity. To assess the binding interactions and stability of the SARS-CoV-2 RdRp-kaempferol complex, we performed in silico techniques, including molecular docking, quantum chemical calculation, and molecular dynamics simulations. We found strong binding affinities and stability between kaempferol and SARS-CoV-2 RdRp variants (Wuhan and Omicron). These findings provide valuable insights into the antiviral properties of kaempferol as a stable inhibitor of SARS-CoV-2 RdRp.Communicated by Ramaswamy H. Sarma.

Background: We examined the trajectory of estimated glomerular filtrate rate (eGFR), associated risk factors, and its relationship with end-stage kidney disease (ESKD) among a multiethnic patient population with type 2 diabetes in Singapore., Methods: A follow-up study included 62 080 individuals with type 2 diabetes aged ≥18 years in a multi-institutional SingHealth Diabetes Registry between 2013 and 2019. eGFR trajectories were analyzed using latent class linear mixed models. Factors associated with eGFR trajectories were evaluated using multinomial logistic regression. The association of eGFR trajectories with ESKD was assessed via competing risk models., Results: Trajectory of kidney function, determined by eGFR, was nonlinear. The trajectory pattern was classified as stable initially then gradual decline (75%), progressive decline (21.9%), and rapid decline (3.1%). Younger age, female sex, Malay ethnicity, lower-income housing type, current smoking, higher glycated hemoglobin, lower low-density lipoprotein, higher triglyceride, uncontrolled blood pressure, albuminuria, cardiovascular disease, hypertension, and higher eGFR levels each were associated with progressive or rapid decline. Compared with the trajectory of stable initially then gradual eGFR decline, progressive decline increased the hazard of ESKD by 6.14-fold (95% confidence interval [CI]: 4.96-7.61)) and rapid decline by 82.55 folds (95% CI: 55.90-121.89)., Conclusions: Three nonlinear trajectory classes of kidney function were identified among multiethnic individuals with type 2 diabetes in Singapore. About one in four individuals had a progressive or rapid decline in eGFR. Our results suggest that eGFR trajectories are correlated with multiple social and modifiable risk factors and inform the risk of ESKD., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear., Purpose: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death., Data Sources: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023., Study Selection: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 ., Data Extraction: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m 2 ), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes., Data Synthesis: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m 2 , of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes ( P for interaction > 0.05 for all)., Limitation: Individual participant-level data for hyperkalemia or acute kidney injury were not available., Conclusion: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD., Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42022307589)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3236.

Background: The SingHypertension primary care clinic intervention, which consisted of clinician training in hypertension management, subsidized single-pill combination medications, nurse-delivered motivational conversations and telephone follow-ups, improved blood pressure control and cardiovascular disease (CVD) risk scores relative to usual care among patients with uncontrolled hypertension in Singapore. This study quantified the incremental cost-effectiveness, in terms of incremental cost per unit reduction disability-adjusted life years, of SingHypertension relative to usual care for patients with hypertension from the health system perspective., Methods and Results: We developed a Markov model to simulate CVD events and associated outcomes for a hypothetical cohort of patients over a 10-year period. Costs were measured in US dollars, and effectiveness was measured in disability-adjusted life years averted. We present base-case results and conducted deterministic and probabilistic sensitivity analyses. Based on a willingness-to-pay threshold of US $55 500 per DALY averted, SingHypertension was cost-effective for patients with hypertension (incremental cost-effectiveness ratio: US $24 765 per disability-adjusted life year averted) relative to usual care. This result held even if risk reduction was assumed to decline linearly to 0 over 10 years but not sooner than 7 years. Incremental cost-effectiveness ratios were most sensitive to the magnitude of the reduction in CVD risk; at least a 0.13% to 0.16% point reduction in 10-year CVD risk is required for cost-effectiveness. Probabilistic sensitivity analysis indicates that SingHypertension has a 78% chance of being cost-effective at the willingness-to-pay threshold., Conclusions: SingHypertension represents good value for the money for reducing CVD incidence, morbidity, and mortality and should be considered for wide-scale implementation in Singapore and possibly other countries., Registration Information: REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02972619.

Hypertension is a leading risk factor for cardiovascular disease in South Asia. The authors aimed to assess the cross-country differences in 24-h ambulatory, daytime, and nighttime systolic blood pressure (SBP) among rural population with uncontrolled clinic hypertension in Bangladesh, Pakistan, and Sri Lanka. The authors studied patients with uncontrolled clinic hypertension (clinic BP ≥ 140/90 mmHg) who underwent ambulatory blood pressure monitoring (ABPM) during the baseline assessment as part of a community-based trial. The authors compared the distribution of ABPM profiles of patients across the three countries, specifically evaluating ambulatory SBP levels with multivariable models that adjusted for patient characteristics. Among the 382 patients (mean age, 58.3 years; 64.7% women), 56.5% exhibited ambulatory hypertension (24-h ambulatory BP ≥ 130/80 mmHg), with wide variation across countries: 72.6% (Bangladesh), 50.0% (Pakistan), and 51.0% (Sri Lanka; P < .05). Compared to Sri Lanka, adjusted mean 24-h ambulatory, daytime, and nighttime SBP were higher by 12.24 mmHg (95% CI 4.28-20.20), 11.96 mmHg (3.87-20.06), and 12.76 mmHg (4.51-21.01) in Bangladesh, separately. However, no significant differences were observed between Pakistan and Sri Lanka (P > .05). Additionally, clinic SBP was significantly associated with 24-h ambulatory (mean 0.38, 95% CI 0.28-0.47), daytime (0.37, 0.27-0.47), and nighttime SBP (0.40, 0.29-0.50) per 1 mmHg increase. The authors observed substantial cross-country differences in the distribution of ABPM profiles among patients with uncontrolled clinic hypertension in rural South Asia. The authors findings indicated the need to incorporate 24-h BP monitoring to mitigate cardiovascular risk, particularly in Bangladesh., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

High blood pressure causes over 10 million preventable deaths annually globally. Populations in low- and middle-income countries suffer the most, experiencing increased uncontrolled blood pressure and cardiovascular disease (CVD) deaths. Despite improvements in high-income countries, disparities persist, notably in the United States, where Black individuals face up to 4× higher CVD mortality than White individuals. Social determinants of health encompass complex, multidimensional factors linked to an individual's birthplace, upbringing, activities, residence, workplaces, socioeconomic and environmental structures, and significantly affect health outcomes, including hypertension and CVD. This review explored how social determinants of health drive disparities in hypertension and related CVD morbidity from a socioecological and life course perspective. We present evidence-based strategies, emphasizing interventions tailored to specific community needs and cross-sector collaboration to address health inequalities rooted in social factors, which are key elements toward achieving the United Nations' Sustainable Development Goal 3.4 for reducing premature CVD mortality by 30% by 2030., Competing Interests: Disclosures None.

Background: We aimed to explore the three-way interaction among age, gender, and kidney function on the risk of all-cause mortality and cardiovascular mortality among patients with type 2 diabetes (T2D)., Methods: In a retrospective cohort study, patients aged > 40 years with T2D with serum creatinine and urine albumin measured from 2013 to 2019 were included from a multi-institutional diabetes registry. The exposure was estimated glomerular filtration rate (eGFR), outcomes were all-cause mortality (primary outcome) and cardiovascular disease (CVD) mortality (secondary outcome). We applied multivariable cox proportional hazards regression analysis to compute the association between eGFR and mortality., Results: A total of 36,556 patients were followed for up to 6 years during which 2492 (6.82%) died from all causes, and 690 (1.9%) died from CVD. We observed a significant three-way interaction (p = 0.021) among age (younger, < 65; older, ≥65 years), gender and eGFR for the risk of all-cause mortality. Using age- and gender-specific eGFR of 90 ml/min/1.73m 2 as the reference point, the adjusted hazard rate (HR) (95% CI) for all-cause mortality at eGFR of 40 ml/min/1.73m 2 was 3.70 (2.29 to 5.99) in younger women and 1.86 (1.08 to 3.19) in younger men. The corresponding adjusted HRs in older women and older men were 2.38 (2.02 to 2.82) and 2.18 (1.85 to 2.57), respectively. Similar results were observed for CVD deaths, although the three-way interaction was not statistically significant. Sensitivity analysis yielded similar results., Conclusions: In this T2D population, younger women with reduced kidney function might be more susceptible to higher risks of all-cause mortality and CVD mortality than younger men., (© 2024. The Author(s).)

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Elevated blood pressure (BP) is associated with increased risk of cardiovascular mortality. However, there is ongoing debate whether intensive BP lowering may paradoxically increase the risk of cardiovascular disease (CVD), especially in patients with type 2 diabetes (T2D). We investigated the association of BP with risk of CVD mortality in patients with T2D., Methods and Results: We used data on 83 721 patients with T2D from a multi-institutional diabetes registry in Singapore from 2013 to 2019. BP was analyzed as categories and restricted cubic splines using Cox multivariable regression analysis stratified by preexisting CVD and age (<65 years versus ≥65 years). The primary outcome was CVD mortality, determined via linkage with the national registry. Among 83 721 patients with T2D (mean age 65.3 years, 50.6% women, 78.9% taking antihypertensive medications), 7.6 per 1000 person-years experienced the primary outcome. Systolic BP had a graded relationship with a significant increase in CVD mortality at levels >120 to 129 mm Hg. Diastolic BP levels >90 mm Hg were significantly associated with CVD mortality in those aged ≥65 years. In addition, diastolic BP <70 mm Hg was associated with a significantly higher risk of CVD mortality in all patients., Conclusions: In patients with T2D, clinic systolic BP levels ≥130 mm Hg or diastolic BP levels ≥90 mm Hg are associated with higher risk of CVD mortality. Diastolic BP <70 mm Hg is also associated with the risk of adverse CVD outcomes, although reverse causality cannot be ruled out.

Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests / declare the following activities and relationships: Dr Kamran Siddiqi's time is supported by a research grant from National Institute for Health and Care Research Grant (NIHR 203248). Dr Adnan Khan's personal time for this work was covered by a Bill & Melinda Gates Foundation [grant number: INV-025171].

Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min -1 per 1.73 m 2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R 2 ) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R 2  = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: This study aims to examine the impact of COVID-19 measures on wellbeing and self-management in medically vulnerable non-COVID patients and their views of novel modalities of care in Singapore., Methods: Patients with cardiovascular disease (CVD), respiratory disease, chronic kidney disease, diabetes and cancer were recruited from the SingHealth cluster and national cohort of older adults. Data on demographics, chronic conditions and perceived wellbeing were collected using questionnaire. We performed multivariable regression to examine factors associated with perceived wellbeing. Qualitative interviews were conducted to elicit patient's experience and thematically analyzed., Results: A total of 91 patients participated. Male patients compared with female patients perceived a lower impact of the pandemic on subjective wellbeing. Patients with CVD compared to those having conditions other than CVD perceived a lower impact. Impacts of the pandemic were primarily described in relation to emotional distress and interference in maintaining self-care. Hampering of physical activity featured prominently, but most did not seek alternative ways to maintain activity. Despite general willingness to try novel care modalities, lack of physical interaction and communication difficulties were perceived as main barriers., Discussion: Findings underline the need to alleviate emotional distress and develop adaptive strategies to empower patients to maintain wellbeing and self-care.

Significance Statement: Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression., Background: Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown., Methods: Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination., Results: Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were -0.41 (95% Bayesian Credible Interval, -0.64 to -0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and -0.06 (95% Bayesian Credible Interval, -0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up., Conclusions: In Phase 2 trials of CKD with sample sizes of 100-200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points., (Copyright © 2023 by the American Society of Nephrology.)

Background: Effective interventions during the coronavirus disease 2019 (COVID-19) pandemic require an understanding of patients' knowledge and perceptions that influence their behaviour. Our study assessed knowledge of COVID-19 among kidney transplant recipients and donors, hitherto unevaluated., Methods: We conducted a cross-sectional survey among 325 kidney transplant recipients and 172 donors between 1 May 2020 and 30 June 2020. The survey questionnaire assessed knowledge levels of COVID-19, sociodemographic data, health status, psychosocial impact of COVID-19 and precautionary behaviours during the pandemic., Results: The mean COVID-19 knowledge score of the study population was 7.5 (standard deviation: 2.2) out of 10. The mean score was significantly higher among kidney recipients compared to kidney donors (7.9 [1.9] vs. 6.7 [2.6]; P <0.001). Younger age (21-49 vs. ≥50 years) and higher education (diploma and higher vs. secondary and lower) were associated with significantly higher knowledge scores in donors, but not among recipients (P-interactions ≤0.01). In both kidney recipients and donors, financial concerns and/or social isolation were associated with lower knowledge levels., Conclusions: Concerted efforts are needed to improve COVID-19 knowledge in kidney transplant recipients and donors, particularly older donors, donors with lower education and patients with financial concerns or feelings of social isolation. Intensive patient education may mitigate the impact of education levels on COVID-19 knowledge levels., Competing Interests: None

Sirtuin 1 (SIRT1) belongs to the histone deacetylase enzyme family and its activity regulates various signaling networks associated with aging. SIRT1 is widely involved in a large number of biological processes, including senescence, autophagy, inflammation, and oxidative stress. In addition, SIRT1 activation may improve lifespan and health in numerous experimental models. Therefore, SIRT1 targeting is a potential strategy to delay or reverse aging and age-related diseases. Although SIRT1 is activated by a wide array of small molecules, only a limited number of phytochemicals that directly interact with SIRT1 have been identified. Using the Geroprotectors.org database and a literature search, the aim of this study was to identify geroprotective phytochemicals that might interact with SIRT1. We performed molecular docking, density functional theory studies, molecular dynamic simulations (MDS), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction to screen potential candidates against SIRT1. After the initial screening of 70 phytochemicals, crocin, celastrol, hesperidin, taxifolin, vitexin, and quercetin had significant binding affinity scores. These six compounds established multiple hydrogen-bonding and hydrophobic interactions with SIRT1 and showed good drug-likeness and ADMET properties. In particular, crocin was further analyzed using MDS to study its complex with SIRT1 during simulation. Crocin has a high reactivity to SIRT1 and can form a stable complex with it, showing a good ability to fit into the binding pocket. Although further investigations are required, our results suggest that these geroprotective phytochemicals, especially crocin, are novel interacting partners of SIRT1., Competing Interests: Conflicts of interests The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Spot urine samples with estimating equations have been used to assess individuals' sodium (salt) intake in association with health outcomes. There is large random and systematic error in estimating sodium intake using this method and spurious health outcome associations. Substantial controversy has resulted from false claims the method is valid. Hence, the World Hypertension League, International Society of Hypertension and Resolve to Save Lives, supported by 21 other health organizations, have issued this policy statement that strongly recommends that research using spot urine samples with estimating equations to assess individuals' sodium (salt) intake in association with health outcomes should not be conducted, funded or published. Literature reviews on the health impacts of reducing dietary sodium that include studies that have used spot and short duration timed urine samples with estimating equations need to explicitly acknowledge that the method is not recommended to be used and is associated with spurious health outcome associations., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework., Competing Interests: Conflict of interest: A.E.S. received speaker honoraria from different pharmaceutical companies and device manufacturers for work unrelated to this paper; P.M.N. has received speaker honoraria from different pharmaceutical companies. K.K. reports research grants from A&D, Omron Healthcare, Fukuda Denshi, Otsuka Pharmaceutical, Otsuka Holdings, CureApp, Sanwa Kagaku Kenkyusho, Daiichi Sankyo, Taisho Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Boehringer-Ingelheim Japan, Pfizer Japan, Fukuda Lifetec, Bristol-Myers Squibb, Mochida Pharmaceutical, Roche Diagnostics; and Consulting fees from A&D, JIMRO, Omron Healthcare, CureApp, Kyowa Kirin, Sanwa Kagaku Kenkyusho, Terumo, Fukuda Denshi, Mochida Pharmaceutical; and Honoraria from Idorsia, Omron Healthcare, Daiichi Sankyo, Novartis Pharma, Mylan EPD; and Participation in Advisory Board of Daiichi Sankyo, Novartis Pharma, Fukuda Denshi outside the submitted work. J.-G.W. reports having received lecture and consulting fees from Novartis, Omron, Servier, and Viatris. M.P.S. has received consulting fees, and/or travel and research support from Medtronic, Abbott, Metavention, ReCor, Novartis, Servier, Pfizer, and Boehringer-Ingelheim. E.S.W.J. has received honoraria from pharmaceutical companies for work unrelated to this publication. N.R.P. has received financial support from several pharmaceutical companies which manufacture BP-lowering agents, for consultancy fees (Servier), research projects, and staff (Servier, Pfizer) and for arranging and speaking at educational meetings (AstraZeneca, Lri Therapharma, Napi, Servier, Sanofi, Eva Pharma, Pfizer, Glenmark Pharma, Alkem Lab, and Emcure India). He holds no stocks and shares in any such companies. This manuscript was handled by Guest Editor Thomas F. Lüscher, (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Quinoa ( Chenopodium quinoa ) is a grain-like, genetically diverse, highly complex, nutritious, and stress-tolerant food that has been used in Andean Indigenous cultures for thousands of years. Over the past several decades, numerous nutraceutical and food companies are using quinoa because of its perceived health benefits. Seeds of quinoa have a superb balance of proteins, lipids, carbohydrates, saponins, vitamins, phenolics, minerals, phytoecdysteroids, glycine betaine, and betalains. Quinoa due to its high nutritional protein contents, minerals, secondary metabolites and lack of gluten, is used as the main food source worldwide. In upcoming years, the frequency of extreme events and climatic variations is projected to increase which will have an impact on reliable and safe production of food. Quinoa due to its high nutritional quality and adaptability has been suggested as a good candidate to offer increased food security in a world with increased climatic variations. Quinoa possesses an exceptional ability to grow and adapt in varied and contrasting environments, including drought, saline soil, cold, heat UV-B radiation, and heavy metals. Adaptations in salinity and drought are the most commonly studied stresses in quinoa and their genetic diversity associated with two stresses has been extensively elucidated. Because of the traditional wide-ranging cultivation area of quinoa, different quinoa cultivars are available that are specifically adapted for specific stress and with broad genetic variability. This review will give a brief overview of the various physiological, morphological and metabolic adaptations in response to several abiotic stresses., Competing Interests: The authors declare that they have no competing interests., (© 2023 Ain et al.)

Background: The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope., Methods: We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR <15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero., Results: There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [-0.05 to 0.03]; baseline UACR [-0.02 to 0.04]; CKD progression rate [-0.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [-0.11 to -0.02]; CKD progression rate [0.01 to 0.15])., Conclusions: These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations., (Copyright © 2023 by the American Society of Nephrology.)

Background: Inconsistent conclusions in past studies on the association between poor glycaemic control and the risk of hospitalization for heart failure (HHF) have been reported largely due to the analysis of non-trajectory-based HbA1c values. Trajectory analysis can incorporate the effects of HbA1c variability across time, which may better elucidate its association with macrovascular complications. Furthermore, studies analysing the relationship between HbA1c trajectories from diabetes diagnosis and the occurrence of HHF are scarce., Methods: This is a prospective cohort study of the SingHealth Diabetes Registry (SDR). 17,389 patients diagnosed with type 2 diabetes mellitus (T2DM) from 2013 to 2016 with clinical records extending to the end of 2019 were included in the latent class growth analysis to extract longitudinal HbA1c trajectories. Association between HbA1c trajectories and risk of first known HHF is quantified with the Cox Proportional Hazards (PH) model., Results: 5 distinct HbA1c trajectories were identified as 1. low stable (36.1%), 2. elevated stable (40.4%), 3. high decreasing (3.5%), 4. high with a sharp decline (10.8%), and 5. moderate decreasing (9.2%) over the study period of 7 years. Poorly controlled HbA1c trajectories (Classes 3, 4, and 5) are associated with a higher risk of HHF. Using the diabetes diagnosis time instead of a commonly used pre-defined study start time or time from recruitment has an impact on HbA1c clustering results., Conclusions: Findings suggest that tracking the evolution of HbA1c with time has its importance in assessing the HHF risk of T2DM patients, and T2DM diagnosis time as a baseline is strongly recommended in HbA1c trajectory modelling. To the authors' knowledge, this is the first study to identify an association between HbA1c trajectories and HHF occurrence from diabetes diagnosis time., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multicomponent, community health-worker (CHW)-led hypertension management program, has been shown to be effective in rural communities in South Asia. This paper presents the acceptability of COBRA-BPS multicomponent intervention among the key stakeholders., Methods: We conducted post-implementation interviews of 87 stakeholder including 23 community health workers (CHWs), 19 physicians and 45 patients in 15 rural communities randomized to COBRA-BPS multicomponent intervention in in Bangladesh, Pakistan, and Sri Lanka. We used Theoretical Framework for Acceptability framework (TFA) with a focus on affective attitude, burden, ethicality, intervention coherence, opportunity cost, perceived effectiveness and self-efficacy., Results: COBRA-BPS multicomponent intervention was acceptable to most stakeholders. Despite some concerns about workload, most CHWs were enthusiastic and felt empowered. Physicians appreciated the training sessions and felt trusted by their patients. Patients were grateful to receive the intervention and valued it. However, patients in Pakistan and Bangladesh expressed the need for supplies of free medicines from the primary health facilities, while those in Sri Lanka were concerned about supplies' irregularities. All stakeholders favoured scaling-up COBRA-BPS at a national level., Conclusions: COBRA-BPS multicomponent intervention is acceptable to the key stakeholders in Bangladesh, Pakistan and Sri Lanka. Community engagement for national scale-up of COBRA-BPS is likely to be successful in all three countries., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jafar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach., Methods: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets., Results: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline., Conclusion: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD., Competing Interests: Conflict of interest: Ku.M. reports grants from NIDDK; grants and personal fees from Kyowa Kirin, personal fees from Akebia outside the submitted work. M.G. reports grants from NIH and National Kidney Foundation outside the submitted work. J.A. reports personal fees from AstraZeneca, Novartis, and Boerhinger Ingelheim outside the submitted work. A.R.C. reports personal fees from Novartis, Reata, and Amgen; grants from Novo Nordisk outside the submitted work. N.E. reports personal fees from Bayer and AG Leverkusen outside the submitted work. K.E. reports grants from Amgen, Astra Zenceca, Bayer, Evotec, and Vifor; personal fees from Akebia, Astra Zeneca, Bayer, Otsuka, and Retrophin outside the submitted work. S.K.J reports salary support from US Government and Department of Veterans Affairs during the conduct of the study. C.K. reports personal fees from Bayer, Abbott, Astra-Zeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Reata, Boehringer Ingelheim, and GSK outside the submitted work. A.S.L. reports grants and contracts from NIH and NKF for studies in CKD and a contract from AstraZeneca for DSMB for clinical trials of dapagliflozin. Ka.M. reports grants from Ministry of Health, Labor, and Welfare, Japan. G.N.N reports personal fees from Renalytix, Daiichi Sankyo, Menarini Medical, Qiming Capital, and Variant Bio; other fees from Pensieve Health, Nexus I Connect outside the submitted work; patent KidneyIntelX pending to Renalytix. M.G.S. reports grants from NIH- NIA/NIDDK/NHLBI during the conduct of the study; personal fees from Cricket Health, Intercept Pharmaceuticals, Bayer Pharmaceuticals, AztraZeneca, Boeringer Ingelheim; grants from Bayer Pharmaceuticals outside the submitted work. M.D.S reports a honoraria from AstraZeneca outside the submitted work. N.S. is a current employee of GSK and employed at AMGA. M.W. reports personal fees from Amgen and Freeline outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation, during the conduct of the study; personal fees from Healthy.io and SomaLogic outside the submitted work. No other potential conflicts of interest relevant to this article were reported. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The availability of electronic health records and access to a large number of routine measurements of serum creatinine and urinary albumin enhance the possibilities for epidemiologic research in kidney disease. However, the frequency of health care use and laboratory testing is determined by health status and indication, imposing certain challenges when identifying patients with kidney injury or disease, when using markers of kidney function as covariates, or when evaluating kidney outcomes. Depending on the specific research question, this may influence the interpretation, generalizability, and/or validity of study results. This review illustrates the heterogeneity of working definitions of kidney disease in the scientific literature and discusses advantages and limitations of the most commonly used approaches using 3 examples. We summarize ways to identify and overcome possible biases and conclude by proposing a framework for reporting definitions of exposures and outcomes in studies of kidney disease using routinely collected health care data., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The acute coronary syndrome is one of the commonest life-threatening illnesses. It encompasses the clinical spectrum of acute myocardial ischemia and includes unstable angina and acute myocardial infarction both with and without ST segment elevation. The acute coronary syndrome can be attributed to a significant hemodynamic insult that leads to atherosclerosis of the epicardial coronary arteries. The main causative risk factors, such as obesity, smoking, and alcohol intake, increase the burden of acute coronary syndrome. Owing to an increase in the utilization of antioxidants, the antioxidant capacity decreases concerning the scavenging of lipid peroxides. Moreover, the thyroid hormones are important regulators of the expression of cardiac genes, and many of the cardiac manifestations of thyroid dysfunction are associated with alterations in triiodothyronine- mediated gene expression. Cardiovascular signs and symptoms of thyroid disease are among the most acute clinically relevant findings that occur in combination with both hypothyroidism and hyperthyroidism. By understanding the cellular mechanism of the action of thyroid hormones on the heart and cardiovascular system, it is possible to explain rhythm disturbances and alterations in cardiac output, blood pressure, cardiac contractility, and vascular resistance that result from thyroid dysfunction. Oxidative stress is thereby induced, together with a decrease in antioxidant capacity for overcoming oxidative stress, which leads to endothelial dysfunction, subsequent atherosclerosis, and, ultimately, acute myocardial infarction. The implications for the identification of the effects of thyroid disease on acute myocardial infarction include the observation that restoration of normal thyroid function repeatedly reverses abnormalities in cardiovascular hemodynamics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Most of the global non-communicable disease (NCD)-related death burden is borne by low and middle-income countries (LMICs). In LMICs like Pakistan, however, a major gap in responding to NCDs is a lack of high-quality research leading to policy development and implementation of NCDs. To assess institutional opportunities and constraints to NCD research and training we conducted a situational analysis for NCD research and training at Aga Khan University Pakistan., Methods: We conducted a descriptive exploratory study using grounded theory as a qualitative approach: semistructured interviews of 16 NCD stakeholders (three excluded) and two focus group discussions with postgraduate and undergraduate trainees were conducted. A simple thematic analysis was done where themes were identified, and then recurring ideas were critically placed in their specific themes and refined based on the consensus of the investigators., Results: The major themes derived were priority research areas in NCDs; methods to improve NCD research integration; barriers to NCD research in LMICs like Pakistan; design of NCD research programme and career paths; and NCD prevention at mass level, policy and link to the government. In general, participants opined that while there was an appetite for NCD research and training, but few high-quality research training programmes in NCDs existed, such programmes needed to be established. The ideal NCD research and training programmes would have in-built protected time, career guidance and dedicated mentorship. Most participants identified cardiovascular diseases as a priority thematic area and health information technology and data science as key methodological approaches to be introduced into research training., Conclusion: We conclude from this qualitative study on NCD research and training that high-quality research training programmes for NCDs are rare. Such programmes need to be established with in-built protected time, career guidance and mentorship for the trainees to improve their research capacity in Pakistan., Competing Interests: Competing interests: ZS has receioved funding from Bill & Melinda Gates Foundation (INV-021944, INV-050389) Fogarty International Center of the National Institutes of Health (D43TW011625); NIHR, UK; Yale University; Duke University; Certara Inc; PHRI., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiovascular disease is a major cause of morbidity and mortality in kidney transplant recipients. Trial evidence to improve cardiovascular outcomes is limited by inconsistent reporting of outcomes, which may also lack patient-relevance. This study aimed to assess the range and consistency of cardiovascular outcomes reported by contemporary trials in kidney transplant recipients., Methods: A systematic review of all randomized controlled trials involving adult kidney transplant recipients that reported at least 1 cardiovascular outcome from January 2012 to December 2019 was performed, including Embase, MEDLINE, Cochrane, and ClinicalTrials.gov electronic databases. Trial characteristics were extracted and all levels of specification of the cardiovascular outcome measures reported were analyzed (the measure definition, metric' and method of aggregation). Measures assessing a similar aspect of cardiovascular disease were categorized into outcomes., Results: From 93 eligible trials involving 27 609 participants, 490 outcome measures were identified. The outcome measures were grouped into 38 outcomes. A cardiovascular composite was the most common outcome reported (40 trials, 43%) followed by cardiovascular mortality (42%) and acute coronary syndrome (31%). Cardiovascular composite was also the most heterogeneous outcome with 77 measures reported followed by cardiovascular mortality (n = 58) and inflammatory biomarkers (n = 51). The most common cardiovascular composite outcome components reported were major cardiovascular events (18 trials), stroke unspecified (11 trials), and myocardial infarction unspecified (10 trials)., Conclusions: There is substantial heterogeneity in cardiovascular outcome reporting in kidney transplant trials., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Competing Interests: Conflict of interest: N.R.P. has received financial support from several pharmaceutical companies which manufacture BP-lowering agents, for consultancy fees (Servier, Aktiia), research projects and staff (Servier, Pfizer), and for arranging and speaking at educational meetings (AstraZeneca, Lri Therapharma, Napi, Servier, Sanofi, Eva Pharma, Pfizer, Emcure India, Dr Reddy’s Laboratories). He holds no stocks and shares in any such companies. He is the Chairman of the Steering Committee of the TIME trial. C.B., A.D., T.H.J., N.A.K., Y.K., D.P., W.W., T.B. have no conflicts of interest to declare. M.P.S. has received consulting fees, and/or travel and research support (Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer-Ingelheim). G.S.S. received consulting and lecture fees (Servier and OMRON). T.U. has received honoraria for lectures and advice during the last 3 years (Boehringer-Ingelheim, ICI, Synlab, Vifor, Cipla-India, and Abbott). A.E.S. received speaker honoraria and/or travel support from Omron, Servier, Takeda, Sanofi, Sun pharmaceuticals, and Abbott. P.M.N. received lecturing fees from Novartis, Novo Nordisk, Boehringer-Ingeheim, and Amgen during recent years. He is a member of a regional advisory group for Sanofi. C.B. has received consulting and/or speaker’s fees (Novartis, Servier, Novo Nordisk, Menarini, Alfasigma).

Objective: The Pre-Diabetes Interventions and Continued Tracking to Ease-out Diabetes (Pre-DICTED) Program is a diabetes prevention trial comparing the diabetes conversion rate at 3 years between the intervention group, which receives the incentivized lifestyle intervention program with stepwise addition of metformin, and the control group, which receives the standard of care. We describe the baseline characteristics and compare Pre-DICTED participants with other diabetes prevention trials cohort., Research Design and Methods: Participants were aged between 21 and 64 years, overweight (body mass index (BMI) ≥23.0 kg/m 2 ), and had pre-diabetes (impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT))., Results: A total of 751 participants (53.1% women) were randomized. At baseline, mean (SD) age was 52.5 (8.5) years and mean BMI (SD) was 29.0 (4.6) kg/m 2 . Twenty-three per cent had both IFG and IGT, 63.9% had isolated IGT, and 13.3% had isolated IFG. Ethnic Asian Indian participants were more likely to report a family history of diabetes and had a higher waist circumference, compared with Chinese and Malay participants. Women were less likely than men to meet the physical activity recommendations (≥150 min of moderate-intensity physical activity per week), and dietary intake varied with both sex and ethnicity. Compared with other Asian diabetes prevention studies, the Pre-DICTED cohort had a higher mean age and BMI., Conclusion: The Pre-DICTED cohort represents subjects at high risk of diabetes conversion. The study will evaluate the effectiveness of a community-based incentivized lifestyle intervention program in an urban Asian context., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A smooth, exceptionally sensitive, correct, and extra reproducible RP-HPLC technique was developed and demonstrated to estimate Sofosbuvir (SOF) in pharmaceutical dosage formulations. This process was carried out by Agilent High-Pressure Liquid Chromatograph 1260 with GI311C Quat. Pump, Phenomenex Luna C-18 (150 mm × 4.6 mm × 5 μm) (USA), and Photodiode Array Detector (PDA) G1315D. The cell section, including acetonitrile and methanol with 80:20 v/v and solution (B) 0.1% phosphoric acid (40:60), was used for the study. However, 10 μL of the sample was injected with a drift flow of 1 mL/min. The separation occurred at a column temperature of 30 °C, and the eluents used PDA set at 260 nm. The retention time of SOF was 5 min. The calibration curve was modified linearly within the range of 0.05-0.15 mg/mL with a correlation coefficient of 0.99 and genuine linear dating among top vicinity and consciousness in the calibration curve. The detection and quantification restrictions were 0.001 and 0.003 mg/mL, respectively. SOF recovery from pharmaceutical components ranged from 98% to 99%. The percentage assay of SOF was 99%. Analytical validation parameters, such as specificity, linearity, precision, accuracy, and selectivity, were studied, and the percentage relative standard deviation (%RSD) was less than 2%. All other key parameters were observed within the desired thresholds. Hence, the proposed RP-HPLC technique was proven effective for developing SOF in bulk and pharmaceutical pill dosage forms. SOF was found to interact with SARS-COV-2 nsp12, and molecular docking results revealed its high affinity and firm binding within the active site groove of nsp12. The key interacting residues include; LYS-72, GLN-75, MET-80 ALA-99, ASN-99, TRP-100, TYR-101 with ASN-99 and TRP-100 forming hydrogen bonds. Molecular Dynamics simulation of SOF and nsp12 complex elucidated that the system was stable throughout 20ns. Therefore, this drug repurposing strategy for SOF can be used for treating COVID-19 infections by performing animal experiments and accurate clinical trials in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To assess the association of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with mortality among older adults in Singapore., Methods: Association of SBP and DBP measured in 2009 for 4443 older adults (69.5±7.4 years; 60-97 years) participating in a nationally representative study with mortality risk through end-December 2015 was assessed using Cox regression., Results: Higher mortality risk was observed at the lower and upper extremes of SBP and DBP. With SBP of 100-119 mmHg as the reference, multivariable mortality hazard ratios [HRs (95% confidence interval)] were SBP <100 mmHg: 2.41 (1.23-4.72); SBP 160-179 mmHg: 1.51 (1.02-2.22); and SBP ≥180 mmHg: 1.78 (1.12-2.81). With DBP of 70-79 mmHg as the reference, HRs were DBP <50 mmHg: 2.41 (1.28-4.54) and DBP ≥110 mmHg: 2.16 (1.09-4.31)., Discussion: Management of high blood pressure among older adults will likely reduce their mortality risk. However, the association of excessively low SBP and DBP values with mortality risk needs further evaluation.

Background: Metal ion aberrant metabolism is essential for health and disease, and its research has sparked a lot of interest. This study aims to compare the critical mineral resources-magnesium (Mg), sodium (Na), calcium (Ca) and potassium (K)-in biological materials (scalp hair, blood, and serum) of 87 Ewing Sarcoma (ES) hypertensive men and women, age range 31-60 years, in an urban area, with 62 nonhypertensive subjects from the same age range and living area., Methods: An atomic-absorption spectrophotometer was used after microwave-induced acid digestion to determine elemental concentrations. The results' authenticity and precision were verified using a traditional wet acid digestion procedure and accredited reference materials. The average convalesces from all elements have been within the 99.2%-99.7% of certified values., Results: In the biological samples from patients with ES hypertension, the amount of Na was found to be higher than in controls. Patients with ES hypertension had lower Mg, K, and Ca levels in their biological samples (scalp hair and blood) than healthy controls of both genders., Conclusions: Ca, Mg, and K deficiency can work with other ES hypertension risk factors. These findings will help physicians and other healthcare professionals determine the depletion of essential micronutrients in the biological samples (blood and scalp hair) of patients with hypertension. After microwave-induced acid digestion, the elemental concentration was determined using an atomic absorption spectrophotometer. The results' authenticity and precision were confirmed using a traditional wet-acid digestion procedure and accredited oriented materials. The average recoveries from all elements have been within the 99.2%-99.7% of certified values., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Nepal is a South Asian country with a high burden of non-communicable diseases. Electronic health technologies are a promising strategy to mitigate the rising burden of non-communicable diseases by strengthening primary healthcare center service delivery. However, electronic health implementation in Nepal is limited. Furthermore, electronic health use at the primary healthcare center level is chronically understudied. This qualitative study seeks to understand the perceived awareness, benefits, and determinants of electronic health uptake in Nepal, focusing on primary healthcare center-level non-communicable disease management., Methods: We conducted in-depth interviews with 27 participants including policymakers, health experts, facility administrators, providers, and non-communicable diseases patients in 2019. We selected six urban primary healthcare center facilities via cluster convenience sampling for recruiting facility administrators, providers, and patients, and used convenience sampling to recruit policymakers and experts. We conducted thematic data analysis inductively and deductively using the electronic health readiness assessment framework to understand perceived barriers and facilitators of electronic health implementation., Results: While there was general awareness and acceptance of electronic health, multiple barriers impede readiness for implementation. These include policy making gaps, language barriers, low user technical literacy, concerns of overreliance on technology, and inadequate training for administrators and providers. Stakeholder suggestions include creating electronic health interfaces that meet the needs of end users (providers and patients), providing training to enable end users to effectively use electronic health technologies, and strong policy support at the national level., Conclusion: We identify several determinants for effectively promoting the use of electronic health for non-communicable diseases service delivery at the primary healthcare center level in Nepal., Competing Interests: Conflict of interest: The author(s) declare that there is no conflict of interest., (© The Author(s) 2022.)

Background: Despite availability of clinical practice guidelines for hypertension management, blood pressure (BP) control remains sub-optimal (<30%) even in high-income countries. This study aims to assess the effectiveness of a potentially scalable multicomponent intervention integrated into primary care system compared to usual care on BP control., Methods and Findings: A cluster-randomized controlled trial was conducted in 8 government clinics in Singapore. The trial enrolled 916 patients aged ≥40 years with uncontrolled hypertension (systolic BP (SBP) ≥140 mmHg or diastolic BP (DBP) ≥90 mmHg). Multicomponent intervention consisted of physician training in risk-based treatment of hypertension, subsidized losartan-HCTZ single-pill combination (SPC) medications, nurse training in motivational conversations (MCs), and telephone follow-ups. Usual care (controls) comprised of routine care in the clinics, no MC or telephone follow-ups, and no subsidy on SPCs. The primary outcome was mean SBP at 24 months' post-baseline. Four clinics (447 patients) were randomized to intervention and 4 (469) to usual care. Patient enrolment commenced in January 2017, and follow-up was during December 2018 to September 2020. Analysis used intention-to-treat principles. The primary outcome was SBP at 24 months. BP at baseline, 12 and 24 months was modeled at the patient level in a likelihood-based, linear mixed model repeated measures analysis with treatment group, follow-up, treatment group × follow-up interaction as fixed effects, and random cluster (clinic) effects. A total of 766 (83.6%) patients completed 2-year follow-up. A total of 63 (14.1%) and 87 (18.6%) patients in intervention and in usual care, respectively, were lost to follow-up. At 24 months, the adjusted mean SBP was significantly lower in the intervention group compared to usual care (-3.3 mmHg; 95% CI: -6.34, -0.32; p = 0.03). The intervention led to higher BP control (odds ratio 1.51; 95% CI: 1.10, 2.09; p = 0.01), lower odds of high (>20%) 10-year cardiovascular risk score (OR 0.67; 95% CI: 0.47, 0.97; p = 0.03), and lower mean log albuminuria (-0.22; 95% CI: -0.41, -0.02; p = 0.03). Mean DBP, mortality rates, and serious adverse events including hospitalizations were not different between groups. The main limitation was no masking in the trial., Conclusions: A multicomponent intervention consisting of physicians trained in risk-based treatment, subsidized SPC medications, nurse-delivered motivational conversation, and telephone follow-ups improved BP control and lowered cardiovascular risk. Wide-scale implementation of a multicomponent intervention such as the one in our trial is likely to reduce hypertension-related morbidity and mortality globally., Trial Registration: Trial Registration: Clinicaltrials.gov NCT02972619., Competing Interests: The authors have declared that no competing interests exist. Author Agnes Koong was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.

Introduction: The burden of chronic kidney disease (CKD) is rising globally including in Singapore. Primary care is the first point of contact for most patients with early stages of CKD. However, several barriers to optimal CKD management exist. Knowing healthcare professionals' (HCPs) perspectives is important to understand how best to strengthen CKD services in the primary care setting. Integrating a theory-based framework, we explored HCPs' perspectives on the facilitators of and barriers to CKD management in primary care clinics in Singapore., Methods: In-depth interviews were conducted on a purposive sample of 20 HCPs including 13 physicians, 2 nurses and 1 pharmacist from three public primary care polyclinics, and 4 nephrologists from one referral hospital. Interviews were audio recorded, transcribed verbatim and thematically analyzed underpinned by the Theoretical Domains Framework (TDF) version 2., Results: Numerous facilitators of and barriers to CKD management identified. HCPs perceived insufficient attention is given to CKD in primary care and highlighted several barriers including knowledge and practice gaps, ineffective CKD diagnosis disclosure, limitations in decision-making for nephrology referrals, consultation time, suboptimal care coordination, and lack of CKD awareness and self-management skills among patients. Nevertheless, intensive CKD training of primary care physicians, structured CKD-care pathways, multidisciplinary team-based care, and prioritizing nephrology referrals with risk-based assessment were key facilitators. Participants underscored the importance of improving awareness and self-management skills among patients. Primary care providers expressed willingness to manage early-stage CKD as a collaborative care model with nephrologists. Our findings provide valuable insights to design targeted interventions to enhance CKD management in primary care in Singapore that may be relevant to other countries., Conclusions: The are several roadblocks to improving CKD management in primary care settings warranting urgent attention. Foremost, CKD deserves greater priority from HCPs and health planners. Multipronged approaches should urgently address gaps in care coordination, patient-physician communication, and knowledge. Strategies could focus on intensive CKD-oriented training for primary care physicians and building novel team-based care models integrating structured CKD management, risk-based nephrology referrals coupled with education and motivational counseling for patients. Such concerted efforts are likely to improve outcomes of patients with CKD and reduce the ESKD burden., (© 2022. The Author(s).)

Objective: This study aimed at determining the feasibility of conducting a large-scale pragmatic effectiveness study on the implementation of multidisciplinary care (MDC) program for patients with advanced chronic kidney disease (CKD)., Methods: This is a single-arm pre-post intervention design pilot study over 12 months. Participants with an estimated glomerular filtration rate (eGFR) between 11 and 20 ml/min/1.73m 2 were screened and recruited at the initial MDC clinic visit and followed for 12 months. Clinical parameters, KDQOL ™ -36, questionnaires, and interviews were collected, administered, and analysed for enrolment and completion rates, baseline characteristics, implementation fidelity, adherence to CKD interventions, eGFR decline, CKD complications, health-related quality of life, and participants' acceptability of the program., Results: The study enrolment and completion rates were 43.1% (50/116 screened) and 66.0% (33/50 recruited) respectively. The participants had a mean age of 68.5 years (SD9.0) and a mean eGFR of 15.4 ml/min/1.73m 2 (3.2). After 12 months of MDC program, there was increased adherence to CKD interventions (difference  - 0.6(1.0), 95%CI  - 1.1,  - 0.1, p = 0.02). There was good participants' acceptability of the program with participants being more satisfied with the waiting time and having a better understanding of kidney failure after attending the program. No difference in the eGFR decline noted (difference 0.0 ml/min/1.73m 2 (5.3), 95%CI  - 1.9, 1.9, p = 1.00)., Conclusion: Our pilot data suggest increased adherence to CKD interventions and good acceptability to MDC program, albeit no difference in eGFR decline probably because of the small sample size. However, reasons for overall low enrolment and completion rates need to be explored and addressed while designing a future large-scale randomised controlled trial., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused significant psychological distress globally. Our study assessed the prevalence of psychological distress and associated factors during COVID-19 pandemic among kidney transplant recipients and kidney donors., Methods: A cross-sectional survey of 497 participants (325 recipients and 172 donors) was conducted from 1st May to 30th June 2020 in Singapore. The survey questionnaire assessed knowledge levels of COVID-19, socio-demographic data, health status, psychosocial impact of COVID-19, and precautionary behaviors during the pandemic. Psychological distress was defined as having anxiety, depression, or stress measured by the validated Depression, Anxiety and Stress Scale-21. Linear regression analyses were used to assess factors associated with higher psychological distress., Results: The prevalence of psychological distress was 14.3% (95% confidence interval: 11.5-17.6%) in the overall population; it was 12.8% (9.79-16.6%) in recipients and 13.4% (9.08-19.6%) in donors with no significant difference (P = 0.67). Younger age (21-49 vs. ≥50 years), unmarried status, non-Singapore citizen, worse health conditions, and worrying about physical and mental health were associated with higher psychological distress. Malays (versus Chinese), taking precautionary measures (hand sanitization), and receiving enough information about COVID-19 were associated with lower psychological distress. No interactions were observed between recipients and donors., Conclusions: At least one in ten recipients and donors suffer from psychological distress during COVID-19 pandemic. Focused health education to younger adults, unmarried individuals, non-Singapore citizens, and those with poor health status could potentially prevent psychological distress in recipients and donors., (© 2022. The Author(s).)

Identifying patients with hypertension at high risk of cardio-metabolic multi-morbidity (CMM) is key for intervention. We examined the independent association of CMM with ethnicity and socioeconomic status (SES) among patients with uncontrolled hypertension. Demographic, socioeconomic, lifestyle, and clinical factors were obtained from 921 patients aged ≥40 years with hypertension in the multiethnic Singapore. CMM was defined as having ≥2 chronic diseases (diabetes mellitus, heart disease, stroke, and chronic kidney disease), which were confirmed by medical records or laboratory measurements. The overall CMM prevalence was 20.9% (95% confidence interval [CI]: 18.4-23.6%). The CMM prevalence was higher in Malays (27.1%) and Indians (30.2%) than Chinese (18.8%), and it was higher among patients with lower SES (ranging from 21.3 to 23.9% using education, employment status, housing ownership and housing types as proxies) compared to those with higher SES (13.1-20.8%). In a multivariate model comprising demographic and socioeconomic factors (age, sex, ethnicity and SES), higher CMM odds were independently associated with ethnic minorities (Malays [OR 1.81; 95% CI: 1.10-2.98] or Indians [OR 2.21; 95% CI: 1.49-3.29] vs. Chinese) and lower SES (unemployment [OR 1.45; 95% CI: 1.02-2.05] and residing in smaller public housing [OR 1.95; 95% CI: 1.16-3.28]). Other correlates of CMM included age, men, central obesity, and poorer dietary quality (lower fruits and vegetables intakes). CMM affected one out of five patients with hypertension in Singapore. Intervention programs should target patients with hypertension, particularly those of ethnic minorities and from lower socioeconomic strata., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects., Methods: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects., Results: The mean acute effect across all studies was -0.21 ml/min per 1.73 m 2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m 2 ). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR., Conclusion: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD., (Copyright © 2022 by the American Society of Nephrology.)

Objectives: Among older adults in China and the US, we aimed to compare the biomarkers of chronic-kidney-diseases (CKD), factors associated with CKD, and the correlation between CKD and mortality., Setting: China and the US., Study Design: Cross-sectional and prospective cohorts., Participants: We included 2019 participants aged 65 and above from the Chinese Longitudinal Healthy Longevity Study (CLHLS) in 2012, and 2177 from US National Health and Nutrition Examination Survey (NHANES) in 2011-2014., Outcomes: Urinary albumin, urinary creatinine, albumin creatinine ratio (ACR), serum creatinine, blood urea nitrogen, plasma albumin, uric acid, and estimated glomerular filtration rate (eGFR). CKD (ACR ≥ 30 mg/g or eGFR< 60 ml/min/1.73m2) and mortality., Analytical Approach: Logistic regression and Cox proportional hazard models. Covariates included age, sex, race, education, income, marital status, health condition, smoking and drinking status, physical activity and body mass index., Results: Chinese participants had lower levels of urinary albumin, ACR, and uric acid than the US (mean: 25.0 vs 76.4 mg/L, 41.7 vs 85.0 mg/g, 292.9 vs 341.3 μmol/L). In the fully-adjusted model, CKD was associated with the risk of mortality only in the US group (hazard ratio [HR], 95% CI: 2.179, 1.561-3.041 in NHANES, 1.091, 0.940-1.266 in CLHLS). Compared to eGFR≥90, eGFR ranged 30-44 ml/min/1.73m2 was only associated with mortality in the US population (HR, 95% CI: 2.249, 1.141-4.430), but not in the Chinese population (HR, 95% CI: 1.408, 0.884-2.241)., Conclusions: The elderly participants in the US sample had worse CKD-related biomarker levels than in China sample, and the association between CKD and mortality was also stronger among the US older adults. This may be due to the biological differences, or co-morbid conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: There is a lack of evidence concerning the effective implementation of strategies for stroke prevention and management, particularly in resource-limited settings. A primary-care-based integrated mobile health intervention (SINEMA intervention) has been implemented and evaluated via a 1-year-long cluster-randomized controlled trial. This study reports the findings from the trial implementation and process evaluation that investigate the implementation of the intervention and inform factors that may influence the wider implementation of the intervention in the future. Methods: We developed an evaluation framework by employing both the RE-AIM framework and the MRC process evaluation framework to describe the implementation indicators, related enablers and barriers, and illustrate some potential impact pathways that may influence the effectiveness of the intervention in the trial. Quantitative data were collected from surveys and extracted from digital health monitoring systems. In addition, we conducted quarterly in-depth interviews with stakeholders in order to understand barriers and enablers of program implementation and effectiveness. Quantitative data analysis and thematic qualitative data analysis were applied, and the findings were synthesized based on the evaluation framework. Results: The SINEMA intervention was successfully implemented in 25 rural villages, reached 637 patients with stroke in rural Northern China during the 12 months of the trial. Almost 90% of the participants received all follow-up visits per protocol, and about half of the participants received daily voice messages. The majority of the intervention components were adopted by village doctors with some adaptation made. The interaction between human-delivered and technology-enabled components reinforced the program implementation and effectiveness. However, characteristics of the participants, doctor-patient relationships, and the healthcare system context attributed to the variation of program implementation and effectiveness. Conclusion: A comprehensive evaluation of program implementation demonstrates that the SINEMA program was well implemented in rural China. Findings from this research provide additional information for program adaptation, which shed light on the future program scale-up. The study also demonstrates the feasibility of combining RE-AIM and MRC process evaluation frameworks in process and implementation evaluation in trials. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03185858., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gong, Sun, Long, Xu, Gu, Bettger, Tan, Ma, Jafar, Oldenburg and Yan.)

Background: Asian populations are at high risk of diabetes and related vascular complications. We examined risk factor control, preventive care, and disparities in these trends among adults with diabetes in Singapore., Methods: The sample included 209,930 adults with diabetes aged≥18 years from a multi-institutional SingHealth Diabetes Registry between 2013 and 2019 in Singapore. We performed logistic generalized estimating equations (GEEs) regression analysis and used linear mixed effect modeling to evaluate the temporal trends., Results: Between 2013 and 2019, the unadjusted control rates of glycated hemoglobin (4.8%, 95%CI (4.4 to 5.1) and low-density lipoprotein cholesterol (LDL-C) (11.5%, 95%CI (11.1 to 11.8)) improved, but blood pressure (BP) control worsened (systolic BP (SBP)/diastolic BP (DBP) <140/90 mmHg: -6.6%, 95%CI (-7.0 to -6.2)). These trends persisted after accounting for the demographics including age, gender, ethnicity, and housing type. The 10-year adjusted risk for coronary heart disease (CHD) (3.4%, 95% (3.3 to 3.5)) and stroke (10.4%, 95% CI (10.3 to 10.5)) increased. In 2019, the control rates of glycated hemoglobin, BP (SBP/DBP<140/90 mmHg), LDL-C, each, and all three risk factors together, accounted for 51.5%, 67.7%, 72.2%, and 24.4%, respectively., Conclusions: Trends in risk factor control improved for glycated hemoglobin and LDL-C, but worsened for BP among diabetic adults in Singapore from 2013 to 2019. Control rates for all risk factors remain inadequate., Competing Interests: The authors have declared that no competing interests exist.