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IMPORTANCE: Elevated serum uric acid (SUA) level may contribute to endothelial dysfunction; therefore, SUA is an attractive target for heart failure with preserved ejection fraction (HFpEF). However, to the authors’ knowledge, no prior randomized clinical trials have evaluated SUA lowering in HFpEF. OBJECTIVE: To investigate the efficacy and safety of the novel urate transporter–1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized clinical trial (32-week duration) conducted from May 2020 to April 2022. The study took place at 59 centers in 12 countries and included patients 40 years and older with HFpEF and SUA level greater than 6 mg/dL. Data were analyzed from August 2022 to May 2024. INTERVENTIONS: Eligible patients were randomized 1:1:1 to once-daily, oral verinurad, 12 mg, plus allopurinol, 300 mg; allopurinol, 300 mg, monotherapy; or placebo for 24 weeks after an 8-week titration period. Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, and the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group. All patients received oral colchicine, 0.5 to 0.6 mg, daily for the first 12 weeks after randomization. MAIN OUTCOMES AND MEASURES: Key end points included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level; and safety/tolerability (including adjudicated cardiovascular events). RESULTS: Among 159 randomized patients (53 per treatment group; median [IQR] age, 71 [40-86] years; 103 male [65%]) with median (IQR) N-terminal pro–brain natriuretic peptide level of 527 (239-1044) pg/mL and SUA level of 7.5 (6.6-8.4) mg/dL, verinurad plus allopurinol (mean change, −59.6%; 95% CI, −64.4% to −54.2%) lowered SUA level to a greater extent than allopurinol (mean change, −37.6%; 95% CI, −45.3% to −28.9%) or placebo (mean change, 0.8%; 95% CI, −11.8% to 15.2%; P < .001). Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; 95% CI, −0.56 to 1.10 mL/kg/min; allopurinol, −0.17 mL/kg/min; 95% CI, −1.03 to 0.69 mL/kg/min; placebo, 0.37 mL/kg/min; 95% CI, −0.45 to 1.19 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; 95% CI, 0.3-8.3; allopurinol, 4.5; 95% CI, 0.3-8.6; placebo, 1.2; 95% CI, −3.0 to 5.3) were similar across groups. There were no adverse safety signals. Deaths or cardiovascular events occurred in 3 patients (5.7%) in the verinurad plus allopurinol group, 8 patients (15.1%) in the allopurinol monotherapy group, and 6 patients (11.3%) in the placebo group. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial show that despite substantial SUA lowering, verinurad plus allopurinol did not result in a significant improvement in peak VO2 or symptoms compared with allopurinol monotherapy or placebo in HFpEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04327024

This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200–5000 mg/g and estimated glomerular filtration rate 25–75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury–related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury–related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.

The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF).

Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.

Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)—ie, the eGFR slope.

Immunoglobulin A (IgA) nephropathy is a common form of glomerulonephritis, which despite use of renin-angiotensin-aldosterone-system blockers and immunosuppressants, often progresses to kidney failure. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial, dapagliflozin reduced the risk of kidney failure and prolonged survival in participants with chronic kidney disease with and without type 2 diabetes, including those with IgA nephropathy. Participants with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2and urinary albumin-to-creatinine ratio 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10mg or placebo, as adjunct to standard care. The primary composite endpoint was a sustained decline in eGFR of 50% or more, end-stage kidney disease, or death from a kidney disease-related or cardiovascular cause. Of 270 participants with IgA nephropathy (254 [94%] confirmed by previous biopsy), 137 were randomized to dapagliflozin and 133 to placebo, and followed for median 2.1 years. Overall, mean age was 51.2 years; mean eGFR, 43.8 mL/min/1.73m2; and median urinary albumin-to-creatinine ratio, 900 mg/g. The primary outcome occurred in six (4%) participants on dapagliflozin and 20 (15%) on placebo (hazard ratio, 0.29; 95% confidence interval, 0.12, 0.73). Mean rates of eGFR decline with dapagliflozin and placebo were −3.5 and −4.7 mL/min/1.73m2/year, respectively. Dapagliflozin reduced the urinary albumin-to-creatinine ratio by 26% relative to placebo. Adverse events leading to study drug discontinuation were similar with dapagliflozin and placebo. There were fewer serious adverse events with dapagliflozin, and no new safety findings in this population. Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile.

Background: Bariatric surgery reduces incidence of albuminuria and end-stage renal disease in patients with obesity. Effects of bariatric surgery on long-term remission and progression of pre-existing obesity-related renal damage are mainly unexplored. Here we investigate the long-term effects of bariatric surgery compared with conventional obesity care on remission and progression of albuminuria. Methods: 4047 patients were included in the Swedish Obese Subjects study. Inclusion criteria were age 37–60 years, BMI ≥ 34 kg/m2in men and BMI ≥ 38 kg/m2in women. Our analysis comprised 803 patients (19.8% of total population, 357 control, 446 surgery) with pre-existing albuminuria including 693 patients (312 control, 381 surgery) with microalbuminuria, and 110 patients (45 control, 65 surgery) with macroalbuminuria. Surgery patients were treated with banding, vertical banded gastroplasty, or gastric bypass. Control patients received conventional obesity care. Results: Total urinary albumin excretion was 36.5% lower in all patients with albuminuria after 15 years, 44.5% lower in patients with microalbuminuria after 15 years, and 27.8% lower in patients with macroalbuminuria after 2 years following bariatric surgery compared with conventional care. In surgery patients with microalbuminuria, remission to normoalbuminuria was higher (OR, 5.9, 2.2, 3.2, p< 0.001) and progression to macroalbuminuria was lower (OR, 0.28, 0.26, 0.25, p≤ 0.02) at 2, 10, and 15 years, respectively, compared with control patients. In surgery patients with macroalbuminuria remission to normo- or microalbuminuria was higher (OR, 3.67, p= 0.003) after 2 years. No differences between surgery and control patients with macroalbuminuria were observed after 10 and 15 years. Surgery slowed progression of eGFR decline after 2 years in patients with microalbuminuria and macroalbuminuria (treatment effect: 1.0 ml/min/1.73 m2/year, p= 0.001 and 1.4 ml/min/1.73 m2/year, p= 0.047, respectively). Conclusion: Bariatric surgery had better effects than conventional obesity care on remission of albuminuria and prevention of eGFR decline, indicating that patients with obesity-related renal damage benefit from bariatric surgery.

Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause.

In patients with type 2 diabetes, intensive glucose control can be renoprotective and albuminuria-lowering treatments can slow the deterioration of kidney function. We assessed the albuminuria-lowering effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin with and without the dipeptidyl peptidase-4 inhibitor saxagliptin, and the effect of dapagliflozin–saxagliptin on glycaemic control in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.

This article presents the various activities starting in the mid 1990s, which led to an internationally agreed Agenda 21 on Sustainable Construction, published by CIB in 1999. Further work, nationally, regionally and internationally to implement the Agenda is described. Sustainable construction is a way for the building and construction industry to respond towards achieving sustainable development from the various environmental, socio-economic and cultural aspects. Trends and approaches in building to meet sustainable development requirements are commented on, as well as the ongoing standardisation on the design life of constructed works.

Objective:Recently we reported a complete relapse in the blood pressure (BP) of obese subjects despite a maintained 16% weight loss over 8 years. This relapse is now analyzed as a function of several variables. Pulse pressure (PP) is an independent risk factor of cardiovascular mortality. We now examine the development of PP in the obese and whether it can be modified by weight‐reducing gastric surgery. Research Methods and Procedures:A total of 1157 patients treated with gastric surgery and 1031 obese controls (body mass index of 41.0 ± 4.6 kg/m2[mean ± SD], age 48 ± 6 years) were followed for 5.5 ± 2.1 (range 3 to 10) years. To separate the effect of weight change from effect of time on BP, the patients were divided in cohorts based on follow‐up time. Results:Gastric surgery resulted in a maximum weight loss after 1 year that was followed by a moderate relapse. After 5.5 years, weight loss in the intervention group was 18 ± 11% of initial body weight. Very little weight change was seen in controls. Systolic BP decreased in the intervention group during the first 6 months but had relapsed to control values at last examination. The adjusted change in PP was +4.7 mm Hg in obese controls but +2.9 mm Hg in the intervention group (p< 0.001). Final BP values were more closely related to follow‐up time and ongoing weight increase than to initial body weight or initial weight loss. Discussion:Effects of time (aging) and weight change per year on BP can be separated. An early increase in PP could be observed in the obese. This increase could be modified by weight‐reducing gastric surgery.

SJÖSTRÖM, c. DAVID, LAUREN LISSNER, HANS WEDEL, and LARS SJÖSTRÖM. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obes Res. Objective: To examine the effect of a large, long standing and intentional weight reduction on the incidence of diabetes, hypertension and lipid disturbances in severely obese individuals as compared to weight‐stable obese controls. Research Methods and Procedures: The ongoing prospective SOS (Swedish Obese Subjects) intervention consists of a surgically treated group and a matched control group obtaining conventional obesity treatment. This report is based on 845 surgically treated patients and 845 controls (BMI41. 0±4. 6 kg/m2(mean±standard deviation [S])) followed for 2 years. Results: Surgically treated patients lost 28±15 kg and controls 0. 5±8. 9 kg (p<0. 0001). Two‐year incidence of hypertension, diabetes, hyperinsulinemia, and lipid disturbances was compared in the two treatment groups. Adjusted odds ratios (95% CI) for the surgically treated group versus controls were 0. 38 (0. 22, 0. 65) for hypertension, 0. 02 (0. 00, 0. 16) for diabetes, 0. 10 (0. 03, 0. 28) for hyperinsulinemia, 0. 10 (0. 04, 0. 25) for hypertriglyceridemia, 0. 28 (0. 16, 0. 49) for low HDL‐cholesterol and 1. 24 (0. 84, 1. 8) for hypercholesterolemia. Compared to controls, the 2‐year recovery rates from hypertension, diabetes, hypo‐HDL, and hypertriglyceridemia were significantly higher in the surgically treated group. Discussion: Intentional weight loss in the obese causes a marked reduction in the 2‐year incidence of hypertension, diabetes and some lipid disturbances. The results suggest that severe obesity can and should be treated.

RICE, TREVA, c. DAVID SJÖSTRÖM, LOUIS PÉRUSSE, D. C. RAO, LARS SJÖSTRÖM, AND CLAUDE BOUCHARD. Segregation analysis of body mass index in a large sample selected for obesity: the Swedish Obese Subjects study. Obes Res. Objective: To investigate a major gene hypothesis for body mass index (BMI) in a large sample of probands (n = 2580, ages 37–57 years) who were selected for obesity (BMI≥34 kg/m2for males and ≥38 kg/m2for females), along with their spouses and first‐degree relatives (n = 11,204 family members). The probands were recruited as part of an intervention trial assessing whether mortality and morbidity were improved after surgical intervention for obesity as part of the Swedish Obese Subjects (SOS) study. Methods and Procedures: The current analyses were based on BMI measures obtained before intervention. Segregation analysis was carried out using the mixed model implementation in PAP (Pedigree Analysis Package), which allowed for ascertainment correction and for genotype‐dependent effects of covariates (sex and age) in both the major gene component and the multifactorial (i. e., polygenic and familial environment) component. Results: Both a major effect and a multifactorial effect were significant. The percentage of the total variance accounted for by the multifactorial effect was 17%‐24% (increasing as a function of age), and by the major effect, 8%‐34% (decreasing as a function of age). Although tests on the transmission probabilities (τS) were not compatible with Mendelian expectations of 1, 1/2, and 0, the equal τS model was rejected (i. e., the effect is transmitted in families) and the point estimates (0. 96,0. 60, and 0. 17) compared favorably to Mendelian expectations. The major effect was transmitted in a codominant fashion, consistent with a gene‐environment interaction. Discussion: These results suggest both multifactorial and major effect etiologies for BMI in these families of extremely obese probands. Before 20 years of age, the major effect dominates the BMI expression, but after age 20, multifactorial effects account for the most variance. Although the major effect is transmitted in these families, the pattern does not appear to be consistent with a simple Mendelian trait. The possibility of additional major loci (i. e., epistasis) and gene by environment interactions may explain these findings.

Abnormal liver tests, as well as morphological changes in the liver, are frequent among obese patients. Other frequent disturbances are visceral fat accumulation, insulin resistance, non‐insulin‐dependent diabetes mellitus (NIDDM), hypertriglyceridemia, and hypertension; these are a set of aberrations known as the metabolic syndrome. In order to investigate a possible relationship between the metabolic syndrome and impaired liver status we examined associations between liver tests, metabolic variables (insulin, glucose, and triglycerids), body composition and nutrition in 1083 men (BMI 28.8–63.8 kg/m2) and 1367 women (BMI 26.7–68.0 kg/m2) in the ongoing intervention study of Swedish Obese Subjects (SOS). Standard biochemical techniques were used to assess liver status and metabolic variables. Lean body mass (LBM) and masses of visceral and subcutaneous adipose tissue (AT) were estimated by means of computed tomography (CT) calibrated anthropometric equations. In both genders aspartate aminotransferase and alanine aminotransferase were, or tended to be, positively correlated to fasting serum insulin, visceral AT (women), and alcohol intake. In women, the aminotransferases were also correlated with fasting blood glucose. In both genders alkaline phosphatase was, or tended to be, positively associated with visceral AT, insulin (women), and glucose. Bilirubin was negatively correlated to insulin and visceral AT in men and women. Additional multivariate analyses indicated that alcohol had less explanatory power than serum insulin for the examined liver tests, especially among women. These results suggest that pathological liver tests in the obese may represent an expression of the metabolic syndrome.

The purpose of this study was to investigate whether upper body obesity and/or visceral obesity are related to cardiovascular risk factors among severely obese subjects, phenomena that have previously been reported in more heterogeneous body weight distri ‐buttons. 2450 severely obese men and women aged 37 to 59 years, with a body mass index of 39 ± 4.5 kg/m2(mean ± SD) were examined cross‐sectionally. Eight cardiovascular risk factors were studied in relation. to the following body composition indicators: four trunk and three limb circumferences, along with weight, height and sagittal trunk diameter. From the latter three measurements lean body mass (LBM, i.e., the non‐adipose tissue mass) and the masses of subcutaneous and visceral adipose tissue were estimated by using sex‐specific prediction equations previously calibrated by computed tomography. Two risk factor patterns could be distinguished: 1. One body compartment‐ risk factor pattern in which the subcutaneous adipose tissue (AT) mass and, in particular, the visceral AT mass were positively related to most risk factors while the lean body mass was negatively related to some risk factors. 2. One subcutaneous adipose tissue distribution‐ risk factor pattern in which the neck circumference was positively and the thigh circumference negatively related to several risk factors. It is concluded that lean body mass (LBM), visceral and subcutaneous adipose tissue masses as well as neck and thigh circumferences, used as indices of subcutaneous adipose tissue distribution, are independently related to cardiovascular risk factors in severely obese men and women.

One of the most promising implications of the phenomenological Ginzburg—Landau (GL) theory of superconductivity is the possible existence of current-carrying metastable states with a negative effective self-inductance. Microscopically this phenomenon can be explained as a result of the depairing mechanism which, when the center-of-mass velocityvs of the Cooper pairs is sufficiently large, can be so strong that a further increase ofvs will lead to a decrease of the total current. Using a one-dimensional formulation of the GL theory we investigate the thermodynamic stability of these states for different external constraints and obtain the result that a negative self-inductance can only be stable if the length of the system in the direction of the current is smaller than a critical value comparable to the GL coherence length ?/?. It is an experimental fact that states of negative self-inductance are realized in Josephson junctions and other types of superconducting weak links because the dc supercurrent can be a decreasing function of the phase variable f. The thermodynamic stability theory can therefore explain why weak links have to be short, and it also provides us with a unifying point of view by treating the phase f and the current as a pair of thermodynamically conjugate variables for arbitrary one-dimensional systems. An important point is the operational phase definition as a thermodynamic parameter that can be controlled by the experimentalist. This requirement is essential for the general validity of the ac Josephson equation and it implies that f must depend on the magnetic self-inductance of the system. By applying the GL theory to weak links we can delimit the validity of the usual dc Josephson equationI ? sin f and see that deviations from this functional form are most likely to be found in thin-film bridges of the Anderson-Dayem (AD) type. When the currentI is the controlled variable the conjugate phase variable f will fluctuate and the magnitude of these fluctuations depends strongly on the functional formI(f). The phase fluctuations for constantI lead to a reduction of the critical current which will be absent when f is the controlled variable. The observed microwave enhancement of the critical current in AD bridges, the so-called Dayem effect, can be explained as a result of a switch from current control to phase control, and the fluctuation formulae explain why the effect is negligible in structures exhibiting the classical Josephson sine law for the current-phase relation.

Hypertension (HTN) and albuminuria are risk factors for cardiovascular (CV) and renal disease in patients (pts) with T2DM. Glycemic, blood pressure (BP) and albuminuria control are critical to reducing CV and renal risk. Dapagliflozin (DAPA) reduces HbA1c and BP in patients with T2DM. The aim of the study was to characterize the effect of DAPA on albuminuria and eGFR. Data was pooled from two studies of pts with T2DM, micro- or macroalbuminuria, and HTN, (NCT01137474, NCT01195662) who were assigned to DAPA 5 mg (n = 87), 10 mg (n = 167) or placebo (PBO; n = 189).