Feasibility of Bariatric Surgery as a Strategy for Secondary Prevention in Cardiovascular Disease: A Report from the Swedish Obese Subjects Trial

Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD

Dielectric secondary relaxation of water in aqueous binary glass-formers

The dielectric relaxation of water in glassy aqueous binary mixtures exhibits an Arrhenius behaviour with a nearly universal activation energy. We here demonstrate that its characteristic relaxation time follows a remarkably general functional dependence on the weight fraction of water for a wide range of molecular systems

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient\u27s progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. ©2017 AACR

Adaptation requirements due to anatomical changes in free-breathing and deep-inspiration breath-hold for standard and dose-escalated radiotherapy of lung cancer patients

<div><p>ABSTRACT</p><p><b>Background.</b> Radiotherapy of lung cancer patients is subject to uncertainties related to heterogeneities, anatomical changes and breathing motion. Use of deep-inspiration breath-hold (DIBH) can reduce the treated volume, potentially enabling dose-escalated (DE) treatments. This study was designed to investigate the need for adaptation due to anatomical changes, for both standard (ST) and DE plans in free-breathing (FB) and DIBH.</p><p><b>Material and methods.</b> The effect of tumor shrinkage (TS), pleural effusion (PE) and atelectasis was investigated for patients and for a CIRS thorax phantom. Sixteen patients were computed tomography (CT) imaged both in FB and DIBH. Anatomical changes were simulated by CT information editing and re-calculations, of both ST and DE plans, in the treatment planning system. PE was systematically simulated by adding fluid in the dorsal region of the lung and TS by reduction of the tumor volume.</p><p><b>Results.</b> Phantom simulations resulted in maximum deviations in mean dose to the GTV-T (_GTV-T) of −1% for 3 cm PE and centrally located tumor, and + 3% for TS from 5 cm to 1 cm diameter for an anterior tumor location. For the majority of the patients, simulated PE resulted in a decreasing _GTV-T with increasing amount of fluid and increasing _GTV-T for decreasing tumor volume. Maximum change in _GTV-T of -3% (3 cm PE in FB for both ST and DE plans) and + 10% (2 cm TS in FB for DE plan) was observed. Large atelectasis reduction increased the _GTV-T with 2% for FB and had no effect for DIBH.</p><p><b>Conclusion.</b> Phantom simulations provided potential adaptation action levels for PE and TS. For the more complex patient geometry, individual assessment of the dosimetric impact is recommended for both ST and DE plans in DIBH as well as in FB. However, DIBH was found to be superior over FB for DE plans, regarding robustness of _GTV-T to TS.</p></div

Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers

The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined

A novel deep learning method for large-scale analysis of bone marrow adiposity using UK Biobank Dixon MRI data

BACKGROUND: Bone marrow adipose tissue (BMAT) represents &gt; 10% fat mass in healthy humans and can be measured by magnetic resonance imaging (MRI) as the bone marrow fat fraction (BMFF). Human MRI studies have identified several diseases associated with BMFF but have been relatively small scale. Population-scale studies therefore have huge potential to reveal BMAT's true clinical relevance. The UK Biobank (UKBB) is undertaking MRI of 100,000 participants, providing the ideal opportunity for such advances.OBJECTIVE: To establish deep learning for high-throughput multi-site BMFF analysis from UKBB MRI data.MATERIALS AND METHODS: We studied males and females aged 60-69. Bone marrow (BM) segmentation was automated using a new lightweight attention-based 3D U-Net convolutional neural network that improved segmentation of small structures from large volumetric data. Using manual segmentations from 61-64 subjects, the models were trained to segment four BM regions of interest: the spine (thoracic and lumbar vertebrae), femoral head, total hip and femoral diaphysis. Models were tested using a further 10-12 datasets per region and validated using datasets from 729 UKBB participants. BMFF was then quantified and pathophysiological characteristics assessed, including site- and sex-dependent differences and the relationships with age, BMI, bone mineral density, peripheral adiposity, and osteoporosis.RESULTS: Model accuracy matched or exceeded that for conventional U-Nets, yielding Dice scores of 91.2% (spine), 94.5% (femoral head), 91.2% (total hip) and 86.6% (femoral diaphysis). One case of severe scoliosis prevented segmentation of the spine, while one case of Non-Hodgkin Lymphoma prevented segmentation of the spine, femoral head and total hip because of T2 signal depletion; however, successful segmentation was not disrupted by any other pathophysiological variables. The resulting BMFF measurements confirmed expected relationships between BMFF and age, sex and bone density, and identified new site- and sex-specific characteristics.CONCLUSIONS: We have established a new deep learning method for accurate segmentation of small structures from large volumetric data, allowing high-throughput multi-site BMFF measurement in the UKBB. Our findings reveal new pathophysiological insights, highlighting the potential of BMFF as a novel clinical biomarker. Applying our method across the full UKBB cohort will help to reveal the impact of BMAT on human health and disease.</p

Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes:a prespecified analysis from the DAPA-CKD trial

BACKGROUND: 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. METHODS: DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an eGFR of 25-75 mL/min per 1·73m2. Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete. FINDINGS: Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8-2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m2 per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m2 (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m2 (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m2 per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m2 per year [0·73 to 1·85]; pinteraction=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m2 per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m2 per year (-0·10 to 1·03; pinteraction=0·040). The total eGFR slope was steeper in patients with higher baseline HbA1c and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA1c and UACR. INTERPRETATION: Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA1c, and higher UACR. FUNDING: AstraZeneca

Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes:a prespecified analysis from the DAPA-CKD trial

BACKGROUND: 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. METHODS: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. FINDINGS: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI -33·1 to -25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of -35·1% (95% CI -39·4 to -30·6; p<0·0001) in patients with type 2 diabetes and -14·8% (-22·9 to -5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change -3·06, 95% CI -5·20 to -0·90; p=0·0056). INTERPRETATION: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. FUNDING: AstraZeneca

Effects of Dapagliflozin in Chronic Kidney Disease, With and Without Other Cardiovascular Medications: DAPA-CKD Trial

Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150