Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment

OBJECTIVE: Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine, cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and anti-tumor processes in ovarian cancer. METHODS: Ovarian cancer patients (N=96) completed assessments of positive psychosocial factors (social support, positive affect and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and IL-6 in ascites fluid were obtained during surgery and analyzed by ELISA. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships. RESULTS: Higher levels of positive affect (β=.22, p=.034), purpose in life (β=.31, p=.021), and social nurturance (β=.24, p=.024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model. CONCLUSIONS: Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study

Operation of a load current multiplier on a nanosecond mega-ampere pulse forming line generator

International audienceWe investigate the operation of a load current multiplier (LCM) on a pulse-forming-line nanosecond pulse-power generator. Potential benefits of using the LCM technique on such generators are studied analytically for a simplified case. A concrete LCM design on the Zebra accelerator (1.9 Ohm, ∼1  MA, 100 ns) is described. This design is demonstrated experimentally with high-voltage power pulses having a rise time of dozens of nanoseconds. Higher currents and magnetic energies were observed in constant-inductance solid-state loads when a better generator-to-load energy coupling was achieved. The load current on Zebra was increased from the nominal 0.8–0.9 MA up to about 1.6 MA. This result was obtained without modifying the generator energetics or architecture and it is in good agreement with the presented numerical simulations. Validation of the LCM technique at a nanosecond time scale is of importance for the high-energy-density physics research

Planar Wire-Array Z-Pinch Implosion Dynamics and X-Ray Scaling at Multiple-MA Drive Currents for a Compact Multisource Hohlraum Configuration

International audienceAn indirect drive configuration is proposed wherein multiple compact Z-pinch x-ray sources surround a secondary hohlraum. Planar compact wire arrays allow reduced primary hohlraum surface area compared to cylindrical loads. Implosions of planar arrays are studied at up to 15 TW x-ray power on Saturn with radiated yields exceeding the calculated kinetic energy, suggesting other heating paths. X-ray power and yield scaling studied from 16 MA motivates viewfactor modeling of four 6-MA planar arrays producing 90 eV radiation temperature in a secondary hohlraum

Modulating Enzyme Activity by Altering Protein Dynamics with Solvent

Optimal enzyme activity depends on a number of factors, including structure and dynamics. The role of enzyme structure is well recognized; however, the linkage between protein dynamics and enzyme activity has given rise to a contentious debate. We have developed an approach that uses an aqueous mixture of organic solvent to control the functionally relevant enzyme dynamics (without changing the structure), which in turn modulates the enzyme activity. Using this approach, we predicted that the hydride transfer reaction catalyzed by the enzyme dihydrofolate reductase (DHFR) from <i>Escherichia coli</i> in aqueous mixtures of isopropanol (IPA) with water will decrease by ∼3 fold at 20% (v/v) IPA concentration. Stopped-flow kinetic measurements find that the pH-independent <i>k</i>_hydride rate decreases by 2.2 fold. X-ray crystallographic enzyme structures show no noticeable differences, while computational studies indicate that the transition state and electrostatic effects were identical for water and mixed solvent conditions; quasi-elastic neutron scattering studies show that the dynamical enzyme motions are suppressed. Our approach provides a unique avenue to modulating enzyme activity through changes in enzyme dynamics. Further it provides vital insights that show the altered motions of DHFR cause significant changes in the enzymeʼs ability to access its functionally relevant conformational substates, explaining the decreased <i>k</i>_hydride rate. This approach has important implications for obtaining fundamental insights into the role of rate-limiting dynamics in catalysis and as well as for enzyme engineering