Explore the vast range of titles available.

This randomized, double-blind trial involving critically ill patients compared balanced multielectrolyte solution with saline as fluid therapy in the ICU. There was no evidence that the risk of death or acute kidney injury was lower with the use of BMES than with saline.

This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms in patients harboring one or two Phe508del alleles.

Background Acute kidney injury (AKI) is an important complication encountered during the course of diabetic ketoacidosis (DKA). Plasma-Lyte with lower chloride concentration than saline has been shown to be associated with reduced incidence of AKI in adults with septic shock. No study has compared this in DKA. Methods This double-blind, parallel-arm, investigator-initiated, randomized controlled trial compared 0.9% saline with Plasma-Lyte-A as initial fluid in pediatric DKA. The study was done in a tertiary care, teaching, and referral hospital in India in children (> 1 month–12 years) with DKA as defined by ISPAD. Children with cerebral edema or known chronic kidney/liver disease or who had received pre-referral fluids and/or insulin were excluded. Sixty-six children were randomized to receive either Plasma-Lyte ( n  = 34) or 0.9% saline ( n  = 32). Main outcomes Primary outcome was incidence of new or progressive AKI, defined as a composite outcome of change in creatinine (defined by KDIGO), estimated creatinine clearance (defined by p-RIFLE), and NGAL levels. The secondary outcomes were resolution of AKI, time to resolution of DKA (pH > 7.3, bicarbonate> 15 mEq/L & normal sensorium), change in chloride, pH and bicarbonate levels, proportion of in-hospital all-cause mortality, need for renal replacement therapy (RRT), and length of ICU and hospital stay. Results Baseline characteristics were similar in both groups. The incidence of new or progressive AKI was similar in both [Plasma-Lyte 13 (38.2%) versus 0.9% saline 15 (46.9%); adjusted OR 1.22; 95% CI 0.43–3.43, p  = 0.70]. The median (IQR) time to resolution of DKA in Plasma-Lyte-A and 0.9% saline were 14.5 (12 to 20) and 16 (8 to 20) h respectively. Time to resolution of AKI was similar in both [Plasma-Lyte 22.1 versus 0.9% saline 18.8 h (adjusted HR 1.72; 95% CI 0.83–3.57; p  = 0.14)]. Length of hospital stay was also similar in both [Plasma-Lyte 9 (8 to 12) versus 0.9% saline 10 (8.25 to 11) days; p  = 0.39]. Conclusions The incidence of new or progressive AKI and resolution of AKI were similar in both groups. Plasma-Lyte-A was similar to 0.9% Saline in time to resolution of DKA, need for RRT, mortality, and lengths of PICU and hospital stay. Trial registration Clinical trial registry of India, CTRI/2018/05/014042 ( ctri.nic.in ) (Retrospectively registered).

Elexacaftor–ivacaftor–tezacaftor therapy is efficacious in cystic fibrosis among patients with at least one copy of the Phe508del allele. In this trial involving patients with either a gating or residual function allele in addition to the Phe508del allele, elexacaftor–ivacaftor–tezacaftor improved lung function as compared with active control therapy.

Triple treatment with elexacaftor, tezacaftor, and ivacaftor in patients with cystic fibrosis who had one Phe508del allele and a minimal-function mutation resulted in sustained improvement in FEV 1 , sweat chloride concentration, and the number of pulmonary exacerbations.

This companion article to the VX-445 report shows that VX-659, a new CFTR potentiator, when administered with tezacaftor and ivacaftor improved lung function, sweat chloride concentration, and symptoms in patients with cystic fibrosis who harbored one or two Phe508del alleles.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Vertex Pharmaceuticals.

•In TOPCAT-Americas, baseline loop diuretic and combined loop and thiazide diuretic therapy was associated with elevated crude risk of CV death and total HHFs compared to no diuretic use.•Higher baseline doses of loop diuretics were associated with higher risk of CV death and total HHFs.•Thiazide monotherapy was not associated with an increased risk of any CV or HF endpoints, but when thiazide was added to loop diuretic therapy, it further increased the risk of CV death. Trials in heart failure with preserved ejection fraction (HFpEF) frequently apply baseline diuretic use as enrichment criterion. However, the role of thiazides and loop diuretic dose for enrichment is unclear. We aimed to assess baseline loop and thiazide diuretic use, loop diuretic dose, and associations with cardiovascular (CV) outcomes in HFpEF. We performed a post-hoc analysis of TOPCAT-Americas. The primary outcome was CV death and total hospitalizations for heart failure (HHF). 1765 patients were followed for a median of 2.9 years. At baseline, loop diuretic monotherapy was used in 67%, thiazide monotherapy in 10% and the combination in 12%. Loop diuretic monotherapy and combined loop+thiazide diuretic treatment were associated with higher risk of the primary outcome (HR 1.59, 95% CI 1.23-2.07, P < .001; and HR 2.07, 95% CI 1.55-2.76, P < .001 respectively), as well as first HHF, total HHFs and the composite of first HHF or CV death. Only combined loop+thiazide diuretic therapy was associated with CV death alone (HR 1.85, 95% CI 1.13-3.04, P = .015). For all above endpoints, the combined diuretic therapy was associated with greater risk than loop diuretics alone. Thiazide monotherapy was not associated with any endpoints. Higher baseline loop diuretic doses were associated with higher risk of all outcomes. In HFpEF, baseline use and higher doses of loop diuretics were associated with higher risk of CV death and total HHFs. Thiazide alone was not associated with any endpoints, but when added to loop diuretics it was associated with additional risk for all outcomes.

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity 1 . The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism 2 – 5 . Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport 6 – 8 . However, the molecular mechanisms that enable these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is gated by two hydrophobic regions and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function, and add information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family. Glutamate transporters conduct chloride ions through an aqueous channel with hydrophobic gates that forms during the glutamate transport cycle.

There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (–7.1 mmHg, 95% confidence interval (CI) –10.5 to –3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure. Salt substitute also lowered diastolic blood pressure (–1.9 mmHg, 95% CI –3.6 to –0.2) and resulted in fewer cardiovascular events (hazard ratio (HR) 0.60, 95% CI 0.38–0.96), but had no effect on total mortality (HR 0.84, 95% CI 0.63–1.13). From a safety standpoint, salt substitute increased mean serum potassium and led to more frequent biochemical hyperkalemia, but was not associated with adverse clinical outcomes. In contrast, salt restriction had no effect on any study outcome. The results of this trial indicate that use of salt substitute, but not efforts to restrict salt supply, may achieve blood pressure lowering and deliver health benefits to residents of elderly care facilities in China. Clinicaltrials.gov registration: NCT03290716 In a cluster-randomized trial performed in 48 residential elderly care facilities in China, use of a low-sodium salt substitute instead of regular salt decreased blood pressure and cardiovascular events, whereas an alternative strategy of restricting salt consumption was not successful and did not have these beneficial effects.