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Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering RNA targeting transthyretin messenger RNA, to treat the disease.

Out-of-hospital cardiac arrest is a leading cause of death worldwide. Establishing vascular access is critical for administering guideline-recommended drugs during cardiopulmonary resuscitation. Both the intraosseous route and the intravenous route are used routinely, but their comparative effectiveness remains unclear. We conducted a randomized clinical trial to compare the effectiveness of initial attempts at intraosseous or intravenous vascular access in adults who had nontraumatic out-of-hospital cardiac arrest. The primary outcome was a sustained return of spontaneous circulation. Key secondary outcomes were survival at 30 days and survival at 30 days with a favorable neurologic outcome, defined by a score of 0 to 3 on the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability). Among 1506 patients who underwent randomization, 1479 were included in the primary analysis (731 in the intraosseous-access group and 748 in the intravenous-access group). The successful establishment of vascular access within two attempts occurred in 669 patients (92%) assigned to the intraosseous-access group and in 595 patients (80%) assigned to the intravenous-access group. Sustained return of spontaneous circulation occurred in 221 patients (30%) in the intraosseous-access group and in 214 patients (29%) in the intravenous-access group (risk ratio, 1.06; 95% confidence interval [CI], 0.90 to 1.24; P = 0.49). At 30 days, 85 patients (12%) in the intraosseous-access group and 75 patients (10%) in the intravenous-access group were alive (risk ratio, 1.16; 95% CI, 0.87 to 1.56); a favorable neurologic outcome at 30 days occurred in 67 patients (9%) and 59 patients (8%), respectively (risk ratio, 1.16; 95% CI, 0.83 to 1.62). Prespecified adverse events were uncommon. There was no significant difference in sustained return of spontaneous circulation between initial intraosseous and intravenous vascular access in adults who had out-of-hospital cardiac arrest. (Funded by the Novo Nordisk Foundation and others; IVIO EU Clinical Trials Register number, 2022-500744-38-00; ClinicalTrials.gov number, NCT05205031.).

In this cluster-randomized, crossover trial, hospital-wide use of lactated Ringer’s solution as compared with normal saline did not alter the incidence of death or hospital readmission within 90 days.

Purpose To determine the effects of the sodium content of maintenance fluid therapy on cumulative fluid balance and electrolyte disorders. Methods We performed a randomized controlled trial of adults undergoing major thoracic surgery, randomly assigned (1:1) to receive maintenance fluids containing 154 mmol/L (Na154) or 54 mmol/L (Na54) of sodium from the start of surgery until their discharge from the ICU, the occurrence of a serious adverse event or the third postoperative day at the latest. Investigators, caregivers and patients were blinded to the treatment. Primary outcome was cumulative fluid balance. Electrolyte disturbances were assessed as secondary endpoints, different adverse events and physiological markers as safety and exploratory endpoints. Findings We randomly assigned 70 patients; primary outcome data were available for 33 and 34 patients in the Na54 and Na154 treatment arms, respectively. Estimated cumulative fluid balance at 72 h was 1369 mL (95% CI 601–2137) more positive in the Na154 arm ( p  < 0.001), despite comparable non-study fluid sources. Hyponatremia < 135 mmol/L was encountered in four patients (11.8%) under Na54 compared to none under Na154 ( p  = 0.04), but there was no significantly more hyponatremia < 130 mmol/L (1 versus 0; p  = 0.31). There was more hyperchloremia > 109 mmol/L under Na154 (24/35 patients, 68.6%) than under Na54 (4/34 patients, 11.8%) ( p  < 0.001). The treating clinicians discontinued the study due to clinical or radiographic fluid overload in six patients receiving Na154 compared to one patient under Na54 (excess risk 14.2%; 95% CI − 0.2–30.4%, p  = 0.05). Conclusions In adult surgical patients, sodium-rich maintenance solutions were associated with a more positive cumulative fluid balance and hyperchloremia; hypotonic fluids were associated with mild and asymptomatic hyponatremia.

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 Current treatments include glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), and tumor necrosis factor (TNF) antagonists. 1 – 3 Many patients do not have a response to therapy, 4 and treatments are associated with important toxic effects. 5 , 6 Natalizumab, a monoclonal antibody that modulates gut and brain lymphocyte migration by antagonizing α 4 β 1 and α 4 β 7 integrin–mediated interactions, 7 is efficacious in the treatment of multiple sclerosis 8 , 9 and Crohn's disease. 10 – 12 Its use in patients with Crohn's disease has been limited by the development in some patients of progressive multifocal . . .

Background Authors of recent meta-analyses have reported that prolonged glucocorticoid treatment is associated with significant improvements in patients with severe pneumonia or acute respiratory distress syndrome (ARDS) of multifactorial etiology. A prospective randomized trial limited to patients with sepsis-associated ARDS is lacking. The objective of our study was to evaluate the efficacy of hydrocortisone treatment in sepsis-associated ARDS. Methods In this double-blind, single-center (Siriraj Hospital, Bangkok), randomized, placebo-controlled trial, we recruited adult patients with severe sepsis within 12 h of their meeting ARDS criteria. Patients were randomly assigned (1:1 ratio) to receive either hydrocortisone 50 mg every 6 h or placebo. The primary endpoint was 28-day all-cause mortality; secondary endpoints included survival without organ support on day 28. Results Over the course of 4 years, 197 patients were randomized to either hydrocortisone ( n  = 98) or placebo ( n  = 99) and were included in this intention-to-treat analysis. The treatment group had significant improvement in the ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen and lung injury score ( p  = 0.01), and similar timing to removal of vital organ support (HR 0.74, 95 % CI 0.51–1.07; p  = 0.107). After adjustment for significant covariates, day 28 survival was similar for the whole group (HR 0.80, 95 % CI 0.46–1.41; p  = 0.44) and for the larger subgroup ( n  = 126) with Acute Physiology and Chronic Health Evaluation II score <25 (HR 0.57, 95 % CI 0.24–1.36; p  = 0.20). With the exception of hyperglycemia (80.6 % vs. 67.7 %; p  = 0.04), the rate of adverse events was similar. Hyperglycemia had no impact on outcome. Conclusions In sepsis-associated ARDS, hydrocortisone treatment was associated with a significant improvement in pulmonary physiology, but without a significant survival benefit. Trial registration ClinicalTrials.gov identifier NCT01284452 . Registered on 18 January 2011.

In two trials involving patients with relapsing multiple sclerosis, the anti-CD20+ monoclonal antibody ocrelizumab was associated with lower annualized relapse rates, lower risk of disability progression, and better MRI features than interferon beta-1a. Despite the availability of several disease-modifying treatments for relapsing forms of multiple sclerosis, patients often continue to have clinical and subclinical disease activity, and neurologic disability continues to accrue. Thus, there is a need for more effective treatments with acceptable safety profiles. 1 – 3 B cells are thought to influence the underlying pathogenesis of multiple sclerosis by means of antigen presentation, 4 autoantibody production, 5 , 6 cytokine regulation, 4 and the formation of ectopic lymphoid aggregates in the meninges, which possibly contribute to cortical demyelination and neurodegeneration. 7 , 8 Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20, a cell-surface antigen that is expressed . . .

Patients with primary progressive MS who received the anti-CD20+ humanized antibody ocrelizumab were less likely to have clinical deterioration that was sustained for 12 weeks than those who received placebo. The drug was associated with decreased lesion activity on MRI. Primary progressive multiple sclerosis accounts for 10 to 15% of the overall population with multiple sclerosis. 1 The course of this disease differs from those of relapsing–remitting and secondary progressive forms of multiple sclerosis in that progression consists mainly of gradual worsening of neurologic disability from symptom onset, although relapses may occur. 1 Phase 3 trials in primary progressive multiple sclerosis have been unsuccessful, 2 – 4 and no disease-modifying treatments have been approved. B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form. 5 Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis . . .

In-line filtration is increasingly used in critically-ill infants but its benefits, by preventing micro-particle infusion in very preterm neonates, remain to be demonstrated. We conducted a randomized controlled trial among very preterm infants allocated to receive either in-line filtration of all the intra-venous lines or standard care without filters. The primary outcome was differences greater than 20% in the median changes in pro-inflammatory cytokine serum concentrations measured at day 3 and day 8 (+/−1) using a Luminex multianalytic profiling technique. Major neonatal complications were analyzed as secondary predefined outcomes. We randomized 146 infants, assigned to filter (n = 73) or control (n = 73) group. Difference over 20% in pro-inflammatory cytokine concentration between day 3 and day 8 was not found statistically different between the two groups, both in intent-to-treat (with imputation) and per protocol (without imputation) analyses. The incidences of most of neonatal complications were found to be similar. Hence, this trial did not evidence a beneficial effect of in-line filtration in very preterm infants on the inflammatory response syndrome and neonatal morbidities. These data should be interpreted according to local standards in infusion preparation and central line management.

Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19. RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation (ie, those who were seronegative) and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio [RR] 0·79, 95% CI 0·69–0·91; p=0·0009). In an analysis of all randomly assigned patients (regardless of baseline antibody status), 943 (19%) of 4839 patients allocated to casirivimab and imdevimab versus 1029 (21%) of 4946 patients allocated to usual care died within 28 days (RR 0·94, 95% CI 0·86–1·02; p=0·14). The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity=0·002). There were no deaths attributed to the treatment, or meaningful between-group differences in the pre-specified safety outcomes of cause-specific mortality, cardiac arrhythmia, thrombosis, or major bleeding events. Serious adverse reactions reported in seven (<1%) participants were believed by the local investigator to be related to treatment with casirivimab and imdevimab. In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.