In a randomized, double-blind, placebo-controlled phase 3 trial of the ChAdOx1 nCoV-19 vaccine in over 32,000 participants from the United States, Chile, and Peru, the incidence of serious adverse ...effects was low (including no cases of vaccine-induced immune thrombotic thrombocytopenia) and the vaccine efficacy was 74%. Efficacy was documented in a range of demographic subgroups.
Summary Background Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment ...of C difficile infection. Methods We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov , number NCT02092935. Findings Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation. Interpretation Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted. Funding Wellcome Trust and Summit Therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background.Community-acquired methicillin-resistant Staphylococcus aureus strains have recently been associated with severe necrotizing infections. Greater than 75% of these strains carry the genes ...for Panton-Valentine leukocidin (PVL), suggesting that this toxin may mediate these severe infections. However, to date, studies have not provided evidence of toxin production. Methods.Twenty-nine community-acquired methicillin-resistant Staphylococcus aureus and 2 community-acquired methicillin-susceptible S. aureus strains were collected from patients with infections of varying severity. Strains were analyzed for the presence of lukF-PV and SCCmecA type. PVL production in lukF-PV gene–positive strains was measured by ELISA, and the amount produced was analyzed relative to severity of infection. Results.Only 2 of the 31 strains tested, 1 methicillin-resistant Staphylococcus aureus abscess isolate and 1 nasal carriage methicillin-susceptible S. aureus isolate, were lukF-PV negative. All methicillin-resistant Staphylococcus aureus strains were SCCmec type IV. PVL was produced by all strains harboring lukF-PV, although a marked strain-to-strain variation was observed. Twenty-six (90%) of 29 strains produced 50–350 ng/mL of PVL; the remaining strains produced PVL in excess of 500 ng/mL. The quantity of PVL produced in vitro did not correlate with severity of infection. Conclusions.Although PVL likely plays an important role in the pathogenesis of these infections, its mere presence is not solely responsible for the increased severity. Factors that up-regulate toxin synthesis in vivo could contribute to more-severe disease and worse outcomes in patients with community-acquired methicillin-resistant Staphylococcus aureus infection.
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BFBNIB, NUK, PNG, UL, UM, UPUK
DURATION-5 demonstrates that continuous exenatide exposure with exenatide once weekly produces superior glycemic control, measured by HbA1c, with less nausea compared to exenatide twice daily.
...Context:
We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes.
Objective:
The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety.
Design:
This was a 24-wk, randomized, open-label, comparator-controlled study.
Setting:
The study was conducted at 43 sites in the United States.
Patients:
The study population was 252 intent-to-treat patients with type 2 diabetes baseline (mean ± sd): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications.
Interventions:
Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk.
Main Outcome Measure:
The change in HbA1c from baseline to wk 24 was measured.
Results:
At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± se) vs. ExBID in HbA1c (−1.6 ± 0.1% vs. −0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (−35 ± 5 mg/dl vs. −12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (−2.3 ± 0.4 kg and −1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred.
Conclusions:
Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.
In patients with diabetes, dysregulation of multiple glucoregulatory hormones results in chronic hyperglycemia and an array of associated microvascular and macrovascular complications. Optimization ...of glycemic control, both overall (glycosylated hemoglobin A1C) and in the postprandial period, may reduce the risk of long-term vascular complications. However, despite significant recent therapeutic advances, most patients with diabetes are unable to attain and/or maintain normal or near-normal glycemia with insulin therapy alone. Pramlintide, an analog of amylin, is the first in a new class of pharmaceutical agents and is indicated as an adjunct to mealtime insulin for the treatment of patients with type 1 and type 2 diabetes. By mimicking the actions of the naturally occurring hormone amylin, pramlintide complements insulin by regulating the appearance of glucose into the circulation after meals via three primary mechanisms of action: slowing gastric emptying, suppressing inappropriate post-meal glucagon secretion, and increasing satiety. In long-term clinical trials, adjunctive pramlintide treatment resulted in improved postprandial glucose control and significantly reduced A1C and body weight compared with insulin alone. The combination of insulin and pramlintide may provide a more physiologically balanced approach to managing diabetes.
This study explored the impact of Strengths Model training, supervision and mentorship on the practice of a group of multi‐disciplinary mental health clinicians that included mental health nurses, ...social workers, psychologists, and occupational therapists. A qualitative approach that combined critical realism and grounded theory was used. The findings demonstrated how a substantive category, Getting to Know Clients Better, facilitated participants' progression through a basic social psychological process, Becoming a Strengths‐Informed Practitioner. This process consisted of a discernible and sustained change towards more person‐centred, hopeful, and recovery‐oriented practice. The findings also described an underlying generative mechanism for this, the Client Becomes Visible, which accorded with theoretical models of empathy, based on enhanced cognitive processing. The strength‐based approach to practice facilitated the establishment of a collaborative relationship and a stronger therapeutic alliance between the client and clinician. The research demonstrated that Strengths Model is an effective vehicle for improving recovery‐orientated mental health services.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
IMPORTANCE: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. OBJECTIVE: To determine the effect of ...human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. DESIGN, SETTING, AND PARTICIPANTS: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019. INTERVENTIONS: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d maximum, 6 mg/d; n = 395) or matching placebo (n = 405) once daily for 6 days. MAIN OUTCOME AND MEASURES: The primary end point was 28-day all-cause mortality. RESULTS: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 54.6% men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients 26.8% vs 119 of 405 patients 29.4%, respectively; P = .32). The absolute risk difference was 2.55% (95% CI, −3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL typically 6 units of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01598831
OBJECTIVE
Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 ...diabetes uncontrolled on metformin.
RESEARCH DESIGN AND METHODS
Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients.
RESULTS
Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3% vs. –0.9% –14 vs. –9 mmol/mol, estimated treatment difference ETD –0.4% 95% CI –0.6, –0.3 –5 mmol/mol (–6, –3); P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (–1.4% vs. –0.9% –15 vs. –9 mmol/mol, ETD –0.5% 95% CI –0.7, –0.4 –6 mmol/mol (–7, –5); P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product −4.7 vs. −3.8 kg; P = 0.0114). Gastrointestinal adverse events were more common with oral semaglutide.
CONCLUSIONS
Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.
This review explores the transformative impact of sensory modulation interventions in acute inpatient mental health care setting utilising meta-ethnography. The methodology by Noblit & Hare guided ...the approach to creating the review. Searches of articles published within the previous 10 years were conducted in Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, and PsycINFO. Searches aimed to identify rich qualitative data on the area of sensory modulation interventions and acute inpatient mental health care. Seven articles were selected for inclusion and a reciprocal translation synthesis was undertaken. Sensory modulation interventions emerged as a key alternative to traditional inpatient practices, including seclusion and restraint and the use of PRN psychotropic medication. It introduces a new dimension within care strategies that emphasise individual preferences and care plans that empower individuals. Sensory modulation interventions serve as an effective means to de-escalation that promotes shared responsibility between staff and individuals in care. The review highlights this practice as a departure from coercive practices and biomedical interventions, promoting meaningful therapeutic engagement. Our findings show that sensory modulation interventions have the potential to create a culture shift in acute inpatient mental health settings towards person-centred, recovery-orientated, trauma-informed clinical practice.
Delafloxacin is an investigational anionic fluoroquinolone being developed to treat infections caused by Gram-positive and -negative organisms. This clinical trial evaluated the efficacy and safety ...of delafloxacin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs).
In a double-blind, Phase 2 trial, 256 patients were randomized (1 : 1 : 1) to 300 mg of delafloxacin, 600 mg of linezolid or 15 mg/kg vancomycin (actual body weight), each administered intravenously twice daily for 5-14 days. Randomization was stratified by infection category. The primary endpoint was the investigator's assessment of cure, defined as complete resolution of baseline signs and symptoms at follow-up. Secondary endpoints included reductions in the total areas of erythema and induration and assessments of bacterial eradication. This trial has been registered at ClinicalTrials.gov under registration number NCT01283581.
Cure rates were significantly greater with delafloxacin versus vancomycin (mean difference: -16.3%; 95% CI, -30.3% to -2.3%; P = 0.031); differences were significant for obese patients (BMI ≥30 kg/m(2); mean difference: -30.0%; 95% CI, -50.7% to -9.3%; P = 0.009), but not for non-obese patients. Cure rates with delafloxacin and linezolid were similar. Using digital measurement, the percentage decrease in total erythema area was significantly greater with delafloxacin versus vancomycin at follow-up (-96.4% versus -84.5%; P = 0.028). There were no differences in bacterial eradication among the treatment groups. The most frequently reported treatment-emergent adverse events were nausea, diarrhoea and vomiting.
These data show that delafloxacin is effective in the treatment of ABSSSIs and is well tolerated.
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