Aims
To assess whether randomized clinical trials (RCTs) proposed to evaluate the treatment of patients with COVID‐19 with hydroxychloroquine (HQ) or chloroquine early in the pandemic included plans ...to measure outcomes that would translate into meaningful efficacy/effectiveness and safety outcomes.
Methods
The World Health Organization International Clinical Trials Registry Platform database was searched for registers of RCTs evaluating HQ or chloroquine, alone or in combination, compared with other treatments for patients diagnosed with COVID‐19. The final search was performed on 8 April 2020.
Results
Among 51 registered RCTs (median sample size 262; interquartile range: 100, 520), 34 (67%) reported a clinical outcome, 12 (24%) a surrogate outcome, and 5 (10%) a combination of clinical and surrogate outcomes as primary endpoints. Six (15%) trials included the World Health Organization scale for clinical improvement as a primary clinical outcome. Clinical improvement and mortality accounted for 45% of the unique domains among 18 clinical outcome domains of efficacy. Twenty‐four (47%) RCTs did not describe plans to assess safety outcomes; when assessed, safety outcomes were determined in generic terms of total, severe or serious adverse events.
Conclusion
The RCTs investigating HQ or chloroquine during the early stages of the COVID‐19 pandemic included heterogeneous and insufficient approaches to measure efficacy/effectiveness and safety relevant to patients and clinical practice. These findings provide insights to inform clinical and regulatory decisions that can be drawn about the efficacy/effectiveness and safety of these agents in patients with COVID‐19. Trialists need to adapt quickly to the research progress on COVID‐19, ensuring that core outcome measures are assessed in ongoing RCTs.
Background
Inhaled short‐acting anticholinergics (SAAC) and short‐acting beta₂‐agonists (SABA) are effective therapies for adult patients with acute asthma who present to the emergency department ...(ED). It is unclear, however, whether the combination of SAAC and SABA treatment is more effective in reducing hospitalisations compared to treatment with SABA alone.
Objectives
To conduct an up‐to‐date systematic search and meta‐analysis on the effectiveness of combined inhaled therapy (SAAC + SABA agents) vs. SABA alone to reduce hospitalisations in adult patients presenting to the ED with an exacerbation of asthma.
Search methods
We searched MEDLINE, Embase, CINAHL, SCOPUS, LILACS, ProQuest Dissertations & Theses Global and evidence‐based medicine (EBM) databases using controlled vocabulary, natural language terms, and a variety of specific and general terms for inhaled SAAC and SABA drugs. The search spanned from 1946 to July 2015. The Cochrane Airways Group provided search results from the Cochrane Airways Group Register of Trials which was most recently conducted in July 2016. An extensive search of the grey literature was completed to identify any other potentially relevant studies.
Selection criteria
Included studies were randomised or controlled clinical trials comparing the effectiveness of combined inhaled therapy (SAAC and SABA) to SABA treatment alone to prevent hospitalisations in adults with acute asthma in the emergency department. Two independent review authors assessed studies for inclusion using pre‐determined criteria.
Data collection and analysis
For dichotomous outcomes, we calculated individual and pooled statistics as risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) using a random‐effects model and reporting heterogeneity (I²). For continuous outcomes, we reported individual trial results using mean differences (MD) and pooled results as weighted mean differences (WMD) or standardised mean differences (SMD) with 95% CIs using a random‐effects model.
Main results
We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias.
Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I² = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02).
Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV₁) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I² = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I² = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I² = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I² = 0%; moderate quality of evidence) than participants receiving SABA alone.
Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I² = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone.
Authors' conclusions
Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild‐moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.
Background
Upper‐limb dysfunction is a commonly reported side effect of treatment for breast cancer and may include decreased shoulder range of motion (the range through which a joint can be moved) ...(ROM) and strength, pain and lymphedema.
Objectives
To review randomized controlled trials (RCTs) evaluating the effectiveness of exercise interventions in preventing, minimi sing, or improving upper‐limb dysfunction due to breast cancer treatment.
Search methods
We searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, EMBASE, CINAHL, and LILACS (to August 2008); contacted experts, handsearched reference lists, conference proceedings, clinical practice guidelines and other unpublished literature sources.
Selection criteria
RCTs evaluating the effectiveness and safety of exercise for upper‐limb dysfunction.
Data collection and analysis
Two authors independently performed the data ion. Investigators were contacted for missing data.
Main results
We included 24 studies involving 2132 participants. Ten of the 24 were considered of adequate methodological quality.
Ten studies examined the effect of early versus delayed implementation of post‐operative exercise. Implementing early exercise was more effective than delayed exercise in the short term recovery of shoulder flexion ROM (Weighted Mean Difference (WMD): 10.6 degrees; 95% Confidence Interval (CI): 4.51 to 16.6); however, early exercise also resulted in a statistically significant increase in wound drainage volume (Standardized Mean Difference (SMD) 0.31; 95% CI: 0.13 to 0.49) and duration (WMD: 1.15 days; 95% CI: 0.65 to 1.65).
Fourteen studies examined the effect of structured exercise compared to usual care/comparison. Of these, six were post‐operative, three during adjuvant treatment and five following cancer treatment. Structured exercise programs in the post‐operative period significantly improved shoulder flexion ROM in the short‐term (WMD: 12.92 degrees; 95% CI: 0.69 to 25.16). Physical therapy treatment yielded additional benefit for shoulder function post‐intervention (SMD: 0.77; 95% CI: 0.33 to 1.21) and at six‐month follow‐up (SMD: 0.75; 95% CI: 0.32 to 1.19). There was no evidence of increased risk of lymphedema from exercise at any time point.
Authors' conclusions
Exercise can result in a significant and clinically meaningful improvement in shoulder ROM in women with breast cancer. In the post‐operative period, consideration should be given to early implementation of exercises, although this approach may need to be carefully weighed against the potential for increases in wound drainage volume and duration. High quality research studies that closely monitor exercise prescription factors (e.g. intensity), and address persistent upper‐limb dysfunction are needed.
Recent studies have observed positive associations between outdoor air pollution and emergency department (ED) visits for asthma. However, few have examined the possible confounding influence of ...aeroallergens, or reported findings among very young children.
A time stratified case-crossover design was used to examine 57,912 ED asthma visits among individuals two years of age and older in the census metropolitan area of Edmonton, Canada between April 1, 1992 and March 31, 2002. Daily air pollution levels for the entire region were estimated from three fixed-site monitoring stations. Similarly, daily levels of aeroallergens were estimated using rotational impaction sampling methods for the period between 1996 and 2002. Odds ratios and their corresponding 95% confidence intervals were estimated using conditional logistic regression with adjustment for temperature, relative humidity and seasonal epidemics of viral related respiratory disease.
Positive associations for asthma visits with outdoor air pollution levels were observed between April and September, but were absent during the remainder of the year. Effects were strongest among young children. Namely, an increase in the interquartile range of the 5-day average for NO2 and CO levels between April and September was associated with a 50% and 48% increase, respectively, in the number of ED visits among children 2 - 4 years of age (p < 0.05). Strong associations were also observed with these pollutants among those 75 years of age and older. Ozone and particulate matter were also associated with asthma visits. Air pollution risk estimates were largely unchanged after adjustment for aeroallergen levels.
Our findings, taken together, suggest that exposure to ambient levels of air pollution is an important determinant of ED visits for asthma, particularly among young children and the elderly.
Background The ability to diagnose and monitor asthma on the basis of noninvasive measurements of airway cellular dysfunction is difficult in the typical clinical setting. Objective Metabolomics is ...the study of molecules created by cellular metabolic pathways. We hypothesized that the metabolic activity of children with asthma would differ from healthy children without asthma. Furthermore, children having an asthma exacerbation would be different compared with children with stable asthma in outpatient clinics. Finally, we hypothesized that1 H-nuclear magnetic resonance (NMR) would measure such differences using urine samples, one of the least invasive forms of biofluid sampling. Methods Children (135 total, ages 4-16 years) were enrolled, having met the criteria of healthy controls (C), stable asthma in the outpatient clinic (AO), or unstable asthma in the emergency department (AED). Partial least squares discriminant analysis was performed on the NMR data to create models of separation (70 metabolites were measured/urine sample). Some NMR data were withheld from modeling to be run blindly to determine possible diagnostic accuracy. Results On the basis of the model of AO versus C, 31 of 33 AO samples were correctly diagnosed with asthma (94% accuracy). Only 1 of 20 C samples was incorrectly labeled as asthma (5% misclassification). On the basis of the AO versus AED model, 31 of the 33 AO samples were correctly diagnosed as outpatient asthma (94% accurate). Conclusion This is the first report suggesting that1 H-NMR analysis of human urine samples has the potential to be a useful clinical tool for physicians treating asthma.
An acute exacerbation of COPD (AECOPD) is associated with increased risk of cardiovascular (CV) events. The elevated risk during an AECOPD may be related to changes in vascular function, arterial ...stiffness, and systemic inflammation; the time course of these measures and their corresponding recovery are poorly understood. Further, physical activity is reduced during an AECOPD, and physical activity may influence the cardiovascular responses to an AECOPD. The purpose of the study was to examine the acute impact of an AECOPD requiring hospitalization on vascular function, arterial stiffness, and systemic inflammation and examine whether physical activity modulates these variables during recovery. Patients hospitalized for an AECOPD were prospectively recruited and compared to control patients with stable COPD. Vascular function, arterial stiffness, and systemic inflammation (CRP, IL-6) were measured at hospital admission, hospital discharge and within 14 days of discharge. Physical activity was electronically tracked daily while in hospital and for 7 days following discharge using a Fitbit. One hundred and twenty-one patients with an AECOPD requiring hospitalization and 33 control patients with stable COPD were enrolled in the study. Vascular function was significantly lower, and systemic inflammation higher at hospital admission in patients with an AECOPD compared to stable COPD. Significant improvements in vascular function and inflammation were observed within 14 days of hospital discharge; however, vascular function remained lower than stable COPD. Physical activity was low at admission and increased following discharge; however, physical activity was unrelated to measures of vascular function or inflammation at any time point. An AECOPD requiring hospitalization is associated with impaired vascular function that persists during recovery. These findings provide a mechanistic link to help explain the enduring increase in CV risk and mortality following a severe AECOPD event.Clinical trial registration: ClinicalTrials.gov #NCT01949727; Registered: 09/20/2013.
Social determinants of health contribute to disparities in pediatric health and health care. Our objective was to synthesize and evaluate the evidence on the association between social determinants ...of health and emergency department (ED) outcomes in pediatric populations.
This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Equity Extension guidelines. Observational epidemiological studies were included if they examined at least 1 social determinant of health from the PROGRESS-Plus framework in relation to ED outcomes among children <18 years old. Effect direction plots were used for narrative results and pooled odds ratios (pOR) with 95% confidence intervals (CI) for meta-analyses.
Fifty-eight studies were included, involving 17,275,090 children and 103,296,839 ED visits. Race/ethnicity and socioeconomic status were the most reported social determinants of health (71% each). Black children had 3 times the odds of utilizing the ED (pOR 3.16, 95% CI 2.46 to 4.08), whereas visits by Indigenous children increased the odds of departure prior to completion of care (pOR 1.58, 95% CI 1.39 to 1.80) compared to White children. Public insurance, low income, neighborhood deprivation, and proximity to an ED were also predictors of ED utilization. Children whose caregivers had a preferred language other than English had longer length of stay and increased hospital admission.
Social determinants of health, particularly race, socioeconomic deprivation, proximity to an ED, and language, play important roles in ED care-seeking patterns of children and families. Increased utilization of ED services by children from racial minority and lower socioeconomic status groups may reflect barriers to health insurance and access to health care, including primary and subspecialty care, and/or poorer overall health, necessitating ED care. An intersectional approach is needed to better understand the trajectories of disparities in pediatric ED outcomes and to develop, implement, and evaluate future policies.
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