Treatment of Non-severe COVID-19 with Molnupiravir: A Systematic Review with Meta-analysis and Trial Sequential Analysis of the Evidence from Randomized Controlled Trials.

Remdesivir for the treatment of COVID-19.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Early intervention for those with high cardiovascular risk is crucial in improving patient outcomes. Traditional prevention strategies for CVD have focused on conventional risk factors, such as overweight, dyslipidaemia, diabetes, and hypertension, which may reflect the potential for cardiovascular insult. Natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), are well-established biomarkers for the detection and diagnostic evaluation of heart failure. They are of interest for CVD prevention because they are secreted by the heart as a protective response to cardiovascular stress, strain, and damage. Therefore, measuring NP levels in patients without heart failure may be valuable for risk stratification, to identify those at highest risk of CVD who would benefit most from intensive risk reduction measures.To assess the effects of natriuretic peptide (NP)-guided treatment for people with cardiovascular risk factors and without heart failure.Searches of the following bibliographic databases were conducted up to 9 July 2019: CENTRAL, MEDLINE, Embase, and Web of Science. Three clinical trial registries were also searched in July 2019.We included randomised controlled trials enrolling adults with one or more cardiovascular risk factors and without heart failure, which compared NP-based screening and subsequent NP-guided treatment versus standard care in all settings (i.e. community, hospital).Two review authors independently screened titles and abstracts and selected studies for inclusion, extracted data, and evaluated risk of bias. Risk ratios (RRs) were calculated for dichotomous data, and mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous data. We contacted trial authors to obtain missing data and to verify crucial study characteristics. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, two review authors independently assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table.We included two randomised controlled trials (three reports) with 1674 participants, with mean age between 64.1 and 67.8 years. Follow-up ranged from 2 years to mean 4.3 years.For primary outcome measures, effect estimates from a single study showed uncertainty for the effect of NP-guided treatment on cardiovascular mortality in patients with cardiovascular risk factors and without heart failure (RR 0.33, 95% CI 0.04 to 3.17; 1 study; 300 participants; low-quality evidence). Pooled analysis demonstrated that in comparison to standard care, NP-guided treatment probably reduces the risk of cardiovascular hospitalisation (RR 0.52, 95% CI 0.40 to 0.68; 2 studies; 1674 participants; moderate-quality evidence). This corresponds to a risk of 163 per 1000 in the control group and 85 (95% CI 65 to 111) per 1000 in the NP-guided treatment group.When secondary outcome measures were evaluated, evidence from a pooled analysis showed uncertainty for the effect of NP-guided treatment on all-cause mortality (RR 0.90, 95% CI 0.60 to 1.35; 2 studies; 1354 participants; low-quality evidence). Pooled analysis indicates that NP-guided treatment probably reduces the risk of all-cause hospitalisation (RR 0.83, 95% CI 0.75 to 0.92; 2 studies; 1354 participants; moderate-quality evidence). This corresponds to a risk of 601 per 1000 in the control group and 499 (95% CI 457 to 553) per 1000 in the NP-guided treatment group. The effect estimate from a single study indicates that NP-guided treatment reduced the risk of ventricular dysfunction (RR 0.61, 95% CI 0.41 to 0.91; 1374 participants; high-quality evidence). The risk in this study's control group was 87 per 1000, compared with 53 (95% CI 36 to 79) per 1000 with NP-guided treatment. Results from the same study show that NP-guided treatment does not affect change in NP level at the end of follow-up, relative to standard care (MD -4.06 pg/mL, 95% CI -15.07 to 6.95; 1 study; 1374 participants; moderate-quality evidence).This review shows that NP-guided treatment is likely to reduce ventricular dysfunction and cardiovascular and all-cause hospitalisation for patients who have cardiovascular risk factors and who do not have heart failure. Effects on mortality and natriuretic peptide levels are less certain. Neither of the included studies were powered to evaluate mortality. Available evidence shows uncertainty regarding the effects of NP-guided treatment on both cardiovascular mortality and all-cause mortality; very low event numbers resulted in a high degree of imprecision in these effect estimates. Evidence also shows that NP-guided treatment may not affect NP level at the end of follow-up.As both trials included in our review were pragmatic studies, non-blinding of patients and practices may have biased results towards a finding of equivalence. Further studies with more adequately powered sample sizes and longer duration of follow-up are required to evaluate the effect of NP-guided treatment on mortality. As two trials are ongoing, one of which is a large multi-centre trial, it is hoped that future iterations of this review will benefit from larger sample sizes across a wider geographical area.

Optimisation of chemotherapy and radiotherapy for untreated Hodgkin lymphoma patients with respect to second malignant neoplasms, overall and progression-free survival: individual participant data analysis.

Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).

AGA Institute Quality Measure Development for the Diagnosis and Management of COVID-19

A reappraisal of corticosteroids use for COVID-19

People with unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI) are managed with a combination of medical therapy, invasive angiography and revascularisation. Specifically, two approaches have evolved: either a 'routine invasive' strategy whereby all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularisation; or a 'selective invasive' (also referred to as 'conservative') strategy in which medical therapy alone is used initially, with a selection of patients for angiography based upon evidence of persistent myocardial ischaemia. Uncertainty exists as to which strategy provides the best outcomes for these patients. This Cochrane review is an update of a Cochrane review originally published in 2006, to provide a robust comparison of these two strategies in the early management of patients with UA/NSTEMI. To determine the benefits and harms associated with the following.1. A routine invasive versus a conservative or 'selective invasive' strategy for the management of UA/NSTEMI in the stent era.2. A routine invasive strategy with and without glycoprotein IIb/IIIa receptor antagonists versus a conservative strategy for the management of UA/NSTEMI in the stent era. We searched the following databases and additional resources up to 25 August 2015: the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, MEDLINE and EMBASE, with no language restrictions. We included prospective randomised controlled trials (RCTs) that compared invasive with conservative or 'selective invasive' strategies in participants with acute UA/NSTEMI. Two review authors screened the records and extracted data in duplicate. Using intention-to-treat analysis with random-effects models, we calculated summary estimates of the risk ratio (RR) with 95% confidence intervals (CIs) for the primary endpoints of all-cause death, fatal and non-fatal myocardial infarction (MI), combined all-cause death or non-fatal MI, refractory angina and re-hospitalisation. We performed further analysis of included studies based on whether glycoprotein IIb/IIIa receptor antagonists were used routinely. We assessed the heterogeneity of included trials using Pearson χ² (Chi² test) and variance (I² statistic) analysis. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 (Review Manager) to create Summary of findings (SoF) tables. Eight RCTs with a total of 8915 participants (4545 invasive strategies, 4370 conservative strategies) were eligible for inclusion. We included three new studies and 1099 additional participants in this review update. In the all-study analysis, evidence did not show appreciable risk reductions in all-cause mortality (RR 0.87, 95% CI 0.64 to 1.18; eight studies, 8915 participants; low quality evidence) and death or non-fatal MI (RR 0.93, 95% CI 0.71 to 1.2; seven studies, 7715 participants; low quality evidence) with invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. There was appreciable risk reduction in MI (RR 0.79, 95% CI 0.63 to 1.00; eight studies, 8915 participants; moderate quality evidence), refractory angina (RR 0.64, 95% CI 0.52 to 0.79; five studies, 8287 participants; moderate quality evidence) and re-hospitalisation (RR 0.77, 95% CI 0.63 to 0.94; six studies, 6921 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies also at six to 12 months follow-up.Evidence also showed increased risks in bleeding (RR 1.73, 95% CI 1.30 to 2.31; six studies, 7584 participants; moderate quality evidence) and procedure-related MI (RR 1.87, 95% CI 1.47 to 2.37; five studies, 6380 participants; moderate quality evidence) with routine invasive strategies compared to conservative (selective invasive) strategies.The low quality evidence were as a result of serious risk of bias and imprecision in the estimate of effect while moderate quality evidence was only due to serious risk of bias. In the all-study analysis, the evidence failed to show appreciable benefit with routine invasive strategies for unstable angina and non-ST elevation MI compared to conservative strategies in all-cause mortality and death or non-fatal MI at six to 12 months. There was evidence of risk reduction in MI, refractory angina and re-hospitalisation with routine invasive strategies compared to conservative (selective invasive) strategies at six to 12 months follow-up. However, routine invasive strategies were associated with a relatively high risk (almost double the risk) of procedure-related MI, and increased risk of bleeding complications. This systematic analysis of published RCTs supports the conclusion that, in patients with UA/NSTEMI, a selectively invasive (conservative) strategy based on clinical risk for recurrent events is the preferred management strategy.

Background: Chronic kidney disease-mineral and bone disorders (CKD-MBD) have been associated with poor health outcomes, including diminished quality and length of life. Standard management for CKD-MBD includes phosphate restricted diet, vitamin D and phosphate binders. Persistently elevated parathyroid hormone levels may require the addition of cinacalcet hydrochloride (cinacalcet), which sensitizes calcium receptors in the parathyroid gland.Purpose: The objective of this systematic review is to compare, in patients with CKD-MBD the effect of cinacalcet versus standard treatment on patient-important outcomes, including parathyroidectomy, fractures, hospitalizations due to cardiovascular events, cardiovascular mortality, all-cause mortality, and intermediate outcomes, in particular Kidney Disease Outcome Quality Initiative targets.Methods: Data sources included MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Web of Science from 1996 to June 2015. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible trials. We calculated the effect estimates (risk ratios or mean differences) and 95% confidence intervals, as well as statistical measures of variability in results across studies using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate quality of evidence about estimates of effect on an outcome-by-outcome basis for all outcomes. We presented our results with a GRADE summary table.Results: Twenty-four trials including 8311 CKD patients proved eligible. The results left considerable uncertainty regarding the impact of cinacalcet on reducing fractures (relative risk [RR] 0.59, 95% confidence interval [CI] 0.13–2.60; heterogeneity: p = 0.03, I2= 78%; very low quality evidence), and indicated that cinacalcet did not reduce hospitalizations due to cardiovascular events (RR 0.93, 95% CI 0.85–1.02, moderate quality of evidence), cardiovascular mortality (RR 0.95, 95% CI 0.84–1.07; heterogeneity p= 0.61, high quality evidence) or all-cause mortality (RR 0.96, 95% CI 0.89–1.04; heterogeneity: p= 0.98, I2= 0%; moderate quality evidence). Cinacalcet reduced the need for parathyroidectomy (RR 0.30, 95% CI 0.22–0.42; heterogeneity: p= 0.70, I2= 0%; absolute effect 55 fewer per 1000 [95% CI 61 fewer to 45 fewer], high quality of evidence). The most common adverse event associated with cinacalcet therapy was gastrointestinal side effects. Cinacalcet increased nausea (RR 2.16, 95% CI 1.46–3.21, absolute effect 158 more per 1000 [95% CI 82 more to 302 more]) and vomiting (RR 2.15, 95% CI 1.66–2.80, absolute effect 63 more per 1000 [95% CI 109 more to 171 more]). Cinacalcet treatment increased the rate of hypocalcemia (RR 6.0, 95% CI 3.65–9.87; heterogeneity: p= 0.71, I2= 0%, absolute effect 20 more per 1000 [95% CI 11 more to 36 more], high quality of evidence).Conclusions: In the hands of clinicians participating in these studies, cinacalcet decreased the rate of parathyroidectomy but had no influence on mortality. Patients and clinicians can trade of the benefit of fewer parathyroidectomies against the adverse effects.

Gastrointestinal paralysis, nausea and vomiting and pain are major clinical problems following abdominal surgery. Anaesthetic and analgesic techniques that reduce pain and postoperative nausea and vomiting (PONV), while preventing or reducing postoperative ileus, may reduce postoperative morbidity, duration of hospitalization and hospital costs. This review was first published in 2001 and was updated by new review authors in 2016. To compare effects of postoperative epidural analgesia with local anaesthetics versus postoperative systemic or epidural opioids in terms of return of gastrointestinal transit, postoperative pain control, postoperative vomiting, incidence of anastomotic leak, length of hospital stay and costs after abdominal surgery. We identified trials by conducting computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 12), MEDLINE (from 1950 to December 2014) and EMBASE (from 1974 to December 2014) and by checking the reference lists of trials retained. When we reran the search in February 2016, we added 16 potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate these studies into formal review findings during the next review update. We included parallel randomized controlled trials comparing effects of postoperative epidural local anaesthetic versus regimens based on systemic or epidural opioids. We rated the quality of studies by using the Cochrane 'Risk of bias' tool. Two review authors independently extracted data and judged the quality of evidence according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) scale. We included 128 trials with 8754 participants in the review, and 94 trials with 5846 participants in the analysis. Trials included in the review were funded as follows: charity (n = 19), departmental resources (n = 8), governmental sources (n = 15) and industry (in part or in total) (n = 15). The source of funding was not specified for the other studies.Results of 22 trials including 1138 participants show that an epidural containing a local anaesthetic will decrease the time required for return of gastrointestinal transit as measured by time to first flatus after an abdominal surgery (standardized mean difference (SMD) -1.28, 95% confidence interval (CI) -1.71 to -0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportionate to the concentration of local anaesthetic used. A total of 28 trials including 1559 participants reported a decrease in time to first faeces (stool) (SMD -0.67, 95% CI -0.86 to -0.47; low quality of evidence; equivalent to 22 hours). Thirty-five trials including 2731 participants found that pain on movement at 24 hours after surgery was also reduced (SMD -0.89, 95% CI -1.08 to -0.70; moderate quality of evidence; equivalent to 2.5 on scale from 0 to 10). From findings of 22 trials including 1154 participants we did not find a difference in the incidence of vomiting within 24 hours (risk ratio (RR) 0.84, 95% CI 0.57 to 1.23; low quality of evidence). From investigators in 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak (RR 0.74, 95% CI 0.41 to 1.32; low quality of evidence). Researchers in 30 trials including 2598 participants noted that epidural analgesia reduced length of hospital stay for an open surgery (SMD -0.20, 95% CI -0.35 to -0.04; very low quality of evidence; equivalent to one day). Data on costs were very limited. An epidural containing a local anaesthetic, with or without the addition of an opioid, accelerates the return of gastrointestinal transit (high quality of evidence). An epidural containing a local anaesthetic with an opioid decreases pain after abdominal surgery (moderate quality of evidence). We did not find a difference in the incidence of vomiting or anastomotic leak (low quality of evidence). For open surgery, an epidural containing a local anaesthetic would reduce the length of hospital stay (very low quality of evidence).

AGA Institute Rapid Review and Recommendations on the Role of Pre-Procedure SARS-CoV-2 Testing and Endoscopy

We conducted a systematic review of observational studies to examine the effects of body mass index (BMI) and obesity (BMI ≥ 30 kg/m2 ) on coronavirus disease 2019 (COVID-19). Medline, Embase, and the Cochrane Library were searched. Sixteen articles were finally included in the meta-analysis, and a random effects model was used. BMI was found to be higher in patients with severe disease than in those with mild or moderate disease (MD 1.6, 95% CI, 0.8-2.4; p = .0002) in China; however, the heterogeneity was high (I2 = 75%). Elevated BMI was associated with invasive mechanical ventilation (IMV) use (MD 4.1, 95% CI, 2.1-6.1; p < .0001) in Western countries, and this result was consistent across studies (I2 = 0%). Additionally, there were increased odds ratios of IMV use (OR 2.0, 95% CI, 1.4-2.9; p < .0001) and hospitalization (OR 1.4, 95% CI, 1.3-1.60; p < .00001) in patients with obesity. There was no substantial heterogeneity (I2 = 0%). In conclusion, obesity or high BMI increased the risk of hospitalization, severe disease and invasive mechanical ventilation in COVID-19. Physicians must be alert to these early indicators to identify critical patients.

Effects of sevoflurane versus other general anaesthesia on emergence agitation in children.

Braces and orthoses for treating osteoarthritis of the knee.

Acute hypoxaemic respiratory failure (AHRF) and mostly acute respiratory distress syndrome (ARDS) are critical conditions. AHRF results from several systemic conditions and is associated with high mortality and morbidity in individuals of all ages. Inhaled nitric oxide (INO) has been used to improve oxygenation, but its role remains controversial. This Cochrane review was originally published in 2003, and has been updated in 2010 and 2016. The primary objective was to examine the effects of administration of inhaled nitric oxide on mortality in adults and children with ARDS. Secondary objectives were to examine secondary outcomes such as pulmonary bleeding events, duration of mechanical ventilation, length of stay, etc. We conducted subgroup and sensitivity analyses, examined the role of bias and applied trial sequential analyses (TSAs) to examine the level of evidence. In this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015 Issue 11); MEDLINE (Ovid SP, to 18 November 2015), EMBASE (Ovid SP, to 18 November 2015), CAB, BIOSIS and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We handsearched the reference lists of the newest reviews and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception until 18 November 2015. We included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data. Two review authors independently extracted data and resolved disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effects of INO in adults and children and on various clinical and physiological outcomes. We presented pooled estimates of the effects of interventions as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias through assessment of trial methodological components and risk of random error through trial sequential analysis. Our primary objective was to assess effects of INO on mortality. We found no statistically significant effects of INO on longest follow-up mortality: 250/654 deaths (38.2%) in the INO group compared with 221/589 deaths (37.5%) in the control group (RR 1.04, 95% CI 0.9 to 1.19; I² statistic = 0%; moderate quality of evidence). We found no statistically significant effects of INO on mortality at 28 days: 202/587 deaths (34.4%) in the INO group compared with 166/518 deaths (32.0%) in the control group (RR 1.08, 95% CI 0.92 to 1.27; I² statistic = 0%; moderate quality of evidence). In children, there was no statistically significant effects of INO on mortality: 25/89 deaths (28.1%) in the INO group compared with 34/96 deaths (35.4%) in the control group (RR 0.78, 95% CI 0.51 to 1.18; I² statistic = 22%; moderate quality of evidence).Our secondary objective was to assess the benefits and harms of INO. For partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), we found significant improvement at 24 hours (mean difference (MD) 15.91, 95% CI 8.25 to 23.56; I² statistic = 25%; 11 trials, 614 participants; moderate quality of evidence). For the oxygenation index, we noted significant improvement at 24 hours (MD -2.31, 95% CI -2.73 to -1.89; I² statistic = 0%; five trials, 368 participants; moderate quality of evidence). For ventilator-free days, the difference was not statistically significant (MD -0.57, 95% CI -1.82 to 0.69; I² statistic = 0%; five trials, 804 participants; high quality of evidence). There was a statistically significant increase in renal failure in the INO groups (RR 1.59, 95% CI 1.17 to 2.16; I² statistic = 0%; high quality of evidence). Evidence is insufficient to support INO in any category of critically ill patients with AHRF. Inhaled nitric oxide results in a transient improvement in oxygenation but does not reduce mortality and may be harmful, as it seems to increase renal impairment.

Exercise for osteoarthritis of the knee.