Physical interventions to interrupt or reduce the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review last published in 2020. We include results from studies from the current COVID-19 pandemic. OBJECTIVES: To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, CINAHL, and two trials registers in October 2022, with backwards and forwards citation analysis on the new studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, glasses, and gargling) to prevent respiratory virus transmission.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 11 new RCTs and cluster-RCTs (610,872 participants) in this update, bringing the total number of RCTs to 78. Six of the new trials were conducted during the COVID-19 pandemic; two from Mexico, and one each from Denmark, Bangladesh, England, and Norway. We identified four ongoing studies, of which one is completed, but unreported, evaluating masks concurrent with the COVID-19 pandemic. Many studies were conducted during non-epidemic influenza periods. Several were conducted during the 2009 H1N1 influenza pandemic, and others in epidemic influenza seasons up to 2016. Therefore, many studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Adherence with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included 12 trials (10 cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and 10 in the community). Wearing masks in the community probably makes little or no difference to the outcome of influenza-like illness (ILI)/COVID-19 like illness compared to not wearing masks (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.84 to 1.09; 9 trials, 276,917 participants; moderate-certainty evidence. Wearing masks in the community probably makes little or no difference to the outcome of laboratory-confirmed influenza/SARS-CoV-2 compared to not wearing masks (RR 1.01, 95% CI 0.72 to 1.42; 6 trials, 13,919 participants; moderate-certainty evidence). Harms were rarely measured and poorly reported (very low-certainty evidence). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). We are very uncertain on the effects of N95/P2 respirators compared with medical/surgical masks on the outcome of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; 3 trials, 7779 participants; very low-certainty evidence). N95/P2 respirators compared with medical/surgical masks may be effective for ILI (RR 0.82, 95% CI 0.66 to 1.03; 5 trials, 8407 participants; low-certainty evidence). Evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirators compared to medical/surgical masks probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; 5 trials, 8407 participants; moderate-certainty evidence). Restricting pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies (very low-certainty evidence).  One previously reported ongoing RCT has now been published and observed that medical/surgical masks were non-inferior to N95 respirators in a large study of 1009 healthcare workers in four countries providing direct care to COVID-19 patients.  Hand hygiene compared to control Nineteen trials compared hand hygiene interventions with controls with sufficient data to include in meta-analyses. Settings included schools, childcare centres and homes. Comparing hand hygiene interventions with controls (i.e. no intervention), there was a 14% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.86, 95% CI 0.81 to 0.90; 9 trials, 52,105 participants; moderate-certainty evidence), suggesting a probable benefit. In absolute terms this benefit would result in a reduction from 380 events per 1000 people to 327 per 1000 people (95% CI 308 to 342). When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.94, 95% CI 0.81 to 1.09; 11 trials, 34,503 participants; low-certainty evidence), and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials, 8332 participants; low-certainty evidence), suggest the intervention made little or no difference. We pooled 19 trials (71, 210 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. Pooled data showed that hand hygiene may be beneficial with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.83 to 0.94; low-certainty evidence), but with high heterogeneity. In absolute terms this benefit would result in a reduction from 200 events per 1000 people to 178 per 1000 people (95% CI 166 to 188). Few trials measured and reported harms (very low-certainty evidence). We found no RCTs on gowns and gloves, face shields, or screening at entry ports. AUTHORS' CONCLUSIONS: The high risk of bias in the trials, variation in outcome measurement, and relatively low adherence with the interventions during the studies hampers drawing firm conclusions. There were additional RCTs during the pandemic related to physical interventions but a relative paucity given the importance of the question of masking and its relative effectiveness and the concomitant measures of mask adherence which would be highly relevant to the measurement of effectiveness, especially in the elderly and in young children. There is uncertainty about the effects of face masks. The low to moderate certainty of evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of RCTs did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness, and although this effect was also present when ILI and laboratory-confirmed influenza were analysed separately, it was not found to be a significant difference for the latter two outcomes. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, as well as the impact of adherence on effectiveness, especially in those most at risk of ARIs.

Reporting of Factorial Randomized Trials: Extension of the CONSORT 2010 Statement.

Importance: Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal. Objective: To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials. Design: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist. Findings: This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported. Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.

Physical interventions to interrupt or reduce the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections (ARIs) pose a global threat. Examples are influenza (H1N1) caused by the H1N1pdm09 virus in 2009, severe acute respiratory syndrome (SARS) in 2003, and coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in 2019. Antiviral drugs and vaccines may be insufficient to prevent their spread. This is an update of a Cochrane Review published in 2007, 2009, 2010, and 2011. The evidence summarised in this review does not include results from studies from the current COVID-19 pandemic. OBJECTIVES: To assess the effectiveness of physical interventions to interrupt or reduce the spread of acute respiratory viruses. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, CINAHL on 1 April 2020. We searched ClinicalTrials.gov, and the WHO ICTRP on 16 March 2020. We conducted a backwards and forwards citation analysis on the newly included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-RCTs of trials investigating physical interventions (screening at entry ports, isolation, quarantine, physical distancing, personal protection, hand hygiene, face masks, and gargling) to prevent respiratory virus transmission. In previous versions of this review we also included observational studies. However, for this update, there were sufficient RCTs to address our study aims.   DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. Three pairs of review authors independently extracted data using a standard template applied in previous versions of this review, but which was revised to reflect our focus on RCTs and cluster-RCTs for this update. We did not contact trialists for missing data due to the urgency in completing the review. We extracted data on adverse events (harms) associated with the interventions. MAIN RESULTS: We included 44 new RCTs and cluster-RCTs in this update, bringing the total number of randomised trials to 67. There were no included studies conducted during the COVID-19 pandemic. Six ongoing studies were identified, of which three evaluating masks are being conducted concurrent with the COVID pandemic, and one is completed. Many studies were conducted during non-epidemic influenza periods, but several studies were conducted during the global H1N1 influenza pandemic in 2009, and others in epidemic influenza seasons up to 2016. Thus, studies were conducted in the context of lower respiratory viral circulation and transmission compared to COVID-19. The included studies were conducted in heterogeneous settings, ranging from suburban schools to hospital wards in high-income countries; crowded inner city settings in low-income countries; and an immigrant neighbourhood in a high-income country. Compliance with interventions was low in many studies. The risk of bias for the RCTs and cluster-RCTs was mostly high or unclear. Medical/surgical masks compared to no masks We included nine trials (of which eight were cluster-RCTs) comparing medical/surgical masks versus no masks to prevent the spread of viral respiratory illness (two trials with healthcare workers and seven in the community). There is low certainty evidence from nine trials (3507 participants) that wearing a mask may make little or no difference to the outcome of influenza-like illness (ILI) compared to not wearing a mask (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.82 to 1.18. There is moderate certainty evidence that wearing a mask probably makes little or no difference to the outcome of laboratory-confirmed influenza compared to not wearing a mask (RR 0.91, 95% CI 0.66 to 1.26; 6 trials; 3005 participants). Harms were rarely measured and poorly reported. Two studies during COVID-19 plan to recruit a total of 72,000 people. One evaluates medical/surgical masks (N = 6000) (published Annals of Internal Medicine, 18 Nov 2020), and one evaluates cloth masks (N = 66,000). N95/P2 respirators compared to medical/surgical masks We pooled trials comparing N95/P2 respirators with medical/surgical masks (four in healthcare settings and one in a household setting). There is uncertainty over the effects of N95/P2 respirators when compared with medical/surgical masks on the outcomes of clinical respiratory illness (RR 0.70, 95% CI 0.45 to 1.10; very low-certainty evidence; 3 trials; 7779 participants) and ILI (RR 0.82, 95% CI 0.66 to 1.03; low-certainty evidence; 5 trials; 8407 participants). The evidence is limited by imprecision and heterogeneity for these subjective outcomes. The use of a N95/P2 respirator compared to a medical/surgical mask probably makes little or no difference for the objective and more precise outcome of laboratory-confirmed influenza infection (RR 1.10, 95% CI 0.90 to 1.34; moderate-certainty evidence; 5 trials; 8407 participants). Restricting the pooling to healthcare workers made no difference to the overall findings. Harms were poorly measured and reported, but discomfort wearing medical/surgical masks or N95/P2 respirators was mentioned in several studies. One ongoing study recruiting 576 people compares N95/P2 respirators with medical surgical masks for healthcare workers during COVID-19. Hand hygiene compared to control Settings included schools, childcare centres, homes, and offices. In a comparison of hand hygiene interventions with control (no intervention), there was a 16% relative reduction in the number of people with ARIs in the hand hygiene group (RR 0.84, 95% CI 0.82 to 0.86; 7 trials; 44,129 participants; moderate-certainty evidence), suggesting a probable benefit. When considering the more strictly defined outcomes of ILI and laboratory-confirmed influenza, the estimates of effect for ILI (RR 0.98, 95% CI 0.85 to 1.13; 10 trials; 32,641 participants; low-certainty evidence) and laboratory-confirmed influenza (RR 0.91, 95% CI 0.63 to 1.30; 8 trials; 8332 participants; low-certainty evidence) suggest the intervention made little or no difference. We pooled all 16 trials (61,372 participants) for the composite outcome of ARI or ILI or influenza, with each study only contributing once and the most comprehensive outcome reported. The pooled data showed that hand hygiene may offer a benefit with an 11% relative reduction of respiratory illness (RR 0.89, 95% CI 0.84 to 0.95; low-certainty evidence), but with high heterogeneity. Few trials measured and reported harms. There are two ongoing studies of handwashing interventions in 395 children outside of COVID-19. We identified one RCT on quarantine/physical distancing. Company employees in Japan were asked to stay at home if household members had ILI symptoms. Overall fewer people in the intervention group contracted influenza compared with workers in the control group (2.75% versus 3.18%; hazard ratio 0.80, 95% CI 0.66 to 0.97). However, those who stayed at home with their infected family members were 2.17 times more likely to be infected. We found no RCTs on eye protection, gowns and gloves, or screening at entry ports. AUTHORS' CONCLUSIONS: The high risk of bias in the trials, variation in outcome measurement, and relatively low compliance with the interventions during the studies hamper drawing firm conclusions and generalising the findings to the current COVID-19 pandemic. There is uncertainty about the effects of face masks. The low-moderate certainty of the evidence means our confidence in the effect estimate is limited, and that the true effect may be different from the observed estimate of the effect. The pooled results of randomised trials did not show a clear reduction in respiratory viral infection with the use of medical/surgical masks during seasonal influenza. There were no clear differences between the use of medical/surgical masks compared with N95/P2 respirators in healthcare workers when used in routine care to reduce respiratory viral infection. Hand hygiene is likely to modestly reduce the burden of respiratory illness. Harms associated with physical interventions were under-investigated. There is a need for large, well-designed RCTs addressing the effectiveness of many of these interventions in multiple settings and populations, especially in those most at risk of ARIs.

Adverse events in people taking macrolide antibiotics versus placebo for any indication.

BACKGROUND: Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment-specific, rather than disease-specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. OBJECTIVES: To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. SELECTION CRITERIA: We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide-resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta-analysis when three or more included studies reported a specific adverse event. MAIN RESULTS: We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin.Most studies (89%) reported some adverse events or at least stated that no adverse events were observed.Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low-quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low-quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate-quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate-quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate-quality evidence) were also reported more often in participants taking macrolides compared to placebo.The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000.The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting.There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration.Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; I² = 46%; low-quality evidence).Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; I² = 0%; low-quality evidence).We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low-quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low-quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low-quality evidence) compared to placebo.We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo.Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate-quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate-quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate-quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non-significant.There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; I² = 11%; low-quality evidence).Only 24 studies (13%) provided useful data on macrolide-resistant bacteria. Macrolide-resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent.Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. AUTHORS' CONCLUSIONS: The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance.

Early intervention (mobilization or active exercise) for critically ill adults in the intensive care unit.

BACKGROUND: Survivors of critical illness often experience a multitude of problems that begin in the intensive care unit (ICU) or present and continue after discharge. These can include muscle weakness, cognitive impairments, psychological difficulties, reduced physical function such as in activities of daily living (ADLs), and decreased quality of life. Early interventions such as mobilizations or active exercise, or both, may diminish the impact of the sequelae of critical illness. OBJECTIVES: To assess the effects of early intervention (mobilization or active exercise), commenced in the ICU, provided to critically ill adults either during or after the mechanical ventilation period, compared with delayed exercise or usual care, on improving physical function or performance, muscle strength and health-related quality of life. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL. We searched conference proceedings, reference lists of retrieved articles, databases of trial registries and contacted experts in the field on 31 August 2017. We did not impose restrictions on language or location of publications. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) or quasi-RCTs that compared early intervention (mobilization or active exercise, or both), delivered in the ICU, with delayed exercise or usual care delivered to critically ill adults either during or after the mechanical ventilation period in the ICU. DATA COLLECTION AND ANALYSIS: Two researchers independently screened titles and abstracts and assessed full-text articles against the inclusion criteria of this review. We resolved any disagreement through discussion with a third review author as required. We presented data descriptively using mean differences or medians, risk ratios and 95% confidence intervals. A meta-analysis was not possible due to the heterogeneity of the included studies. We assessed the quality of evidence with GRADE. MAIN RESULTS: We included four RCTs (a total of 690 participants), in this review. Participants were adults who were mechanically ventilated in a general, medical or surgical ICU, with mean or median age in the studies ranging from 56 to 62 years. Admitting diagnoses in three of the four studies were indicative of critical illness, while participants in the fourth study had undergone cardiac surgery. Three studies included range-of-motion exercises, bed mobility activities, transfers and ambulation. The fourth study involved only upper limb exercises. Included studies were at high risk of performance bias, as they were not blinded to participants and personnel, and two of four did not blind outcome assessors. Three of four studies reported only on those participants who completed the study, with high rates of dropout. The description of intervention type, dose, intensity and frequency in the standard care control group was poor in two of four studies.Three studies (a total of 454 participants) reported at least one measure of physical function. One study (104 participants) reported low-quality evidence of beneficial effects in the intervention group on return to independent functional status at hospital discharge (59% versus 35%, risk ratio (RR) 1.71, 95% confidence interval (CI) 1.11 to 2.64); the absolute effect is that 246 more people (95% CI 38 to 567) per 1000 would attain independent functional status when provided with early mobilization. The effects on physical functioning are uncertain for a range measures: Barthel Index scores (early mobilization: median 75 control: versus 55, low quality evidence), number of ADLs achieved at ICU (median of 3 versus 0, low quality evidence) or at hospital discharge (median of 6 versus 4, low quality evidence). The effects of early mobilization on physical function measured at ICU discharge are uncertain, as measured by the Acute Care Index of Function (ACIF) (early mobilization mean: 61.1 versus control: 55, mean difference (MD) 6.10, 95% CI -11.85 to 24.05, low quality evidence) and the Physical Function ICU Test (PFIT) score (5.6 versus 5.4, MD 0.20, 95% CI -0.98 to 1.38, low quality evidence). There is low quality evidence that early mobilization may have little or no effect on physical function measured by the Short Physical Performance Battery score at ICU discharge from one study of 184 participants (mean 1.6 in the intervention group versus 1.9 in usual care, MD -0.30, 95% CI -1.10 to 0.50), or at hospital discharge (MD 0, 95% CI -1.00 to 0.90). The fourth study, which examined postoperative cardiac surgery patients did not measure physical function as an outcome.Adverse effects were reported across the four studies but we could not combine the data. Our certainty in the risk of adverse events with either mobilization strategy is low due to the low rate of events. One study reported that in the intervention group one out of 49 participants (2%) experienced oxygen desaturation less than 80% and one of 49 (2%) had accidental dislodgement of the radial catheter. This study also found cessation of therapy due to participant instability occurred in 19 of 498 (4%) of the intervention sessions. In another study five of 101 (5%) participants in the intervention group and five of 109 (4.6%) participants in the control group had postoperative pulmonary complications deemed to be unrelated to intervention. A third study found one of 150 participants in the intervention group had an episode of asymptomatic bradycardia, but completed the exercise session. The fourth study reported no adverse events. AUTHORS' CONCLUSIONS: There is insufficient evidence on the effect of early mobilization of critically ill people in the ICU on physical function or performance, adverse events, muscle strength and health-related quality of life at this time. The four studies awaiting classification, and the three ongoing studies may alter the conclusions of the review once these results are available. We assessed that there is currently low-quality evidence for the effect of early mobilization of critically ill adults in the ICU due to small sample sizes, lack of blinding of participants and personnel, variation in the interventions and outcomes used to measure their effect and inadequate descriptions of the interventions delivered as usual care in the studies included in this Cochrane Review.

Systemic corticosteroids for acute otitis media in children.

BACKGROUND: Acute otitis media (AOM) is a common acute infection in children. Pain is its most prominent and distressing symptom. Antibiotics are commonly prescribed for AOM, although they have only a modest effect in reducing pain at two to three days. There is insufficient evidence for benefits of other treatment options, including systemic corticosteroids. However, systemic corticosteroids are potent anti-inflammatory drugs, and so theoretically could be effective, either alone or as an addition to antibiotics. OBJECTIVES: To assess the effects of systemic corticosteroids (oral or parenteral), with or without antibiotics, for AOM in children. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) which contains the Cochrane ARI Group's Specialised Register, MEDLINE (Ovid), Embase (Elsevier), CINAHL (EBSCO), Web of Science (Thomson Reuters), and LILACS (BIREME) for published studies, and ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for completed and ongoing studies, to 20 February 2018. We checked the reference lists of all primary studies and review articles for additional references and contacted experts in the field to identify additional unpublished materials. SELECTION CRITERIA: We included randomised controlled trials of children with AOM that compared any systemic corticosteroid (oral or parenteral) with placebo, either with antibiotics (corticosteroid plus antibiotic versus placebo plus antibiotic) or without antibiotics (corticosteroid versus placebo). DATA COLLECTION AND ANALYSIS: Three review authors (EDS, RR, YP) independently screened the titles and abstracts and retrieved the full texts of potentially relevant studies. We independently extracted study characteristics and outcome data from the included studies, and assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed study quality using the GRADE method. MAIN RESULTS: We included two studies involving 252 children with AOM aged from three months to six years receiving hospital ambulatory care who were treated with intramuscular ceftriaxone, and who were then randomised to the corticosteroid group (corticosteroid and corticosteroid plus antihistamine) or the placebo group (antihistamine and double placebo). In one study, children also had a needle aspiration of middle ear fluid. Both studies were at unclear risk of bias for allocation concealment, and unclear to high risk of bias for selective reporting.One study (N = 179) included pain as an outcome, but we were unable to derive the proportion of children with persistent pain at Day 5 and Day 14. Reduction of overall or specific symptoms was presented as improvement in clinical symptoms and resolution of inflamed tympanic membranes without the need for additional antibiotic treatment: at Day 5 (94% of children in the treatment group (N = 89) versus 89% in the placebo group (N = 90); risk ratio (RR) 1.06, 95% confidence interval (CI) 0.97 to 1.16) and Day 14 (91% versus 87%; RR 1.05, 95% CI 0.95 to 1.17). Low-quality evidence meant that we are uncertain of the effectiveness of corticosteroids for this outcome.The second study (N = 73) reported a reduction of overall or specific symptoms without additional antibiotic treatment during the first two weeks as a favourable outcome. Children in the treatment group had more favourable outcomes (adjusted odds ratio 65.9, 95% CI 1.28 to 1000; P = 0.037), although the numbers were small. We were unable to pool the results with the other study because it did not report the proportion of children with this outcome by treatment group. Only one study reported adverse effects of corticosteroids (e.g. drowsiness, nappy rash), but did not quantify incidence, so we were unable to draw conclusions about adverse effects. Neither study reported a reduction in overall or specific symptom duration. AUTHORS' CONCLUSIONS: The evidence for the effect of systemic corticosteroids on AOM is of low to very low quality, meaning the effect of systemic corticosteroids on important clinical outcomes in AOM remains uncertain. Large, high-quality studies are required to resolve the question.

Introduction to systematic reviews and meta-analysis.

Systematic reviews provide a method for collating and synthesizing research, and are used to inform healthcare decision making by clinicians, consumers and policy makers. A core component of many systematic reviews is a meta-analysis, which is a statistical synthesis of results across studies. In this review article, we introduce meta-analysis, focusing on the different meta-analysis models, their interpretation, how a model should be selected and discuss potential threats to the validity of meta-analyses. We illustrate the application of meta-analysis using data from a review examining the effects of early use of inhaled corticosteroids in the emergency department treatment of acute asthma.

Educational interventions for the management of cancer-related fatigue in adults.

BACKGROUND: Cancer-related fatigue is reported as the most common and distressing symptom experienced by patients with cancer. It can exacerbate the experience of other symptoms, negatively affect mood, interfere with the ability to carry out everyday activities, and negatively impact on quality of life. Educational interventions may help people to manage this fatigue or to cope with this symptom, and reduce its overall burden. Despite the importance of education for managing cancer-related fatigue there are currently no systematic reviews examining this approach. OBJECTIVES: To determine the effectiveness of educational interventions for managing cancer-related fatigue in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), and MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, OTseeker and PEDro up to 1st November 2016. We also searched trials registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of educational interventions focused on cancer-related fatigue where fatigue was a primary outcome. Studies must have aimed to evaluate the effect of educational interventions designed specifically to manage cancer-related fatigue, or to evaluate educational interventions targeting a constellation of physical symptoms or quality of life where fatigue was the primary focus. The studies could have compared educational interventions with no intervention or wait list controls, usual care or attention controls, or an alternative intervention for cancer-related fatigue in adults with any type of cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion and extracted data. We resolved differences in opinion by discussion. Trial authors were contacted for additional information. A third independent person checked the data extraction. The main outcome considered in this review was cancer-related fatigue. We assessed the evidence using GRADE and created a 'Summary of Findings' table. MAIN RESULTS: We included 14 RCTs with 2213 participants across different cancer diagnoses. Four studies used only 'information-giving' educational strategies, whereas the remainder used mainly information-giving strategies coupled with some problem-solving, reinforcement, or support techniques. Interventions differed in delivery including: mode of delivery (face to face, web-based, audiotape, telephone); group or individual interventions; number of sessions provided (ranging from 2 to 12 sessions); and timing of intervention in relation to completion of cancer treatment (during or after completion). Most trials compared educational interventions to usual care and meta-analyses compared educational interventions to usual care or attention controls. Methodological issues that increased the risk of bias were evident including lack of blinding of outcome assessors, unclear allocation concealment in over half of the studies, and generally small sample sizes. Using the GRADE approach, we rated the quality of evidence as very low to moderate, downgraded mainly due to high risk of bias, unexplained heterogeneity, and imprecision.There was moderate quality evidence of a small reduction in fatigue intensity from a meta-analyses of eight studies (1524 participants; standardised mean difference (SMD) -0.28, 95% confidence interval (CI) -0.52 to -0.04) comparing educational interventions with usual care or attention control. We found low quality evidence from twelve studies (1711 participants) that educational interventions had a small effect on general/overall fatigue (SMD -0.27, 95% CI -0.51 to -0.04) compared to usual care or attention control. There was low quality evidence from three studies (622 participants) of a moderate size effect of educational interventions for reducing fatigue distress (SMD -0.57, 95% CI -1.09 to -0.05) compared to usual care, and this could be considered clinically significant. Pooled data from four studies (439 participants) found a small reduction in fatigue interference with daily life (SMD -0.35, 95% CI -0.54 to -0.16; moderate quality evidence). No clear effects on fatigue were found related to type of cancer treatment or timing of intervention in relation to completion of cancer treatment, and there were insufficient data available to determine the effect of educational interventions on fatigue by stage of disease, tumour type or group versus individual intervention.Three studies (571 participants) provided low quality evidence for a reduction in anxiety in favour of the intervention group (mean difference (MD) -1.47, 95% CI -2.76 to -0.18) which, for some, would be considered clinically significant. Two additional studies not included in the meta-analysis also reported statistically significant improvements in anxiety in favour of the educational intervention, whereas a third study did not. Compared with usual care or attention control, educational interventions showed no significant reduction in depressive symptoms (four studies, 881 participants, SMD -0.12, 95% CI -0.47 to 0.23; very low quality evidence). Three additional trials not included in the meta-analysis found no between-group differences in the symptoms of depression. No between-group difference was evident in the capacity for activities of daily living or physical function when comparing educational interventions with usual care (4 studies, 773 participants, SMD 0.33, 95% CI -0.10 to 0.75) and the quality of evidence was low. Pooled evidence of low quality from two of three studies examining the effect of educational interventions compared to usual care found an improvement in global quality of life on a 0-100 scale (MD 11.47, 95% CI 1.29 to 21.65), which would be considered clinically significant for some.No adverse events were reported in any of the studies. AUTHORS' CONCLUSIONS: Educational interventions may have a small effect on reducing fatigue intensity, fatigue's interference with daily life, and general fatigue, and could have a moderate effect on reducing fatigue distress. Educational interventions focused on fatigue may also help reduce anxiety and improve global quality of life, but it is unclear what effect they might have on capacity for activities of daily living or depressive symptoms. Additional studies undertaken in the future are likely to impact on our confidence in the conclusions.The incorporation of education for the management of fatigue as part of routine care appears reasonable. However, given the complex nature of this symptom, educational interventions on their own are unlikely to optimally reduce fatigue or help people manage its impact, and should be considered in conjunction with other interventions. Just how educational interventions are best delivered, and their content and timing to maximise outcomes, are issues that require further research.

The Effect of Distal Femoral Resection on Fixed Flexion Deformity in Total Knee Arthroplasty.

This study aims to quantify the relationship between distal femoral bone resection and correction of fixed flexion in total knee arthroplasty (TKA). Two previous studies have reported conflicting results. Spacers attached to the trial femoral component simulated additional distal femoral resection and the degree of knee flexion was recorded using computer navigation. The 2-mm augment produced an average of 3.37° of flexion deformity, 4-mm augment 6.68°, and 6-mm augment 11.38°. The amount of pre-resection flexion contracture significantly impacted on the effect of each augment. From our results, an additional 3.55 mm of distal femoral bone resection is required to correct 10° fixed flexion and produced less correction of flexion deformity as traditionally believed in TKA.

Palliative pharmacological sedation for terminally ill adults.

BACKGROUND: Terminally ill people experience a variety of symptoms in the last hours and days of life, including delirium, agitation, anxiety, terminal restlessness, dyspnoea, pain, vomiting, and psychological and physical distress. In the terminal phase of life, these symptoms may become refractory, and unable to be controlled by supportive and palliative therapies specifically targeted to these symptoms. Palliative sedation therapy is one potential solution to providing relief from these refractory symptoms. Sedation in terminally ill people is intended to provide relief from refractory symptoms that are not controlled by other methods. Sedative drugs such as benzodiazepines are titrated to achieve the desired level of sedation; the level of sedation can be easily maintained and the effect is reversible. OBJECTIVES: To assess the evidence for the benefit of palliative pharmacological sedation on quality of life, survival, and specific refractory symptoms in terminally ill adults during their last few days of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 11), MEDLINE (1946 to November 2014), and EMBASE (1974 to December 2014), using search terms representing the sedative drug names and classes, disease stage, and study designs. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs, non-RCTs, and observational studies (e.g. before-and-after, interrupted-time-series) with quantitative outcomes. We excluded studies with only qualitative outcomes or that had no comparison (i.e. no control group or no within-group comparison) (e.g. single arm case series). DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of citations, and full text of potentially eligible studies. Two review authors independently carried out data extraction using standard data extraction forms. A third review author acted as arbiter for both stages. We carried out no meta-analyses due to insufficient data for pooling on any outcome; therefore, we reported outcomes narratively. MAIN RESULTS: The searches resulted in 14 included studies, involving 4167 adults, of whom 1137 received palliative sedation. More than 95% of people had cancer. No studies were randomised or quasi-randomised. All were consecutive case series, with only three having prospective data collection. Risk of bias was high, due to lack of randomisation. No studies measured quality of life or participant well-being, which was the primary outcome of the review. Five studies measured symptom control, using four different methods, so pooling was not possible. The results demonstrated that despite sedation, delirium and dyspnoea were still troublesome symptoms in these people in the last few days of life. Control of other symptoms appeared to be similar in sedated and non-sedated people. Only one study measured unintended adverse effects of sedative drugs and found no major events; however, four of 70 participants appeared to have drug-induced delirium. The study noticed no respiratory suppression. Thirteen of the 14 studies measured survival time from admission or referral to death, and all demonstrated no statistically significant difference between sedated and non-sedated groups. AUTHORS' CONCLUSIONS: There was insufficient evidence about the efficacy of palliative sedation in terms of a person's quality of life or symptom control. There was evidence that palliative sedation did not hasten death, which has been a concern of physicians and families in prescribing this treatment. However, this evidence comes from low quality studies, so should be interpreted with caution. Further studies that specifically measure the efficacy and quality of life in sedated people, compared with non-sedated people, and quantify adverse effects are required.

Exercise versus no exercise for the occurrence, severity and duration of acute respiratory infections.

BACKGROUND: Acute respiratory infections (ARIs) last for less than 30 days and are the most common acute diseases affecting people worldwide. Exercise has been shown to improve health generally and may be effective in reducing the occurrence, severity and duration of acute respiratory infections. OBJECTIVES: To evaluate the effectiveness of exercise for altering the occurrence, severity or duration of acute respiratory infections. SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1948 to July week 1, 2014), EMBASE (2010 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014), SPORTDiscus (1985 to July 2014), PEDro (searched on 11 July 2014), OTseeker (searched on 11 July 2014), the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov (searched on 11 July 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of exercise for ARIs in the general population. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials using a standard form. We contacted trial authors to request missing data. One review author entered data and a second review author checked this. There were sufficient differences in the populations trialled and in the nature of the interventions to use the random-effects model (which makes fewer assumptions than the fixed-effect model) in the analysis. MAIN RESULTS: We included 11 trials involving 904 adults, published between 1990 and 2014. Eight studies were conducted in the USA, and one each in Canada, Spain and Turkey. Sample sizes ranged from 20 to 154 participants aged between 18 and 85 years old. The proportion of female participants varied between 52% and 100%. The duration of follow-up in the studies varied from seven days to 12 months. The exercise type most prescribed for the intervention was aerobic (walking in 70% of the studies, or bicycle riding or treadmill) at least five times a week. Duration was 30 to 45 minutes at moderate intensity. Participants were supervised in 90% of the studies.For four of the primary outcomes the results did not differ significantly and all were low-quality evidence (number of ARI episodes per person per year, rate ratio 0.91 (95% confidence interval (CI) 0.59 to 1.42); proportion of participants who experienced at least one ARI over the study period, risk ratio 0.76 (95% CI 0.57 to 1.01); severity of ARI symptoms, mean difference (MD) -110 (95% CI -324 to 104); and number of symptom days in the follow-up period, MD -2.1 days (95% CI -4.4 to 0.3)). However, one primary outcome, the number of symptom days per episode of illness, was reduced in those participants who exercised (MD -1.1 day, 95% CI -1.7 to -0.5, moderate-quality evidence).We found no significant differences for the secondary outcomes (laboratory parameters (blood lymphocytes, salivary secretory immunoglobulin and neutrophils); quality of life outcomes; cost-effectiveness and exercise-related injuries).There was good adherence to the intervention with no difference between the exercise and non-exercise groups.We rated the quality of evidence for the primary outcomes as low for most outcomes using the GRADE criteria: allocation concealment was not reported and there was a lack of blinding; in addition, there was imprecision (the CI is very wide because of a small number of participants) and inconsistency, which may be due to differences in study design. AUTHORS' CONCLUSIONS: We cannot determine whether exercise is effective at altering the occurrence, severity or duration of acute respiratory infections. One analysis of four trials suggests that the number of days of illness per episode of infection might be reduced by exercise. The small size of the studies, risk of bias and heterogeneous populations trialled all contribute to the uncertainty. Larger studies, with less risk of bias from patient selection, blinding of outcomes assessors, reporting of all outcomes measured and with registration of study protocols, are required to settle the question.

Interventions to facilitate shared decision making to address antibiotic use for acute respiratory infections in primary care.

BACKGROUND: Shared decision making is an important component of patient-centred care. It is a set of communication and evidence-based practice skills that elicits patients' expectations, clarifies any misperceptions and discusses the best available evidence for benefits and harms of treatment. Acute respiratory infections (ARIs) are one of the most common reasons for consulting in primary care and obtaining prescriptions for antibiotics. However, antibiotics offer few benefits for ARIs, and their excessive use contributes to antibiotic resistance - an evolving public health crisis. Greater explicit consideration of the benefit-harm trade-off within shared decision making may reduce antibiotic prescribing for ARIs in primary care. OBJECTIVES: To assess whether interventions that aim to facilitate shared decision making increase or reduce antibiotic prescribing for ARIs in primary care. SEARCH METHODS: We searched CENTRAL (2014, Issue 11), MEDLINE (1946 to November week 3, 2014), EMBASE (2010 to December 2014) and Web of Science (1985 to December 2014). We searched for other published, unpublished or ongoing trials by searching bibliographies of published articles, personal communication with key trial authors and content experts, and by searching trial registries at the National Institutes of Health and the World Health Organization. SELECTION CRITERIA: Randomised controlled trials (RCTs) (individual level or cluster-randomised), which evaluated the effectiveness of interventions that promote shared decision making (as the focus or a component of the intervention) about antibiotic prescribing for ARIs in primary care. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and collected data. Antibiotic prescribing was the primary outcome, and secondary outcomes included clinically important adverse endpoints (e.g. re-consultations, hospital admissions, mortality) and process measures (e.g. patient satisfaction). We assessed the risk of bias of all included trials and the quality of evidence. We contacted trial authors to obtain missing information where available. MAIN RESULTS: We identified 10 published reports of nine original RCTs (one report was a long-term follow-up of the original trial) in over 1100 primary care doctors and around 492,000 patients.The main risk of bias came from participants in most studies knowing whether they had received the intervention or not, and we downgraded the rating of the quality of evidence because of this.We meta-analysed data using a random-effects model on the primary and key secondary outcomes and formally assessed heterogeneity. Remaining outcomes are presented narratively.There is moderate quality evidence that interventions that aim to facilitate shared decision making reduce antibiotic use for ARIs in primary care (immediately after or within six weeks of the consultation), compared with usual care, from 47% to 29%: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55 to 0.68. Reduction in antibiotic prescribing occurred without an increase in patient-initiated re-consultations (RR 0.87, 95% CI 0.74 to 1.03, moderate quality evidence) or a decrease in patient satisfaction with the consultation (OR 0.86, 95% CI 0.57 to 1.30, low quality evidence). There were insufficient data to assess the effects of the intervention on sustained reduction in antibiotic prescribing, adverse clinical outcomes (such as hospital admission, incidence of pneumonia and mortality), or measures of patient and caregiver involvement in shared decision making (such as satisfaction with the consultation; regret or conflict with the decision made; or treatment compliance following the decision). No studies assessed antibiotic resistance in colonising or infective organisms. AUTHORS' CONCLUSIONS: Interventions that aim to facilitate shared decision making reduce antibiotic prescribing in primary care in the short term. Effects on longer-term rates of prescribing are uncertain and more evidence is needed to determine how any sustained reduction in antibiotic prescribing affects hospital admission, pneumonia and death.

PRISMA for Abstracts: reporting systematic reviews in journal and conference abstracts.

Elaine Beller and colleagues from the PRISMA for Abstracts group provide a reporting guidelines for reporting abstracts of systematic reviews in journals and at conferences.

Interventions for erythropoietin-resistant anaemia in dialysis patients.

BACKGROUND: People living with end-stage kidney disease (ESKD) often develop anaemia. Erythropoiesis-simulating agents (ESAs) are often given to people living with ESKD to maintain haemoglobin at a level to minimise need for transfusion. However, about 5% to 10% of patients with ESKD exhibit resistance to ESAs, and observational studies have shown that patients requiring high doses of ESA are at increased risk of mortality. OBJECTIVES: This review aimed to study the effects of interventions for the treatment of ESA-resistant anaemia in people with ESKD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for randomised controlled trials (RCT) that involved participants with ESKD on dialysis or who were pre-dialysis patients with chronic kidney disease (stage 5). Date of last search: April 2013. SELECTION CRITERIA: ESA resistance was defined as failure to achieve or maintain haemoglobin/haematocrit levels within the desired target range despite appropriate ESA doses (erythropoietin ≥ 450 U/kg/wk intravenously or ≥ 300 U/kg/wk subcutaneously; darbepoetin ≥ 1.5 µg/kg/wk) in people who were not nutritionally deficient, or who had haematological or bleeding disorders. Extended inclusion criteria for ESA hyporesponsive state were: erythropoietin dose ≥ 300 U/kg/wk and ≥ 150 U/kg/wk for intravenous administration; or ≥ 200 U/kg/wk and ≥ 100 U/kg/wk for subcutaneous administration; or darbepoetin dose ≥ 1.0 µg/kg/wk). DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: Titles and abstracts of 521 records were screened, of which we reviewed 99 from the full text. Only two studies matched our inclusion criteria. One study compared intravenous vitamin C versus no study medication for six months in 42 ESKD patients on haemodialysis who required intravenous erythropoietin (dose ≥ 450 U/kg/wk). The other included study compared high-flux dialyser versus low-flux dialyser for six months in 48 haemodialysis patients who required subcutaneous erythropoietin (dose ≥ 200 U/kg/wk). Because interventions differed, data could not be combined for quantitative meta-analysis. AUTHORS' CONCLUSIONS: There was inadequate evidence identified to inform recommendation of any intervention to ameliorate ESA hyporesponsiveness. Adequately powered RCTs are required to establish the safety and efficacy of interventions to improve responsiveness to ESA therapy.

Consensus Statement for Protocols of Factorial Randomized Trials: Extension of the SPIRIT 2013 Statement.

Importance: Trial protocols outline a trial's objectives as well as the methods (design, conduct, and analysis) that will be used to meet those objectives, and transparent reporting of trial protocols ensures objectives are clear and facilitates appraisal regarding the suitability of study methods. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, no extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement, which provides guidance on reporting of trial protocols, for factorial trials is available. Objective: To develop a consensus-based extension to the SPIRIT 2013 Statement for factorial trials. Evidence Review: The SPIRIT extension for factorial trials was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework. First, a list of reporting recommendations was generated using a scoping review of methodological articles identified using a MEDLINE search (inception to May 2019), which was supplemented with relevant articles from the personal collections of the authors. Second, a 3-round Delphi survey (January to June 2022, completed by 104 panelists from 14 countries) was conducted to assess the importance of items and identify additional recommendations. Third, a hybrid consensus meeting was held, attended by 15 panelists to finalize selection and wording of the checklist. Findings: This SPIRIT extension for factorial trials modified 9 of the 33 items in the SPIRIT 2013 checklist. Key reporting recommendations were that the rationale for using a factorial design should be provided, including whether an interaction is hypothesized; the treatment groups that will form the main comparisons should be identified; and statistical methods for each main comparison should be provided, including how interactions will be assessed. Conclusions and Relevance: In this consensus statement, 9 factorial-specific items were provided that should be addressed in all protocols of factorial trials to increase the trial's utility and transparency.

The femoral intercondylar notch is an accurate landmark for the resection depth of the distal femur in total knee arthroplasty.

INTRODUCTION: Conventionally, the depth of distal femoral resection in total knee arthroplasty is referenced from the most prominent distal femoral condyle. This surgical technique does not consider pathological alterations of articular surfaces or severity of knee deformity. It has been hypothesized that the femoral intercondylar notch is a clinically reliable and more accurate alternative landmark for the resection depth of the distal femur in primary total knee arthroplasty. METHODS: The resection depths of the distal femur at the medial and lateral femoral condyles and intercondylar notch were measured using computer navigation in 406 total knee arthroplasties. Variability between the bone resection depths was analyzed by standard deviation, 95% confidence interval and variance. Clinical follow-up of outcome to a minimum of 12 months was performed to further inform and validate the analysis. RESULTS: Mean resection depth of the medial condyle was 10.7 mm, of the lateral condyle 7.9 mm and of the femoral intercondylar notch 1.9 mm. The femoral intercondylar notch had the lowest variance in resection depth among the three landmarks assessed, with a variance of 1.7 mm2 compared to 2.8 mm2 for the medial femoral condyle and 5.1 mm2 for the lateral femoral condyle. The intercondylar notch reference had the lowest standard deviation and 95% confidence interval. The resection depth referencing the notch was not sensitive to the degree of flexion contracture pre-operatively, whereas the medial and lateral condyles were. For varus deformed knees, distal femoral resection depth at the notch averaged 2 mm, which corresponds to the femoral prosthesis thickness at the intercondylar region, while for valgus deformed knees, the resection was flush with the intercondylar notch. CONCLUSIONS: The femoral intercondylar notch is a clinically practical and reproducible landmark for appropriate and accurate resection depth of the distal femur in primary total knee arthroplasty. LEVEL OF EVIDENCE: Level III: Retrospective cohort study.

Oral prednisolone for acute otitis media in children: a pilot, pragmatic, randomised, open-label, controlled study (OPAL study).

BACKGROUND: Acute otitis media (AOM) is associated with high antibiotic prescribing rates. Antibiotics are somewhat effective in improving pain and middle ear effusion (MEE); however, they have unfavourable effects. Alternative treatments, such as corticosteroids as anti-inflammatory agents, are needed. Evidence for the efficacy of these remains inconclusive. We conducted a pilot study to test feasibility of a proposed large-scale randomised controlled trial (RCT) to assess the efficacy of corticosteroids for AOM. METHODS: We conducted a pilot, pragmatic, parallel, open-label RCT of oral corticosteroids for paediatric AOM in primary and secondary/tertiary care centres in Indonesia. Children aged 6 months-12 years with AOM were randomised to either prednisolone or control (1:1). Physicians were blinded to allocation. Our objectives were to test the feasibility of our full RCT procedures and design, and assess the mechanistic effect of corticosteroids, using tympanometry, in suppressing middle ear inflammation by reducing MEE. RESULTS: We screened 512 children; 62 (38%) of 161 eligible children were randomised and 60 were analysed for the primary clinical outcome. All study procedures were completed successfully by healthcare personnel and parents/caregivers, despite time constraints and high workload. All eligible, consenting children were appropriately randomised. One child did not take the medication and four received additional oral corticosteroids. Our revised sample size calculation verified 444 children are needed for the full RCT. Oral corticosteroids did not have any discernible effects on MEE resolution and duration. There was no correlation between pain or other symptoms and MEE change. However, prednisolone may reduce pain intensity at day 3 (Visual Analogue Scale mean difference - 7.4 mm, 95% confidence interval (CI) - 13.4 to - 1.3, p = 0.018), but cause drowsiness (relative risk (RR) 1.8, 95% CI 1.1 to 2.8, p = 0.016). Tympanometry curves at day 7 may be improved (RR 1.8, 95% CI 1.0 to 2.9). We cannot yet confirm these as effects of corticosteroids due to insufficient sample size in this pilot study. CONCLUSIONS: It is feasible to conduct a large, pragmatic RCT of corticosteroids for paediatric AOM in Indonesia. Although oral corticosteroids may reduce pain and improve tympanometry curves, it requires an adequately powered clinical trial to confirm this. TRIAL REGISTRATION: Study registry number: ACTRN12618000049279. Name of registry: the Australian New Zealand Clinical Trials Registry (ANZCTR). Date of registration: 16 January 2018.

Determinants of changes in blood glucose response to short-term exercise training in patients with Type 2 diabetes.

The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory fitness in patients with Type 2 diabetes, and to identify and establish criteria for patients who are more likely to improve their blood glucose from short-term exercise training. A randomized, controlled trial of exercise training, comprising two supervised and one non-supervised sessions of individualized cardiorespiratory and resistance exercise per week, was performed in 132 healthy patients with Type 2 diabetes (exercise training group, n=68), with the aim of accumulating a minimum of 150 min of moderate-intensity exercise for 4 weeks. BMI, waist circumference, blood pressure, blood lipid profile, blood glucose, insulin, insulin sensitivity [calculated by HOMA(IR) (homoeostasis model assessment of insulin resistance) and QUICKI (quantitative insulin check index)], beta-cell function (calculated by HOMA(beta-Cell)), HbA(1c) (glycated haemoglobin) and VO(2max) (maximal oxygen consumption) were measured at baseline and at 4 weeks. The exercise training group had significant improvements in VO(2max), BMI and triacylglycerols (triglycerides). There were no significant changes in blood glucose, HOMA(IR), QUICKI or HOMA(beta-Cell). Decreases in blood glucose were significantly predicted by baseline blood glucose and HbA(1c), with these variables accounting for 15.9% of the change in blood glucose (P<0.001). ROC (receiver operator characteristic) curve analysis revealed that patients with a blood glucose >8.85 mmol/l (sensitivity=73%, specificity=78%) and HbA(1c) >7.15% (sensitivity=79%, specificity=60%) were more likely to achieve a clinically significant decrease in blood glucose. In conclusion, in apparently healthy patients with Type 2 diabetes, a 4-week exercise intervention improved cardiorespiratory fitness, BMI and triacylglycerols. Elevated blood glucose and HbA(1c) predicted improvements in blood glucose.

Parental experiences and preferences which influence subsequent use of post-discharge health services for children born very preterm.

AIM: Parents are ultimately responsible for organising and accessing health services for their children. How parents experience those services are likely to influence subsequent use. Understanding parental preference for service provision can inform compliance strategies with recommended child health recommendations. The aim of this study was to explore parental experiences and preferences which influence subsequent use of post-discharge health services for children born preterm with a birthweight < or =1250 g. METHODS: Focus groups consisted of randomly selected families recruited from a population-based cross-sectional cohort study of 2-, 4- and 7-year-old children corrected age for prematurity. Parents were asked to consider which aspects of childhood health service delivery influenced subsequent use. Transcripts were analysed and themes constructed. SWOT analysis evaluated health service practices by systematically mapping parents' accounts of the perceived strengths (S), weaknesses (W), opportunities (O) and threats (T) of services in relation to subsequent use. RESULTS: Fifteen parents participated in three groups (by children's age). Three dominant themes emerged and included (i) assistance with accessing appropriate services; (ii) provision of consistent information and comprehensive child health records; and (iii) support of parental self-efficacy in the health care of their child. CONCLUSION: Primary health carers are ideally suited to co-ordinate and provide continuity to improve parental involvement and compliance with health promoting recommendations for their preterm children. This approach may improve interagency co-operation and access to services enabling early identification and intervention. Adopting these strategies may be effective in optimising child health follow-up strategies and improve uptake of recommended intervention and prevention programmes.

Measuring sensorineural disability in preterm children using a public health screening strategy: a randomised controlled trial.

AIM: To assess the efficacy of a preterm-targeted screening programme against the routine Australian National Health Medical Research Council (NHMRC) universal child health screening programme to detect disability in a general practice setting in children born < or =31 weeks gestation at 12-months of age. METHODS: Multi-centred trial involving 202 preterm children randomised to receive the preterm-targeted or NHMRC programme. Primary outcome, correct identification of neurosensory disability by general practitioners assessed against gold standard paediatric assessments. Sensitivity analysis estimated interrater agreement and screening accuracy. Secondary outcomes, post natal depression (PND), parental stress, health service use, screening programme helpfulness and correct identification of levels of disability severity. RESULTS: Of the 195 infants with data on the primary outcome in the preterm-targeted group, their general practitioners correctly identified the disability status of 61/93 (65.6%) children, as compared with 69/102 (67.6%) in the NHMRC group (odds ratios (OR) 0.91 95% confidence interval (CI) 0.50, 1.65). Responses where general practitioners were unsure of a child's disability status were coded as incorrect and not paired for sensitivity analysis. Sensitivity analysis for 180 diagnostic pairs showed fair interrater agreement for both groups (preterm-targeted k = 0.30 vs. NHMRC k = 0.29) with screening test results favouring the preterm-targeted group with greater sensitivity (73% vs. 33%) but lower specificity (70% vs. 92%) resulting in more over referrals (30% vs. 8%); however, these had a significantly lower mean Developmental Quotient (DQ) score compared with non-disabled children. PND scores were higher in preterm-targeted group (OR 1.33 95% CI 0.01, 2.66). CONCLUSION: The preterm-targeted programme used by general practitioners: (i) did not improve overall identification of disability status compared to the NHMRC universal programme (Australian New Zealand Clinical Trails Registry number, ACTRN 12606000472572); however (ii) it did demonstrate greater efficacy as a screening tool in accurately identifying disabled children.