Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required.  OBJECTIVES: Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract). Effectiveness of convalescent plasma We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone.  Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences.  We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence).  Safety of convalescent plasma We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group.  We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence).  A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline).  Effectiveness of convalescent plasma We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence).  We identified no study reporting quality of life.  Safety of convalescent plasma We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence). This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. AUTHORS' CONCLUSIONS: We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.

Telerehabilitation for chronic respiratory disease.

BACKGROUND: Pulmonary rehabilitation is a proven, effective intervention for people with chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and bronchiectasis. However, relatively few people attend or complete a program, due to factors including a lack of programs, issues associated with travel and transport, and other health issues. Traditionally, pulmonary rehabilitation is delivered in-person on an outpatient basis at a hospital or other healthcare facility (referred to as centre-based pulmonary rehabilitation). Newer, alternative modes of pulmonary rehabilitation delivery include home-based models and the use of telehealth. Telerehabilitation is the delivery of rehabilitation services at a distance, using information and communication technology. To date, there has not been a comprehensive assessment of the clinical efficacy or safety of telerehabilitation, or its ability to improve uptake and access to rehabilitation services, for people with chronic respiratory disease. OBJECTIVES: To determine the effectiveness and safety of telerehabilitation for people with chronic respiratory disease. SEARCH METHODS: We searched the Cochrane Airways Trials Register, and the Cochrane Central Register of Controlled Trials; six databases including MEDLINE and Embase; and three trials registries, up to 30 November 2020. We checked reference lists of all included studies for additional references, and handsearched relevant respiratory journals and meeting abstracts. SELECTION CRITERIA: All randomised controlled trials and controlled clinical trials of telerehabilitation for the delivery of pulmonary rehabilitation were eligible for inclusion. The telerehabilitation intervention was required to include exercise training, with at least 50% of the rehabilitation intervention being delivered by telerehabilitation. DATA COLLECTION AND ANALYSIS: We used standard methods recommended by Cochrane. We assessed the risk of bias for all studies, and used the ROBINS-I tool to assess bias in non-randomised controlled clinical trials. We assessed the certainty of evidence with GRADE. Comparisons were telerehabilitation compared to traditional in-person (centre-based) pulmonary rehabilitation, and telerehabilitation compared to no rehabilitation. We analysed studies of telerehabilitation for maintenance rehabilitation separately from trials of telerehabilitation for initial primary pulmonary rehabilitation. MAIN RESULTS: We included a total of 15 studies (32 reports) with 1904 participants, using five different models of telerehabilitation. Almost all (99%) participants had chronic obstructive pulmonary disease (COPD). Three studies were controlled clinical trials. For primary pulmonary rehabilitation, there was probably little or no difference between telerehabilitation and in-person pulmonary rehabilitation for exercise capacity measured as 6-Minute Walking Distance (6MWD) (mean difference (MD) 0.06 metres (m), 95% confidence interval (CI) -10.82 m to 10.94 m; 556 participants; four studies; moderate-certainty evidence). There may also be little or no difference for quality of life measured with the St George's Respiratory Questionnaire (SGRQ) total score (MD -1.26, 95% CI -3.97 to 1.45; 274 participants; two studies; low-certainty evidence), or for breathlessness on the Chronic Respiratory Questionnaire (CRQ) dyspnoea domain score (MD 0.13, 95% CI -0.13 to 0.40; 426 participants; three studies; low-certainty evidence). Participants were more likely to complete a program of telerehabilitation, with a 93% completion rate (95% CI 90% to 96%), compared to a 70% completion rate for in-person rehabilitation. When compared to no rehabilitation control, trials of primary telerehabilitation may increase exercise capacity on 6MWD (MD 22.17 m, 95% CI -38.89 m to 83.23 m; 94 participants; two studies; low-certainty evidence) and may also increase 6MWD when delivered as maintenance rehabilitation (MD 78.1 m, 95% CI 49.6 m to 106.6 m; 209 participants; two studies; low-certainty evidence). No adverse effects of telerehabilitation were noted over and above any reported for in-person rehabilitation or no rehabilitation. AUTHORS' CONCLUSIONS: This review suggests that primary pulmonary rehabilitation, or maintenance rehabilitation, delivered via telerehabilitation for people with chronic respiratory disease achieves outcomes similar to those of traditional centre-based pulmonary rehabilitation, with no safety issues identified. However, the certainty of the evidence provided by this review is limited by the small number of studies, of varying telerehabilitation models, with relatively few participants. Future research should consider the clinical effect of telerehabilitation for individuals with chronic respiratory diseases other than COPD, the duration of benefit of telerehabilitation beyond the period of the intervention, and the economic cost of telerehabilitation.

No inexplicable disagreements between real-world data-based nonrandomized controlled studies and randomized controlled trials were found.

OBJECTIVES: We assessed disagreements between nonrandomized controlled studies based on real-world data (NRCS-RWDs) and randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: We systematically searched for studies that compared treatment effect estimates from NRCS-RWDs and RCTs on the same clinical question. We assessed the potential difference between NRCS-RWDs and RCTs related to internal and external validity. We calculated various meta-epidemiological measures to assess agreement. In case of disagreements, we tried to identify the probable causes of disagreements. RESULTS: We included 12 studies comparing 15 treatment effect estimates of NRCS-RWDs and RCTs. There were many potential causes of disagreement. Ninety-five percent confidence intervals overlapped for 12 of 15 treatment effect estimates. Our analysis on predicted vs. observed overlap showed that there were no more disagreements than expected by chance. We observed only two substantial differences between the 15 treatment effect estimates. In both cases, we identified risk of bias in the NRCS-RWDs as the most probable cause of disagreement. CONCLUSION: Our findings suggest that there are clinical questions where the difference in risk of bias between a well-conducted NRCS-RWD and an RCT is negligible. In our analysis, threats to external validity appeared to have no or only a weak impact on the disagreements of treatment effect estimates.

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020. SELECTION CRITERIA: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs). MAIN RESULTS: This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms.  Effectiveness of convalescent plasma for people with COVID-19  We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence).  We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence).  No studies reported on quality of life.  Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE.  The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence).  17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy.  While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here.

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020. SELECTION CRITERIA: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs.  MAIN RESULTS: This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19  We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome.  Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event.  Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence).  Serious adverse events (14 studies, 5201 participants)  Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events. AUTHORS' CONCLUSIONS: We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19.  While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.

Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.

BACKGROUND: The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. AIM: To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. METHODS: The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. RESULTS: After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2  = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. CONCLUSION: Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.

Tracking health commodity inventory and notifying stock levels via mobile devices: a mixed methods systematic review.

BACKGROUND: Health systems need timely and reliable access to essential medicines and health commodities, but problems with access are common in many settings. Mobile technologies offer potential low-cost solutions to the challenge of drug distribution and commodity availability in primary healthcare settings. However, the evidence on the use of mobile devices to address commodity shortages is sparse, and offers no clear way forward. OBJECTIVES: Primary objective To assess the effects of strategies for notifying stock levels and digital tracking of healthcare-related commodities and inventory via mobile devices across the primary healthcare system Secondary objectives To describe what mobile device strategies are currently being used to improve reporting and digital tracking of health commodities To identify factors influencing the implementation of mobile device interventions targeted at reducing stockouts of health commodities SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Global Index Medicus WHO, POPLINE K4Health, and two trials registries in August 2019. We also searched Epistemonikos for related systematic reviews and potentially eligible primary studies. We conducted a grey literature search using mHealthevidence.org, and issued a call for papers through popular digital health communities of practice. Finally, we conducted citation searches of included studies. We searched for studies published after 2000, in any language. SELECTION CRITERIA: For the primary objective, we included individual and cluster-randomised trials, controlled before-after studies, and interrupted time series studies. For the secondary objectives, we included any study design, which could be quantitative, qualitative, or descriptive, that aimed to describe current strategies for commodity tracking or stock notification via mobile devices; or aimed to explore factors that influenced the implementation of these strategies, including studies of acceptability or feasibility. We included studies of all cadres of healthcare providers, including lay health workers, and others involved in the distribution of health commodities (administrative staff, managerial and supervisory staff, dispensary staff); and all other individuals involved in stock notification, who may be based in a facility or a community setting, and involved with the delivery of primary healthcare services. We included interventions aimed at improving the availability of health commodities using mobile devices in primary healthcare settings. For the primary objective, we included studies that compared health commodity tracking or stock notification via mobile devices with standard practice. For the secondary objectives, we included studies of health commodity tracking and stock notification via mobile device, if we could extract data relevant to our secondary objectives. DATA COLLECTION AND ANALYSIS: For the primary objective, two authors independently screened all records, extracted data from the included studies, and assessed the risk of bias. For the analyses of the primary objectives, we reported means and proportions where appropriate. We used the GRADE approach to assess the certainty of the evidence, and prepared a 'Summary of findings' table. For the secondary objective, two authors independently screened all records, extracted data from the included studies, and applied a thematic synthesis approach to synthesise the data. We assessed methodological limitation using the Ways of Evaluating Important and Relevant Data (WEIRD) tool. We used the GRADE-CERQual approach to assess our confidence in the evidence, and prepared a 'Summary of qualitative findings' table. MAIN RESULTS: Primary objective For the primary objective, we included one controlled before-after study conducted in Malawi. We are uncertain of the effect of cStock plus enhanced management, or cStock plus effective product transport on the availability of commodities, quality and timeliness of stock management, and satisfaction and acceptability, because we assessed the evidence as very low-certainty. The study did not report on resource use or unintended consequences. Secondary objective For the secondary objectives, we included 16 studies, using a range of study designs, which described a total of eleven interventions. All studies were conducted in African (Tanzania, Kenya, Malawi, Ghana, Ethiopia, Cameroon, Zambia, Liberia, Uganda, South Africa, and Rwanda) and Asian (Pakistan and India) countries. Most of the interventions aimed to make data about stock levels and potential stockouts visible to managers, who could then take corrective action to address them. We identified several factors that may influence the implementation of stock notification and tracking via mobile device. These include challenges tied to infrastructural issues, such as poor access to electricity or internet, and broader health systems issues, such as drug shortages at the national level which cannot be mitigated by interventions at the primary healthcare level (low confidence). Several factors were identified as important, including strong partnerships with local authorities, telecommunication companies, technical system providers, and non-governmental organizations (very low confidence); availability of stock-level data at all levels of the health system (low confidence); the role of supportive supervision and responsive management (moderate confidence); familiarity and training of health workers in the use of the digital devices (moderate confidence); availability of technical programming expertise for the initial development and ongoing maintenance of the digital systems (low confidence); incentives, such as phone credit for personal use, to support regular use of the system (low confidence); easy-to-use systems built with user participation (moderate confidence); use of basic or personal mobile phones to support easier adoption (low confidence); consideration for software features, such as two-way communication (low confidence); and data availability in an easy-to-use format, such as an interactive dashboard (moderate confidence). AUTHORS' CONCLUSIONS: We need more, well-designed, controlled studies comparing stock notification and commodity management via mobile devices with paper-based commodity management systems. Further studies are needed to understand the factors that may influence the implementation of such interventions, and how implementation considerations differ by variations in the intervention.

Diagnostic stewardship of C. difficile testing: a quasi-experimental antimicrobial stewardship study.

OBJECTIVE: We evaluated whether a diagnostic stewardship initiative consisting of ASP preauthorization paired with education could reduce false-positive hospital-onset (HO) Clostridioides difficile infection (CDI). DESIGN: Single center, quasi-experimental study. SETTING: Tertiary academic medical center in Chicago, Illinois. PATIENTS: Adult inpatients were included in the intervention if they were admitted between October 1, 2016, and April 30, 2018, and were eligible for C. difficile preauthorization review. Patients admitted to the stem cell transplant (SCT) unit were not included in the intervention and were therefore considered a contemporaneous noninterventional control group. INTERVENTION: The intervention consisted of requiring prescriber attestation that diarrhea has met CDI clinical criteria, ASP preauthorization, and verbal clinician feedback. Data were compared 33 months before and 19 months after implementation. Facility-wide HO-CDI incidence rates (IR) per 10,000 patient days (PD) and standardized infection ratios (SIR) were extracted from hospital infection prevention reports. RESULTS: During the entire 52 month period, the mean facility-wide HO-CDI-IR was 7.8 per 10,000 PD and the SIR was 0.9 overall. The mean ± SD HO-CDI-IR (8.5 ± 2.0 vs 6.5 ± 2.3; P < .001) and SIR (0.97 ± 0.23 vs 0.78 ± 0.26; P = .015) decreased from baseline during the intervention. Segmented regression models identified significant decreases in HO-CDI-IR (Pstep = .06; Ptrend = .008) and SIR (Pstep = .1; Ptrend = .017) trends concurrent with decreases in oral vancomycin (Pstep < .001; Ptrend < .001). HO-CDI-IR within a noninterventional control unit did not change (Pstep = .125; Ptrend = .115). CONCLUSIONS: A multidisciplinary, multifaceted intervention leveraging clinician education and feedback reduced the HO-CDI-IR and the SIR in select populations. Institutions may consider interventions like ours to reduce false-positive C. difficile NAAT tests.

Study filters for non-randomized studies of interventions consistently lacked sensitivity upon external validation.

BACKGROUND: Little evidence is available on searches for non-randomized studies (NRS) in bibliographic databases within the framework of systematic reviews. For instance, it is currently unclear whether, when searching for NRS, effective restriction of the search strategy to certain study types is possible. The following challenges need to be considered: 1) For non-randomized controlled trials (NRCTs): whether they can be identified by established filters for randomized controlled trials (RCTs). 2) For other NRS types (such as cohort studies): whether study filters exist for each study type and, if so, which performance measures they have. The aims of the present analysis were to identify and validate existing NRS filters in MEDLINE as well as to evaluate established RCT filters using a set of MEDLINE citations. METHODS: Our analysis is a retrospective analysis of study filters based on MEDLINE citations of NRS from Cochrane reviews. In a first step we identified existing NRS filters. For the generation of the reference set, we screened Cochrane reviews evaluating NRS, which covered a broad range of study types. The citations of the studies included in the Cochrane reviews were identified via the reviews' bibliographies and the corresponding PubMed identification numbers (PMIDs) were extracted from PubMed. Random samples comprising up to 200 citations (i.e. 200 PMIDs) each were created for each study type to generate the test sets. RESULTS: A total of 271 Cochrane reviews from 41 different Cochrane groups were eligible for data extraction. We identified 14 NRS filters published since 2001. The study filters generated between 660,000 and 9.5 million hits in MEDLINE. Most filters covered several study types. The reference set included 2890 publications classified as NRS for the generation of the test sets. Twelve test sets were generated (one for each study type), of which 8 included 200 citations each. None of the study filters achieved sufficient sensitivity (≥ 92%) for all of the study types targeted. CONCLUSIONS: The performance of current NRS filters is insufficient for effective use in daily practice. It is therefore necessary to develop new strategies (e.g. new NRS filters in combination with other search techniques). The challenges related to NRS should be taken into account.

Thulium laser VapoResection of the prostate versus traditional transurethral resection of the prostate or transurethral plasmakinetic resection of prostate for benign prostatic obstruction: a systematic review and meta-analysis.

PURPOSE: To compare the efficacy and safety of thulium laser VapoResection of the prostate (ThuVaRP) versus standard traditional transurethral resection of the prostate (TURP) or plasmakinetic resection of prostate (PKRP) for benign prostatic obstruction. METHODS: Systematic searches were performed in the Medline, EMBASE, the Cochrane Library, Web of Science, and CNKI in December 2017. The outcomes of demographic and clinical characteristics, perioperative variables, complications, and postoperative efficacy including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum flow rate (Qmax), and postvoid residual (PVR) were assessed. RESULTS: 16 studies were selected in the meta-analysis including nine randomized controlled trials (RCTs) and seven non-RCTs. Among of them, nine studies compared ThuVaRP with PKRP, while seven studies compared ThuVaRP with TURP. It seemed that ThuVaRP needed longer operation time than TURP (WMD = 6.41, 95% CI 1.38-11.44, p = 0.01) and PKRP (WMD = 10.15, 95% CI 5.20-15.10, p < 0.0001). ThuVaRP was associated with less serum hemoglobin decreased, catheterization time, and the length of hospital stay compared with TURP (WMD = - 0.58, 95% CI - 0.77 to 0.38, p < 0.00001; WMD = - 1.89, 95% CI - 2.67 to 1.11, p < 0.00001; WMD = - 2.25, 95% CI - 2.91 to 1.60, p < 0.00001) and PKRP (WMD = - 0.28, 95% CI - 0.46 to 0.10, p = 0.002; WMD = - 1.88, 95% CI - 2.87 to 0.89, p = 0.0002; WMD = - 2.08, 95% CI - 2.63 to 1.54, p<0.00001). According to our assessment, there was no significantly difference in postoperative efficacy. CONCLUSIONS: The pooled data indicated that ThuVaRP had a nearly efficacy to TURP and PKRP based on IPSS, QoL, Qmax, and PVR. Although ThuVaRP was associated with longer operation time, it got distinct superiority on serum hemoglobin decreased, catheterization time, and hospital stay.

Larger effect sizes in nonrandomized studies are associated with higher rates of EMA licensing approval.

OBJECTIVES: The aim of this study was to evaluate how often the European Medicines Agency (EMA) has authorized drugs based on nonrandomized studies and whether there is an association between treatment effects and EMA preference for further testing in randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: We reviewed all initial marketing authorizations in the EMA database on human medicines between 1995 and 2015 and included authorizations granted without randomized data. We extracted data on treatment effects and EMA preference for further testing in RCTs. RESULTS: Of 723 drugs, 51 were authorized based on nonrandomized data. These 51 drugs were licensed for 71 indications. In the 51 drug-indication pairs with no preference for further RCT testing, effect estimates were large [odds ratio (OR): 12.0 (95% confidence interval {CI}: 8.1-17.9)] compared to effect estimates in the 20 drug-indication pairs for which future RCTs were preferred [OR: 4.3 (95% CI 2.8-6.6)], with a significant difference between effects (P = 0.0005). CONCLUSION: Nonrandomized data were used for 7% of EMA drug approvals. Larger effect sizes were associated with greater likelihood of approval based on nonrandomized data alone. We did not find a clear treatment effect threshold for drug approval without RCT evidence.

A scoping review and survey provides the rationale, perceptions, and preferences for the integration of randomized and nonrandomized studies in evidence syntheses and GRADE assessments.

OBJECTIVES: To review the literature and obtain preferences and perceptions from experts regarding the role of randomized studies (RSs) and nonrandomized studies (NRSs) in systematic reviews of intervention effects. STUDY DESIGN AND SETTING: Scoping review and survey of experts. Using levels of certainty developed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, experts expressed their preferences about the use of RS and NRS in health syntheses. RESULTS: Of 189 respondents, 123 had the expertise required to answer the questionnaire; 116 provided their extent of agreement with approaches to use NRS with RS. Most respondents would include NRS when RS was unfeasible (83.6%) or unethical (71.5%) and a majority to maximize the body of evidence (66.3%), compare results in NRS and RS (53.5%) and to identify subgroups (51.7%). Sizable minorities would include NRS and RS to address the effect of randomization (29.5%) or because the question being addressed was a public-health intervention (36.5%). In summary of findings tables, most respondents would include both bodies of evidence-in two rows in the same table-when RS provided moderate, low, or very-low certainty evidence; even when RS provided high certainty evidence, a sizable minority (25%) would still present results from both bodies of evidence. Very few (3.6%) would, under realistic circumstances, pool RS and NRS results. CONCLUSIONS: Most experts would include both RS and NRS in the same review under a wide variety of circumstances, but almost all would present results of two bodies of evidence separately.

New designs for basket clinical trials in oncology.

The established molecular heterogeneity of human cancers has had profound effects on the design of cancer therapeutics. Most cancer drugs are today targeted to molecular alterations present in cancer cells. Tumors of the same primary site, however, often differ with regard to the alterations that they harbor. Consequently, this heterogeneity has required the development of new paradigms for clinical development. In this paper, we review some clinical trial designs finding active use in co-development of therapeutics and predictive biomarkers to inform their use in oncology.

Task-oriented interventions for children with developmental co-ordination disorder.

BACKGROUND: Developmental co-ordination disorder (DCD) is a common childhood disorder, which can persist into adolescence and adulthood. Children with DCD have difficulties in performing the essential motor tasks required for self-care, academic, social and recreational activities. OBJECTIVES: To assess the effectiveness of task-oriented interventions on movement performance, psychosocial functions, activity, and participation for children with DCD and to examine differential intervention effects as a factor of age, sex, severity of DCD, intervention intensity, and type of intervention. SEARCH METHODS: In March 2017, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, 13 other databases, and five trials registers. We also searched reference lists, and contacted members of the mailing list of the International Conference on DCD to identify additional studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs that compared the task-oriented intervention with either an inactive control intervention or an active control intervention in children and adolescents aged four to 18 years with a diagnosis of DCD.Types of outcome measures included changes in motor function, as assessed by standardised performance outcome tests and questionnaires; adverse events; and measures of participation. DATA COLLECTION AND ANALYSIS: All review authors participated in study selection, data extraction, and assessments of risk of bias and quality, and two review authors independently performed all tasks. Specifically, two review authors independently screened titles and abstracts to eliminate irrelevant studies, extracted data from the included studies, assessed risk of bias, and rated the quality of the evidence using the GRADE approach. In cases of ambiguity or information missing from the paper, one review author contacted trial authors. MAIN RESULTS: This review included 15 studies (eight RCTs and seven quasi-RCTs). Study characteristicsThe trials included 649 participants of both sexes, ranging in age from five to 12 years.The participants were from Australia, Canada, China, Sweden, Taiwan, and the UK.Trials were conducted in hospital settings; at a university-based clinic, laboratory, or centre; in community centres; at home or school, or both at home and school.The durations of task-oriented interventions were mostly short term (less than six months), with the total number of sessions ranging from five to 50. The length of each session ranged from 30 to 90 minutes, and the frequencies ranged from once to seven times per week.We judged the risk of bias as moderate to high across the studies. Some elements were impossible to achieve (such as blinding of administering personnel or participants). KEY RESULTS: primary outcomesA meta-analysis of two RCTs and four quasi-RCTs found in favour of task-oriented interventions for improved motor performance compared to no intervention (mean difference (MD) -3.63, 95% confidence interval (CI) -5.88 to -1.39; P = 0.002; I2 = 43%; 6 trials, 169 children; very low-quality evidence).A meta-analysis of two RCTs found no effect of task-oriented interventions for improved motor performance compared to no intervention (MD -2.34, 95% CI -7.50 to 2.83; P = 0.38; I2 = 42%; 2 trials, 51 children; low-quality evidence).Two studies reported no adverse effects or events. Through personal correspondence, the authors of nine studies indicated that no injuries had occurred. KEY RESULTS: secondary outcomesDue to the limited number of studies with complete and consistent data, we were unable to perform any meta-analyses on our secondary measures or any subgroup analysis on age, sex, severity of DCD, and intervention intensity. AUTHORS' CONCLUSIONS: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. The conclusions drawn from previous reviews, which unanimously reported beneficial effects of intervention, are inconsistent with our conclusions. This review highlights the need for carefully designed and executed RCTs to investigate the effect of interventions for children with DCD.

Reports of uncontrolled clinical trials for directly placed restorations in vital teeth.

Uncontrolled trials are criticized as unreliable. This study aimed to establish how the number of published reports from uncontrolled clinical trials compares to that of controlled trials for directly placed restorations in vital teeth and whether their annual number is increasing, stable or decreasing. PubMed was searched and suitable citations of uncontrolled and controlled trial reports published between 1990-2016 were included. Reference check and hand searching were conducted. The median annual report number with 25 and 75% percentile was calculated for both types of trials. 695 reports were found. The median number of reports per year was 4 (3-7) and 22 (15-26) from uncontrolled and controlled trials, respectively. A statistically significant decreasing ratio of uncontrolled to controlled trial reports was observed (p = 0.01) by linear regression analysis. The number of reports of uncontrolled clinical trials listed in PubMed over the last 27 years appears at least five times smaller than that of controlled clinical trials and its number in relation to that of controlled trials seems to decrease over time.

Computer-generated reminders delivered on paper to healthcare professionals: effects on professional practice and healthcare outcomes.

BACKGROUND: Clinical practice does not always reflect best practice and evidence, partly because of unconscious acts of omission, information overload, or inaccessible information. Reminders may help clinicians overcome these problems by prompting them to recall information that they already know or would be expected to know and by providing information or guidance in a more accessible and relevant format, at a particularly appropriate time. This is an update of a previously published review. OBJECTIVES: To evaluate the effects of reminders automatically generated through a computerized system (computer-generated) and delivered on paper to healthcare professionals on quality of care (outcomes related to healthcare professionals' practice) and patient outcomes (outcomes related to patients' health condition). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers up to 21 September 2016 together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included individual- or cluster-randomized and non-randomized trials that evaluated the impact of computer-generated reminders delivered on paper to healthcare professionals, alone (single-component intervention) or in addition to one or more co-interventions (multi-component intervention), compared with usual care or the co-intervention(s) without the reminder component. DATA COLLECTION AND ANALYSIS: Review authors working in pairs independently screened studies for eligibility and abstracted data. For each study, we extracted the primary outcome when it was defined or calculated the median effect size across all reported outcomes. We then calculated the median improvement and interquartile range (IQR) across included studies using the primary outcome or median outcome as representative outcome. We assessed the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We identified 35 studies (30 randomized trials and five non-randomized trials) and analyzed 34 studies (40 comparisons). Twenty-nine studies took place in the USA and six studies took place in Canada, France, Israel, and Kenya. All studies except two took place in outpatient care. Reminders were aimed at enhancing compliance with preventive guidelines (e.g. cancer screening tests, vaccination) in half the studies and at enhancing compliance with disease management guidelines for acute or chronic conditions (e.g. annual follow-ups, laboratory tests, medication adjustment, counseling) in the other half.Computer-generated reminders delivered on paper to healthcare professionals, alone or in addition to co-intervention(s), probably improves quality of care slightly compared with usual care or the co-intervention(s) without the reminder component (median improvement 6.8% (IQR: 3.8% to 17.5%); 34 studies (40 comparisons); moderate-certainty evidence).Computer-generated reminders delivered on paper to healthcare professionals alone (single-component intervention) probably improves quality of care compared with usual care (median improvement 11.0% (IQR 5.4% to 20.0%); 27 studies (27 comparisons); moderate-certainty evidence). Adding computer-generated reminders delivered on paper to healthcare professionals to one or more co-interventions (multi-component intervention) probably improves quality of care slightly compared with the co-intervention(s) without the reminder component (median improvement 4.0% (IQR 3.0% to 6.0%); 11 studies (13 comparisons); moderate-certainty evidence).We are uncertain whether reminders, alone or in addition to co-intervention(s), improve patient outcomes as the certainty of the evidence is very low (n = 6 studies (seven comparisons)). None of the included studies reported outcomes related to harms or adverse effects of the intervention. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that computer-generated reminders delivered on paper to healthcare professionals probably slightly improves quality of care, in terms of compliance with preventive guidelines and compliance with disease management guidelines. It is uncertain whether reminders improve patient outcomes because the certainty of the evidence is very low. The heterogeneity of the reminder interventions included in this review also suggests that reminders can probably improve quality of care in various settings under various conditions.

Injected corticosteroids for treating plantar heel pain in adults.

BACKGROUND: Plantar heel pain, commonly resulting from plantar fasciitis, often results in significant morbidity. Treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), orthoses, physical therapy, physical agents (e.g. extracorporeal shock wave therapy (ESWT), laser) and invasive procedures including steroid injections. OBJECTIVES: To assess the effects (benefits and harms) of injected corticosteroids for treating plantar heel pain in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (the Cochrane Library), MEDLINE, Embase, CINAHL, clinical trials registries and conference proceedings. Latest search: 27 March 2017. SELECTION CRITERIA: Randomised and quasi-randomised trials of corticosteroid injections in the treatment of plantar heel pain in adults were eligible for inclusion. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcome measures. We used a fixed-effect model unless heterogeneity was significant, when a random-effects model was considered. We assessed the overall quality of evidence for individual outcomes using the GRADE approach. MAIN RESULTS: We included a total of 39 studies (36 randomised controlled trials (RCTs) and 3 quasi-RCTs) that involved a total of 2492 adults. Most studies were small (median = 59 participants). Participants' mean ages ranged from 34 years to 59 years. When reported, most participants had heel pain for several months. The trials were usually conducted in outpatient specialty clinics of tertiary care hospitals in 17 countries. Steroid injection was given with a local anaesthetic agent in 34 trials. Follow-up was from one month to over two years. With one exception, trials were assessed at high risk of bias in one or more domains, mostly relating to lack of blinding, including lack of confirmation of allocation concealment. With two exceptions, we rated the available evidence as very low quality, implying in each case that we are 'very uncertain about the estimate'.The 39 trials covered 18 comparisons, with six of the seven trials with three or four groups providing evidence towards two comparisons.Eight trials (724 participants) compared steroid injection versus placebo or no treatment. Steroid injection may lead to lower heel pain visual analogue scores (VAS) (0 to 100; higher scores = worse pain) in the short-term (< 1 month) (MD -6.38, 95% CI -11.13 to -1.64; 350 participants; 5 studies; I² = 65%; low quality evidence). Based on a minimal clinically significant difference (MCID) of 8 for average heel pain, the 95% CI includes a marginal clinical benefit. This potential benefit was diminished when data were restricted to three placebo-controlled trials. Steroid injection made no difference to average heel pain in the medium-term (1 to 6 months follow-up) (MD -3.47, 95% CI -8.43 to 1.48; 382 participants; 6 studies; I² = 40%; low quality evidence). There was very low quality evidence for no effect on function in the medium-term and for an absence of serious adverse events (219 participants, 4 studies). No studies reported on other adverse events, such as post-injection pain, and on return to previous activity. There was very low quality evidence for fewer treatment failures (defined variously as persistent heel pain at 8 weeks, steroid injection at 12 weeks, and unrelieved pain at 6 months) after steroid injection.The available evidence for other comparisons was rated as very low quality. We are therefore very uncertain of the estimates for the relative effects on people with heel pain of steroids compared with other interventions in:1. Tibial nerve block with anaesthetic (2 trials); orthoses (4 trials); oral NSAIDs (2 trials); and intensive physiotherapy (1 trial).2. Physical modalities: ESWT (5 trials); laser (2 trials); and radiation therapy (1 trial).3. Other invasive procedures: locally injectable NSAID (1 trial); platelet-rich plasma injections (5 trials); autologous blood injections (2 trials); botulinum toxin injections (2 trials); cryopreserved human amniotic membrane injection (1 trial); localised peppering with a needle (1 trial); dry needling (1 trial); and mini scalpel needle release (1 trial).We are also uncertain about the estimates from trials testing different techniques of local steroid injection: ultrasonography-guided versus palpation-guided (5 trials); and scintigraphy-guided versus palpation-guided (1 trial).An exploratory analysis involving pooling data from 21 trials reporting on adverse events revealed two ruptures of plantar fascia (reported in 1 trial) and three injection site infections (reported in 2 trials) in 699 participants allocated to steroid injection study arms. Five trials reported a total of 27 participants with less serious short-term adverse events in the 699 participants allocated steroid injection study arms. Reported treatments were analgesia, ice or both. Given the high risk of selective reporting for these outcomes and imprecision, this evidence was rated at very low quality. AUTHORS' CONCLUSIONS: We found low quality evidence that local steroid injections compared with placebo or no treatment may slightly reduce heel pain up to one month but not subsequently. The available evidence for other outcomes of this comparison was very low quality. Where available, the evidence from comparisons of steroid injections with other interventions used to treat heel pain and of different methods of guiding the injection was also very low quality. Although serious adverse events relating to steroid injection were rare, these were under-reported and a higher risk cannot be ruled out.Further research should focus on establishing the effects (benefits and harms) of injected steroids compared with placebo in typical clinical settings, subsequent to a course of unsuccessful conservative therapy. Ideally, this should be preceded by research, including patient involvement, aimed to obtain consensus on the priority questions for treating plantar heel pain.

Quasi-experimental study designs series-paper 9: collecting data from quasi-experimental studies.

OBJECTIVE: To identify variables that must be coded when synthesizing primary studies that use quasi-experimental designs. STUDY DESIGN AND SETTING: All quasi-experimental (QE) designs. RESULTS: When designing a systematic review of QE studies, potential sources of heterogeneity-both theory-based and methodological-must be identified. We outline key components of inclusion criteria for syntheses of quasi-experimental studies. We provide recommendations for coding content-relevant and methodological variables and outlined the distinction between bivariate effect sizes and partial (i.e., adjusted) effect sizes. Designs used and controls used are viewed as of greatest importance. Potential sources of bias and confounding are also addressed. CONCLUSION: Careful consideration must be given to inclusion criteria and the coding of theoretical and methodological variables during the design phase of a synthesis of quasi-experimental studies. The success of the meta-regression analysis relies on the data available to the meta-analyst. Omission of critical moderator variables (i.e., effect modifiers) will undermine the conclusions of a meta-analysis.

Quasi-experimental study designs series-paper 7: assessing the assumptions.

Quasi-experimental designs are gaining popularity in epidemiology and health systems research-in particular for the evaluation of health care practice, programs, and policy-because they allow strong causal inferences without randomized controlled experiments. We describe the concepts underlying five important quasi-experimental designs: Instrumental Variables, Regression Discontinuity, Interrupted Time Series, Fixed Effects, and Difference-in-Differences designs. We illustrate each of the designs with an example from health research. We then describe the assumptions required for each of the designs to ensure valid causal inference and discuss the tests available to examine the assumptions.