Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Patients' Perspectives on How to Improve Endometriosis Care: A Large Qualitative Study Within the ComPaRe-Endometriosis e-Cohort.

Background: Endometriosis is a chronic gynecological condition that affects about 10% of women of reproductive age. Despite its prevalence, diagnosis is often delayed, misdiagnosis is common, and treatment options are poor. This study aimed at capturing ideas to improve endometriosis care from the patients' perspectives. Materials and Methods: We analyzed cross-sectional data from 1,000 adult patients in ComPaRe-Endometriosis (a French prospective e-cohort focused on endometriosis) who answered to the open-ended question: "If you had a magic wand, what would you change about your health care?". The free-text responses were analyzed by qualitative thematic analysis using an inductive approach. Results: Patients had a mean age of 34.1 years (standard deviation = 8.1); 56% and 42% had stage IV disease or deep endometriosis, respectively. They elicited 2,487 ideas to improve the management of endometriosis, which were categorized into 61 areas of improvement, further grouped into 14 themes. The top five areas of improvement were mentioned by >10% of the patients and were to (1) train caregivers to develop their knowledge on the disease, (2) provide better management of daily pain and pain attacks, (3) take patient-reported symptoms seriously, (4) standardize diagnostic processes to improve early detection, and (5) have caregivers listen more to the patients. Conclusions: We identified 61 areas for improvement in endometriosis care. These results reflect patients' expectations in terms of management of their disease and will be useful to design a better global care for endometriosis from the patients' perspectives.

Cultural competence in a primary healthcare center in Santiago de Chile: a mixed methods design.

BACKGROUND: The immigrant population in Chile is growing significantly, challenging the health care system's capacity to provide sensitive and effective care. AIM: To assess the cultural competence of Chilean primary health workers. MATERIAL AND METHODS: This mixed-methods study used a quantitative scale and semi-structured interviews to examine the cultural competence of a Chilean primary health care team in their care for the international migrant population. The study pointed to specific variables that were associated with increased cultural competence, including age, intercultural life experiences, and having received relevant training. RESULTS: The two approaches produced largely convergent results. The dimensions of cultural competence with the highest scores on the quantitative scale were also the theoretical dimensions with the greatest discursive density in the qualitative analysis. CONCLUSIONS: The analysis provides a starting point for policies aimed at the development of cultural competence in the national scenario, suggesting a general direction to foster transcultural competence in health, such as formal training and the promotion of informal spaces ofsensibilization.

Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Interleukin-1 blocking agents for treating COVID-19.

BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19. OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).

Completeness and Mismatch of Patient-Important Outcomes After Trauma.

To assess the completeness of the collection of patient-important outcomes and the mismatch between outcomes measured in research and patients' important issues after trauma. Summary Background Data: To date, severe trauma has mainly been assessed using in-hospital mortality. Yet, with 80 to 90% survivors discharged from hospital, it is critical to assess the collection of patient important long-term outcomes of trauma. Methods: Mixed methods study combining a systematic review of outcomes and their comparison with domains elicited by patients during a qualitative study. We searched Medline, EMBASE and clinicaltrials.gov from January 1, 2014 to September 30, 2019 and extracted all outcomes from reports including severe trauma. We compared these outcomes with 97 domains that matter to trauma survivors identified in a previous qualitative study. We defined as patient-important outcome as the 10 most frequently elicited domains in the qualitative study. We assessed the number of domains captured in each report to illustrate the completeness of the collection of patient-important outcomes. We also assessed the mismatch between outcomes collected and what matters to patients. Findings: Among the 116 reports included in the systematic review, we identified 403 outcomes collected with 154 unique measurements tools. Beside mortality, measurement tools most frequently used were the Glasgow Outcome Scale (31.0%, n=36), questions on patients' return to work (20,7%, n=24) and the EQ-5D (19.0%, n=22). The comparison between the outcomes identified in the systematic review and the domains from the qualitative study found that 10.3% (n=12) reports did not collect any patient-important domains and one collected all 10 patient-important domains. By examining each of the 10 patient-important domains, none was collected in more than 72% of reports and only five were among the ten most frequently measured domains in studies. Conclusion: The completeness of the collection of the long-term patient-important outcomes after trauma can be improved. There was a mismatch between the domains used in the literature and those considered important by patients during a qualitative study.

Secondary electronic sources demonstrated very good sensitivity for identifying studies evaluating interventions for COVID-19.

OBJECTIVES: To assess the sensitivity of two secondary electronic sources of COVID-19 studies: 1) the Cochrane COVID-19 Study Register (https://covid-19.cochrane.org/); and, 2) the Living Overview of the Evidence (L•OVE) COVID-19 platform (https://iloveevidence.com/). STUDY DESIGN AND SETTING: We identified reports of randomized controlled trials (RCTs) and observational studies (OS) assessing preventive interventions or treatment for COVID-19. The reference standard comprised all reports included in the COVID-NMA platform (covid-nma.com), in two major living systematic reviews of RCTs assessing pharmacologic treatment of COVID-19, or identified in either of the two secondary sources evaluated. The search for all sources was conducted through September 7, 2020. Our primary outcome was the proportion of the reports included in the reference standard that were identified by each secondary source. RESULTS: We identified 680 reports, 91 RCT reports, 97 RCT protocols, and 492 OS reports. The Cochrane COVID-19 Study Register identified 88% [95% confidence interval, 79-94] of the RCT reports, 90% [82-95] of the RCT protocols, and 82% [78-85] of the OS reports. The L•OVE platform identified 100% [97-100] of the RCT reports and RCT protocols and 100% [99-100] of the OS reports. CONCLUSION: These platforms proved to be a viable screening alternative to searching every individual source.

Development and Validation of the Long Coronavirus Disease (COVID) Symptom and Impact Tools: A Set of Patient-Reported Instruments Constructed From Patients' Lived Experience.

BACKGROUND: To develop and validate patient-reported instruments, based on patients' lived experiences, for monitoring the symptoms and impact of long coronavirus disease (covid). METHODS: The long covid Symptom and Impact Tools (ST and IT) were constructed from the answers to a survey with open-ended questions to 492 patients with long COVID. Validation of the tools involved adult patients with suspected or confirmed coronavirus disease 2019 (COVID-19) and symptoms extending over 3 weeks after onset. Construct validity was assessed by examining the relations of the ST and IT scores with health-related quality of life (EQ-5D-5L), function (PCFS, post-COVID functional scale), and perceived health (MYMOP2, Measure yourself medical outcome profile 2). Reliability was determined by a test-retest. The "patient acceptable symptomatic state" (PASS) was determined by the percentile method. RESULTS: Validation involved 1022 participants (55% with confirmed COVID-19, 79% female, and 12.5% hospitalized for COVID-19). The long COVID ST and IT scores were strongly correlated with the EQ-5D-5L (rs = -0.45 and rs = -0.59, respectively), the PCFS (rs = -0.39 and rs = -0.55), and the MYMOP2 (rs = -0.40 and rs = -0.59). Reproducibility was excellent with an interclass correlation coefficient of 0.83 (95% confidence interval .80 to .86) for the ST score and 0.84 (.80 to .87) for the IT score. In total, 793 (77.5%) patients reported an unacceptable symptomatic state, thereby setting the PASS for the long covid IT score at 30 (28 to 33). CONCLUSIONS: The long covid ST and IT tools, constructed from patients' lived experiences, provide the first validated and reliable instruments for monitoring the symptoms and impact of long covid.

Revalidación de títulos extranjeros en la Facultad de Medicina de la Universidad de Chile / Foreign diplomas revalidation in the school of medicine at university of Chile

Introducción: Chile se ha consolidado como uno de los mayores destinos migratorios de la región, por lo que ha aumentado también la migración de profesionales de la salud, quienes deben acreditar su formación ante la autoridad chilena pertinente. Los países sin convenios vigentes deben revalidar el título profesional en la Universidad de Chile. Objetivo: Describir las postulaciones de revalidación de títulos profesionales emitidos por universidades extranjeras a las ocho carreras pertenecientes a la Facultad de Medicina de la Universidad de Chile. Métodos: Estudio formulado desde el paradigma positivista. Se utilizaron métodos de análisis cuantitativos, de tipo descriptivo, transversal y basados en fuentes secundarias de información. La muestra ascendió a 1616 postulaciones de revalidación de títulos de profesionales de salud emitidos en el extranjero. Se realizó un análisis cuantitativo de estadística descriptiva mediante el programa STATA 16. Se consideraron como principales variables: el país emisor del título, el título a revalidar y el estado en el proceso de revalidación. Una vez consolidado este análisis, se trianguló con una revisión literaria efectuada entre junio de 2018 y abril de 2019, para establecer si la descripción podía interpretarse desde el fenómeno del drenaje de cerebros. Resultados: Las carreras con mayores tasas de solicitud de revalidación fueron Medicina y Enfermería. Un 32,55 por ciento de las solicitudes correspondieron a títulos emitidos por universidades venezolanas y un 17,51 por ciento del total, a universidades cubanas, por lo que estas se consolidan como las dos principales. Conclusiones: Las solicitudes de revalidación de títulos han ido creciendo a lo largo de los años. La migración de profesionales de la salud a Chile no responde al fenómeno de drenaje de cerebros, sino es consecuencia de los cambios políticos y sociales de la región, y la estabilidad política chilena desde los noventa(AU)

Introduction: Chile has established itself as one of the largest migratory destinations in the region, a reason why health professionals' migration has also increased; in this respect, they must accredit their training before any relevant Chilean authority. For the case of countries without current agreements, the diploma must be revalidated with the University of Chile. Objective: To describe the applications for revalidating diplomas issued by foreign universities corresponding to the eight majors belonging to the School of Medicine at University of Chile. Methods: This is a study designed following the positivist paradigm. Quantitative analysis methods were used, together with descriptive and cross-sectional methods based on secondary sources of information. The sample amounted to 1616 applications for revalidating health-related diplomas issued abroad. A quantitative analysis of descriptive statistics was performed using the STATA 16 software. The main variables considered were country issuing the diploma, diploma to be revalidated, and revalidation status. Once this analysis was completed, it was triangulated with a literary review carried out between June 2018 and April 2019, in order to establish if the description could be interpreted based on the brain drain phenomenon. Results: The majors with the highest application rates for revalidation were Medicine and Nursing. 32.55 percent of the applications corresponded to diplomas issued by Venezuelan universities; while 17.51percent of the total, to Cuban universities, a reason why these are consolidated as the two main ones. Conclusions: Applications for revalidating diplomas have been growing over the years. Health professionals' migration to Chile is not due to the brain drain phenomenon, but a consequence of the political and social changes in the region, as well as the Chilean political stability since the nineties(AU)

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Accuracy in detecting inadequate research reporting by early career peer reviewers using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process: a cross-sectional diagnostic study.

BACKGROUND: The peer review process has been questioned as it may fail to allow the publication of high-quality articles. This study aimed to evaluate the accuracy in identifying inadequate reporting in RCT reports by early career researchers (ECRs) using an online CONSORT-based peer-review tool (COBPeer) versus the usual peer-review process. METHODS: We performed a cross-sectional diagnostic study of 119 manuscripts, from BMC series medical journals, BMJ, BMJ Open, and Annals of Emergency Medicine reporting the results of two-arm parallel-group RCTs. One hundred and nineteen ECRs who had never reviewed an RCT manuscript were recruited from December 2017 to January 2018. Each ECR assessed one manuscript. To assess accuracy in identifying inadequate reporting, we used two tests: (1) ECRs assessing a manuscript using the COBPeer tool (after completing an online training module) and (2) the usual peer-review process. The reference standard was the assessment of the manuscript by two systematic reviewers. Inadequate reporting was defined as incomplete reporting or a switch in primary outcome and considered nine domains: the eight most important CONSORT domains and a switch in primary outcome(s). The primary outcome was the mean number of domains accurately classified (scale from 0 to 9). RESULTS: The mean (SD) number of domains (0 to 9) accurately classified per manuscript was 6.39 (1.49) for ECRs using COBPeer versus 5.03 (1.84) for the journal's usual peer-review process, with a mean difference [95% CI] of 1.36 [0.88-1.84] (p < 0.001). Concerning secondary outcomes, the sensitivity of ECRs using COBPeer versus the usual peer-review process in detecting incompletely reported CONSORT items was 86% [95% CI 82-89] versus 20% [16-24] and in identifying a switch in primary outcome 61% [44-77] versus 11% [3-26]. The specificity of ECRs using COBPeer versus the usual process to detect incompletely reported CONSORT domains was 61% [57-65] versus 77% [74-81] and to identify a switch in primary outcome 77% [67-86] versus 98% [92-100]. CONCLUSIONS: Trained ECRs using the COBPeer tool were more likely to detect inadequate reporting in RCTs than the usual peer review processes used by journals. Implementing a two-step peer-review process could help improve the quality of reporting. TRIAL REGISTRATION: Clinical.Trials.gov NCT03119376 (Registered April, 18, 2017).

A Methodologic Systematic Review of Mobile Health Behavior Change Randomized Trials.

CONTEXT: Mobile health helps providers offer accessible, affordable, tailored behavior change interventions. However, research assessing mobile health interventions may feature methodologic shortcomings and poor reporting. This review aims to summarize the characteristics, methods, and intervention reporting of RCTs evaluating mobile health behavior change interventions. EVIDENCE ACQUISITION: This was a methodologic systematic review of RCTs assessing mobile health behavior change interventions published in PubMed from January 1, 2014 to January 1, 2018, in journals with the upper half of Impact Factors (Clarivate Analytics). Three reviewers independently extracted sample characteristics. Primary outcomes were classified as patient-important or not using definitions from the literature. Any non-patient-important outcomes were then reclassified by a panel of 3 patients. Intervention reporting was assessed by the mobile health Evidence Reporting and Assessment checklist. Data were analyzed in December 2018. EVIDENCE SYNTHESIS: Most of the 231 included RCTs assessed text messaging (51%) or smartphone app (28%) interventions aiming to change nutrition and physical activity (36%) or treatment adherence (25%). Only 8% of RCTs had a patient-important primary outcome, follow-up of ≥6 months, and intent-to-treat analysis. Most primary outcomes were behavioral measures (60%). Follow-up was <3 months in 29% of RCTs. Regarding reporting, 12 of the 16 checklist items were reported in less than half of RCTs (e.g., usability/content testing, 32%; data security, 13%). CONCLUSIONS: Reports of RCTs assessing mobile health behavior change interventions lack information that would be useful for providers, including reporting of long-term intervention impact on patient-important primary outcomes and information needed for intervention replicability.

Factores sociales del estado de salud autorreportado de personas mayores, en Chile / Factors influencing self-reported health in Chilean older people

Background Self-reported health is subjective and depends on external factors such as socioeconomic status, presence of chronic diseases and working status, among others. Aim To determine which factors influence self-reported health among older people in Chile. Material and Methods A secondary analysis of the National Socioeconomic Characterization survey done in 2015. A dichotomous response model was used classifying health status as good or bad. A logit regression model was carried out. Results The model had a good calibration and correctly classified 72 and 68% of men and women, respectively. The main factors that influenced health status self-perception were: not having health problems; having undergone a mental health interview, to receive supplemental nutrition, education, to have a productive work; and to having a social network. Conclusions There are health, cultural, economic and environmental factors that influence self-perceived health status.

Patients' views of wearable devices and AI in healthcare: findings from the ComPaRe e-cohort.

Wearable biometric monitoring devices (BMDs) and artificial intelligence (AI) enable the remote measurement and analysis of patient data in real time. These technologies have generated a lot of "hype," but their real-world effectiveness will depend on patients' uptake. Our objective was to describe patients' perceptions of the use of BMDs and AI in healthcare. We recruited adult patients with chronic conditions in France from the "Community of Patients for Research" (ComPaRe). Participants (1) answered quantitative and open-ended questions about the potential benefits and dangers of using of these new technologies and (2) participated in a case-vignette experiment to assess their readiness for using BMDs and AI in healthcare. Vignettes covered the use of AI to screen for skin cancer, remote monitoring of chronic conditions to predict exacerbations, smart clothes to guide physical therapy, and AI chatbots to answer emergency calls. A total of 1183 patients (51% response rate) were enrolled between May and June 2018. Overall, 20% considered that the benefits of technology (e.g., improving the reactivity in care and reducing the burden of treatment) greatly outweighed the dangers. Only 3% of participants felt that negative aspects (inadequate replacement of human intelligence, risks of hacking and misuse of private patient data) greatly outweighed potential benefits. We found that 35% of patients would refuse to integrate at least one existing or soon-to-be available intervention using BMDs and AI-based tools in their care. Accounting for patients' perspectives will help make the most of technology without impairing the human aspects of care, generating a burden or intruding on patients' lives.

Patients' perspective on how to improve the care of people with chronic conditions in France: a citizen science study within the ComPaRe e-cohort.

BACKGROUND: This study aimed to involve patients with chronic conditions in generating ideas for improving their care. METHODS: We performed a citizen science study. Participants were adult patients with chronic conditions recruited in Community of Patients for Research 'ComPaRe,' a French e-cohort of patients with chronic conditions. Participants generated ideas to improve their care in answer to the open-ended question, 'If you had a magic wand, what would you change in your healthcare?' Three researchers and two patients independently extracted ideas from open-ended answers by using thematic analysis. Ideas were grouped into areas for improvement at the consultation, hospital/clinic and health system levels. Findings were validated and enriched by a second sample of participants recruited in ComPaRe. RESULTS: Between May 2017 and April 2018, a total of 1636 patients provided 3613 ideas to improve consultations (1701 ideas related to 58 areas for improvement), hospitals/clinics (928 ideas related to 41 areas for improvement) and the health system (984 ideas related to 48 areas for improvement). At the consultation level, most ideas were related to improving physician-patient discussions, informing patients about their own care, and adapting treatment to patient preferences and context. At the hospital/clinic level, most ideas aimed at improving the coordination and collaboration in care. At the health system level, most ideas were related to decreasing the administrative burden imposed on patients, improving access to care and reducing the costs of care. CONCLUSION: Patients have many ideas to improve their care, from the content of consultations to the organisation of hospitals. Our study provides the proof of concept for a method to leverage patients' practical knowledge of the care system to improve it.

Inadequate reporting of concomitant medications in rheumatology randomized controlled trials of pharmacologic interventions.

OBJECTIVES: To investigate how the use of pharmacologic concomitant medications (CMs) is planned and reported in rheumatology randomized controlled trials (RCTs). METHODS: We searched PubMed for RCTs on rheumatic diseases published in leading medical journals in the past 2 years. CMs potentially influencing primary outcome(s) were identified by a panel of experts and included in the analysis. Information on trial characteristics, how the use of CMs was planned and conducted throughout the trial were extracted. Data were summarized as number (%) for qualitative, and median (range) for continuous variables. RESULTS: The 109 RCTs were mainly international (65%), industry-funded (81%) studies, including 267 CMs potentially influencing primary outcome(s). Forty-one RCTs (38%) did not provide any data about the dosages of CMs allowed. Information on whether the intake of a permitted CM could have been modified during the study was missing in 24 (22%) or incompletely reported in 23 (21%) RCTs. As regards CMs use throughout the study, the baseline number of patients on CMs per arm and the mean baseline dosage was lacking in 20 (18%) and 57 (52%) trials, respectively. Ninety-five percent of RCTs did not provide any information on cumulative/mean exposure to CMs. Two of 109 trials described how many patients had modified CM dosage for reasons permitted by the protocol, and 3 reported the number of patients violating protocol because of an incorrect CM intake. CONCLUSIONS: The use of CMs potentially impacting on primary outcome is poorly reported in rheumatology RCTs.

Time-dependent biases in observational studies of comparative effectiveness research in rheumatology. A methodological review.

OBJECTIVE: To assess to what extent time-dependent biases (ie, immortal time bias (ITB) and time-lag bias (TLB)) occur in the latest rheumatology observational studies, describe their main mechanisms and increase the awareness on this topic. METHODS: We searched PubMed for observational studies on rheumatic diseases published in leading medical journals in the last 5 years. Only studies with a time-to-event analysis exploring the association of one or more interventional strategies with an outcome were included. Each study was labelled as free from bias, at risk of TLB, at risk of misclassified ITB if the period of immortal time was incorrectly attributed to an intervention group, or at risk of excluded ITB if the immortal time was discarded from the analysis. RESULTS: We included 78 papers. Most studies were performed in Europe or North America (46% each), were not industry funded (62%) and had a safety primary outcome (59%). In total, 13 (17%) studies were considered at risk of time-dependent biases. Among the studies at risk of ITB (n=8; 10%), in 5 (6%), waiting time to receive treatment was wrongly attributed to the treatment exposure group, which indicated misclassified ITB. Five (6%) studies were at risk of TLB: patients on conventional synthetic disease-modifying antirheumatic drugs (DMARD; first-line drugs) were compared with patients on biologic DMARDs (second or third-line drugs) without accounting for disease duration or prior medication use. CONCLUSIONS: One in six comparative effectiveness observational studies published in leading rheumatology journals is potentially flawed by time-dependent biases.

[Factors influencing self-reported health in Chilean older people]. / Factores sociales del estado de salud autorreportado de personas mayores, en Chile.

Background Self-reported health is subjective and depends on external factors such as socioeconomic status, presence of chronic diseases and working status, among others. Aim To determine which factors influence self-reported health among older people in Chile. Material and Methods A secondary analysis of the National Socioeconomic Characterization survey done in 2015. A dichotomous response model was used classifying health status as good or bad. A logit regression model was carried out. Results The model had a good calibration and correctly classified 72 and 68% of men and women, respectively. The main factors that influenced health status self-perception were: not having health problems; having undergone a mental health interview, to receive supplemental nutrition, education, to have a productive work; and to having a social network. Conclusions There are health, cultural, economic and environmental factors that influence self-perceived health status.

Association Between Publication Characteristics and Treatment Effect Estimates: A Meta-epidemiologic Study.

Background: Evidence about the effect on meta-analysis results of including unpublished trials or those published in languages other than English is unclear or discordant. Purpose: To compare treatment effects between published and unpublished randomized controlled trials (RCTs) and between trials published in English and other languages using a meta-epidemiologic approach. Data Sources: Cochrane reviews published between March 2011 and January 2017 and trial references cited in the reviews. Study Selection: RCTs included in meta-analyses of 3 or more trials with a binary efficacy outcome. Data Extraction: Trial characteristics were extracted by original review authors. A single reviewer assessed publication status and language, with quality assurance by another investigator. Data Synthesis: Among 5659 RCTs included in 698 meta-analyses, 5303 (93.7%) were published in journal articles and 356 (6.3%) were unpublished. Of journal articles, 92.6% (4910 of 5303) were published in English and 7.4% (393 of 5303) in another language. Treatment effects were larger in published than unpublished trials (combined ratio of odds ratios [ROR] for 174 meta-analyses, 0.90 [95% CI, 0.82 to 0.98]; I2 = 19.3%; τ2 = 0.0492). Treatment effects were also larger for trials published in a language other than English than in English (combined ROR for 147 meta-analyses, 0.86 [CI, 0.78 to 0.95]; I2 = 0%; τ2 = 0.0000). Limitation: Reliance on the primary reference cited by review authors as the record of interest. Conclusion: In meta-analyses, treatment effects were larger in published than unpublished trials and, for published trials, in those published in a language other than English than in English. Primary Funding Source: Cochrane France.