Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes.

BACKGROUND: Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. METHODS: We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. RESULTS: Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the 'blood and lymphatic system' domain, followed by "adverse event" (77%) and "need for further resources" (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting. CONCLUSION: This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020214247.

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19.

BACKGROUND: Oral nirmatrelvir/ritonavir (Paxlovid) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. It remains to be evaluated for which indications and patient populations the drug is suitable. OBJECTIVES: To assess the efficacy and safety of nirmatrelvir/ritonavir plus standard of care (SoC) compared to SoC with or without placebo, or any other intervention for treating COVID-19 or preventing SARS-CoV-2 infection. To explore equity aspects in subgroup analyses. To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Scopus, and World Health Organization COVID-19 Research Database, identifying completed and ongoing studies without language restrictions and incorporating studies up to 15 May 2023. This is a LSR. We conduct update searches every two months and make them publicly available on the open science framework (OSF) platform. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing nirmatrelvir/ritonavir plus SoC to SoC with or without placebo, or any other intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. We screened all studies for research integrity. Studies were ineligible if they had been retracted, or if they were not prospectively registered including appropriate ethics approval. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology and used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the following outcomes: 1. to treat outpatients with mild COVID-19; 2. to treat inpatients with moderate to severe COVID-19: mortality, clinical worsening or improvement, quality of life, (serious) adverse events, and viral clearance; 3. to prevent SARS-CoV-2 infection in postexposure prophylaxis (PEP); and 4. pre-exposure prophylaxis (PrEP) scenarios: SARS-CoV-2 infection, development of COVID-19 symptoms, mortality, admission to hospital, quality of life, and (serious) adverse events. We explored inequity by subgroup analysis for elderly people, socially-disadvantaged people with comorbidities, populations from low-income countries and low- to middle-income countries, and people from different ethnic and racial backgrounds. MAIN RESULTS: As of 15 May 2023, we included two RCTs with 2510 participants with mild and mild to moderate symptomatic COVID-19 in outpatient and inpatient settings comparing nirmatrelvir/ritonavir plus SoC to SoC with or without placebo. All trial participants were without previous confirmed SARS-CoV-2 infection and at high risk for progression to severe disease. Randomization coincided with the Delta wave for outpatients and Omicron wave for inpatients. Outpatient trial participants and 73% of inpatients were unvaccinated. Symptom onset in outpatients was no more than five days before randomisation and prior or concomitant therapies including medications highly dependent on CYP3A4 were not allowed. We excluded two studies due to concerns with research integrity. We identified 13 ongoing studies. Three studies are currently awaiting classification. Nirmatrelvir/ritonavir for treating people with asymptomatic or mild COVID-19 in outpatient settings Nirmatrelvir/ritonavir plus SoC compared to SoC plus placebo may reduce all-cause mortality at 28 days (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.68; 1 study, 2224 participants; low-certainty evidence) and admission to hospital or death within 28 days (RR 0.13, 95% CI 0.07 to 0.27; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus SoC may reduce serious adverse events during the study period compared to SoC plus placebo (RR 0.24, 95% CI 0.15 to 0.41; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus SoC probably has little or no effect on treatment-emergent adverse events (RR 0.95, 95% CI 0.82 to 1.10; 1 study, 2224 participants; moderate-certainty evidence), and probably increases treatment-related adverse events such as dysgeusia and diarrhoea during the study period compared to SoC plus placebo (RR 2.06, 95% CI 1.44 to 2.95; 1 study, 2224 participants; moderate-certainty evidence). Nirmatrelvir/ritonavir plus SoC probably decreases discontinuation of study drug due to adverse events compared to SoC plus placebo (RR 0.49, 95% CI 0.30 to 0.80; 1 study, 2224 participants; moderate-certainty evidence). No studies reported improvement of clinical status, quality of life, or viral clearance. Nirmatrelvir/ritonavir for treating people with moderate to severe COVID-19 in inpatient settings We are uncertain whether nirmatrelvir/ritonavir plus SoC compared to SoC reduces all-cause mortality at 28 days (RR 0.63, 95% CI 0.21 to 1.86; 1 study, 264 participants; very low-certainty evidence), or increases viral clearance at seven days (RR 1.06, 95% CI 0.71 to 1.58; 1 study, 264 participants; very low-certainty evidence) and 14 days (RR 1.05, 95% CI 0.92 to 1.20; 1 study, 264 participants; very low-certainty evidence). No studies reported improvement or worsening of clinical status and quality of life. We did not include data for safety outcomes due to insufficient and inconsistent information. Subgroup analyses for equity For outpatients, the outcome 'admission to hospital or death' was investigated for equity regarding age (less than 65 years versus 65 years or greater) and ethnicity. There were no subgroup differences for age or ethnicity. For inpatients, the outcome 'all-cause mortality' was investigated for equity regarding age (65 years or less versus greater than 65 years). There was no difference between subgroups of age. No further equity-related subgroups were reported, and no subgroups were reported for other outcomes. Nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection (PrEP and PEP) No studies available. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests nirmatrelvir/ritonavir reduces the risk of all-cause mortality and hospital admission or death in high-risk, unvaccinated COVID-19 outpatients infected with the Delta variant of SARS-CoV-2. There is low- to moderate-certainty evidence of the safety of nirmatrelvir/ritonavir. Very low-certainty evidence exists regarding the effects of nirmatrelvir/ritonavir on all-cause mortality and viral clearance in mildly to moderately affected, mostly unvaccinated COVID-19 inpatients infected with the Omicron variant of SARS-CoV-2. Insufficient and inconsistent information prevents the assessment of safety outcomes. No reliable differences in effect size and direction were found regarding equity aspects. There is no available evidence supporting the use of nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection. We are continually updating our search and making search results available on the OSF platform.

Locating Medical Information during an Infodemic: Information Seeking Behavior and Strategies of Health-Care Workers in Germany.

BACKGROUND: The COVID-19 pandemic has led to a flood of-often contradictory-evidence. HCWs had to develop strategies to locate information that supported their work. We investigated the information-seeking of different HCW groups in Germany. METHODS: In December 2020, we conducted online surveys on COVID-19 information sources, strategies, assigned trustworthiness, and barriers-and in February 2021, on COVID-19 vaccination information sources. Results were analyzed descriptively; group comparisons were performed using χ2-tests. RESULTS: For general COVID-19-related medical information (413 participants), non-physicians most often selected official websites (57%), TV (57%), and e-mail/newsletters (46%) as preferred information sources-physicians chose official websites (63%), e-mail/newsletters (56%), and professional journals (55%). Non-physician HCWs used Facebook/YouTube more frequently. The main barriers were insufficient time and access issues. Non-physicians chose abstracts (66%), videos (45%), and webinars (40%) as preferred information strategy; physicians: overviews with algorithms (66%), abstracts (62%), webinars (48%). Information seeking on COVID-19 vaccination (2700 participants) was quite similar, however, with newspapers being more often used by non-physicians (63%) vs. physician HCWs (70%). CONCLUSION: Non-physician HCWs more often consulted public information sources. Employers/institutions should ensure the supply of professional, targeted COVID-19 information for different HCW groups.

Public information needs and preferences on COVID-19: a cross-sectional study.

BACKGROUND: Right from the beginning of the SARS-CoV-2 pandemic the general public faced the challenge to find reliable and understandable information in the overwhelming flood of information. To enhance informed decision-making, evidence-based information should be provided. Aim was to explore the general public's information needs and preferences on COVID-19 as well as the barriers to accessing evidence-based information. METHODS: We performed a cross-sectional study. Nine hundred twenty-seven panel members were invited to an online survey (12/2020-02/2021). The HeReCa-online-panel is installed at the Martin Luther University Halle-Wittenberg to assess regularly the general public's view on health issues in five regions in Germany. The survey was set up in LimeSurvey, with nine items, multiple-choice and open-ended questions that allowed to gather qualitative data. Quantitative data were analysed descriptively and a content analysis was carried out to categorise the qualitative data. RESULTS: Six hundred thirty-six panel members provided data; mean age 52 years, 56.2% female, and 64.9% with higher education qualifications. Asked about relevant topics related to COVID-19, most participants selected vaccination (63.8%), infection control (52%), and long-term effects (47.8%). The following 11 categories were derived from the qualitative analysis representing the topics of interest: vaccination, infection control, long-term effects, therapies, test methods, mental health, symptoms, structures for pandemic control, infrastructure in health care, research. Participants preferred traditional media (TV 70.6%; radio 58.5%; newspaper 32.7%) to social media, but also used the internet as sources of information, becoming aware of new information on websites (28.5%) or via email/newsletter (20.1%). The knowledge question (Which European country is most affected by the SARS-CoV-2 pandemic?) was correctly answered by 7.5% of participants. The Robert Koch Institute (93.7%) and the World Health Organization (78%) were well known, while other organisations providing health information were rarely known (< 10%). Barriers to accessing trustworthy information were lack of time (30.7%), little experience (23.1%), uncertainty about how to get access (22.2%), complexity and difficulties in understanding (23.9%), and a lack of target group orientation (15,3%). CONCLUSIONS: There are extensive information needs regarding various aspects on COVID-19 among the general population. In addition, target-specific dissemination strategies are still needed to reach different groups.

Peri-operative management of neuromuscular blockade: A guideline from the European Society of Anaesthesiology and Intensive Care.

Recent data indicated a high incidence of inappropriate management of neuromuscular block, with a high rate of residual paralysis and relaxant-associated postoperative complications. These data are alarming in that the available neuromuscular monitoring, as well as myorelaxants and their antagonists basically allow well tolerated management of neuromuscular blockade. In this first European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block, we aim to present aggregated and evidence-based recommendations to assist clinicians provide best medical care and ensure patient safety. We identified three main clinical questions: Are myorelaxants necessary to facilitate tracheal intubation in adults? Does the intensity of neuromuscular blockade influence a patient's outcome in abdominal surgery? What are the strategies for the diagnosis and treatment of residual paralysis? On the basis of this, PICO (patient, intervention, comparator, outcome) questions were derived that guided a structured literature search. A stepwise approach was used to reduce the number of trials of the initial research ( n  = 24 000) to the finally relevant clinical studies ( n  = 88). GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was used for formulating the recommendations based on the findings of the included studies in conjunction with their methodological quality. A two-step Delphi process was used to determine the agreement of the panel members with the recommendations: R1 We recommend using a muscle relaxant to facilitate tracheal intubation (1A). R2 We recommend the use of muscle relaxants to reduce pharyngeal and/or laryngeal injury following endotracheal intubation (1C). R3 We recommend the use of a fast-acting muscle relaxant for rapid sequence induction intubation (RSII) such as succinylcholine 1 mg kg -1 or rocuronium 0.9 to 1.2 mg kg -1 (1B). R4 We recommend deepening neuromuscular blockade if surgical conditions need to be improved (1B). R5 There is insufficient evidence to recommend deep neuromuscular blockade in general to reduce postoperative pain or decrease the incidence of peri-operative complications. (2C). R6 We recommend the use of ulnar nerve stimulation and quantitative neuromuscular monitoring at the adductor pollicis muscle to exclude residual paralysis (1B). R7 We recommend using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents (rocuronium, vecuronium) (1A). R8 We recommend advanced spontaneous recovery (i.e. TOF ratio >0.2) before starting neostigmine-based reversal and to continue quantitative monitoring of neuromuscular blockade until a TOF ratio of more than 0.9 has been attained. (1C).

Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis.

Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.

Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis.

BACKGROUND: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial. MATERIAL AND METHODS: This report updates our systematic review and random-effects meta-analysis on randomized controlled trials (RCTs) comparing standard prophylactic anticoagulation and intermediate or therapeutic anticoagulation in COVID-19 patients. We searched eligible studies for the update up to 4 February 2022 by weekly monitoring of RCTs in the Cochrane COVID-19 Study Register. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: For this update we included five new trials; a total of 13 RCTs with 7364 patients. Certainty of evidence was very low to low. We are uncertain whether low-dose prophylactic anticoagulation is favoured over placebo or no anticoagulation in the outpatient- or post-discharge-setting. In hospitalized patients with moderate and severe COVID-19, intermediate-dose anticoagulation may have little or no effect on thrombotic events or death (RR 1.03, 95 % CI 0.86-1.24), but may increase severe bleeding non-significantly (RR 1.48, 95 % CI 0.53-4.15). Therapeutic-dose anticoagulation may decrease thrombotic events or deaths in hospitalized patients with moderate COVID-19 (RR 0.64, 95 % CI 0.38-1.07; fixed-effect model RR 0.72, 95 % CI 0.57-0.91), but may have little or no effect in patients with severe disease (RR 0.98, 95 % CI 0.86-1.12). With therapeutic-dose anticoagulation, the risk of major bleeding may increase regardless of COVID-19 severity (RR 1.78, 95 % CI 1.15-2.74). CONCLUSIONS: Hospitalized, moderately ill COVID-19 patients may benefit from therapeutic-dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19.

BACKGROUND: Oral nirmatrelvir/ritonavir (Paxlovid®) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. Due to its novelty, there are currently few published study results. It remains to be evaluated for which indications and patient populations the drug is suitable.  OBJECTIVES: To assess the efficacy and safety of nirmatrelvir/ritonavir (Paxlovid®) plus standard of care compared to standard of care with or without placebo, or any other intervention for treating COVID-19 and for preventing SARS-CoV-2 infection. To explore equity aspects in subgroup analyses. To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Scopus, and WHO COVID-19 Global literature on coronavirus disease database, identifying completed and ongoing studies without language restrictions and incorporating studies up to 11 July 2022.  This is a LSR. We conduct monthly update searches that are being made publicly available on the open science framework (OSF) platform. SELECTION CRITERIA: Studies were eligible if they were randomized controlled trials (RCTs) comparing nirmatrelvir/ritonavir plus standard of care with standard of care with or without placebo, or any other intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. We screened all studies for research integrity. Studies were ineligible if they had been retracted, or if they were not prospectively registered including appropriate ethics approval. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology and used the Cochrane risk of bias 2 tool. We rated the certainty of evidence using the GRADE approach for the following outcomes: 1. to treat outpatients with mild COVID-19; 2. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, quality of life, (serious) adverse events, and viral clearance; 3. to prevent SARS-CoV-2 infection in post-exposure prophylaxis (PEP); and 4. pre-exposure prophylaxis (PrEP) scenarios: SARS-CoV-2 infection, development of COVID-19 symptoms, mortality, admission to hospital, quality of life, and (serious) adverse events. We explored inequity by subgroup analysis for elderly people, socially-disadvantaged people with comorbidities, populations from LICs and LMICs, and people from different ethnic and racial backgrounds. MAIN RESULTS: As of 11 July 2022, we included one RCT with 2246 participants in outpatient settings with mild symptomatic COVID-19 comparing nirmatrelvir/ritonavir plus standard of care with standard of care plus placebo. Trial participants were unvaccinated, without previous confirmed SARS-CoV-2 infection, had a symptom onset of no more than five days before randomization, and were at high risk for progression to severe disease. Prohibited prior or concomitant therapies included medications highly dependent on CYP3A4 for clearance and CYP3A4 inducers.  We identified eight ongoing studies. Nirmatrelvir/ritonavir for treating COVID-19 in outpatient settings with asymptomatic or mild disease For the specific population of unvaccinated, high-risk patients nirmatrelvir/ritonavir plus standard of care compared to standard of care plus placebo may reduce all-cause mortality at 28 days (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.68; 1 study, 2224 participants; estimated absolute effect: 11 deaths per 1000 people receiving placebo compared to 0 deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence, and admission to hospital or death within 28 days (RR 0.13, 95% CI 0.07 to 0.27; 1 study, 2224 participants; estimated absolute effect: 61 admissions or deaths per 1000 people receiving placebo compared to eight admissions or deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence). Nirmatrelvir/ritonavir plus standard of care may reduce serious adverse events during the study period compared to standard of care plus placebo (RR 0.24, 95% CI 0.15 to 0.41; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably has little or no effect on treatment-emergent adverse events (RR 0.95, 95% CI 0.82 to 1.10; 1 study, 2224 participants; moderate-certainty evidence), and probably increases treatment-related adverse events such as dysgeusia and diarrhoea during the study period compared to standard of care plus placebo (RR 2.06, 95% CI 1.44 to 2.95; 1 study, 2224 participants; moderate-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably decreases discontinuation of study drug due to adverse events compared to standard of care plus placebo (RR 0.49, 95% CI 0.30 to 0.80; 1 study, 2224 participants; moderate-certainty evidence). No study results were identified for improvement of clinical status, quality of life, and viral clearance.  Subgroup analyses for equity Most study participants were younger than 65 years (87.1% of the : modified intention to treat (mITT1) population with 2085 participants), of white ethnicity (71.5%), and were from UMICs or HICs (92.1% of study centres). Data on comorbidities were insufficient.  The outcome 'admission to hospital or death' was investigated for equity: age (< 65 years versus ≥ 65 years) and ethnicity (Asian versus Black versus White versus others). There was no difference between subgroups of age. The effects favoured treatment with nirmatrelvir/ritonavir for the White ethnic group. Estimated effects in the other ethnic groups included the line of no effect (RR = 1). No subgroups were reported for comorbidity status and World Bank country classification by income level. No subgroups were reported for other outcomes. Nirmatrelvir/ritonavir for treating COVID-19 in inpatient settings with moderate to severe disease No studies available. Nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection (PrEP and PEP) No studies available. AUTHORS' CONCLUSIONS: There is low-certainty evidence that nirmatrelvir/ritonavir reduces the risk of all-cause mortality and hospital admission or death based on one trial investigating unvaccinated COVID-19 participants without previous infection that were at high risk and with symptom onset of no more than five days. There is low- to moderate-certainty evidence that nirmatrelvir/ritonavir is safe in people without prior or concomitant therapies including medications highly dependent on CYP3A4. Regarding equity aspects, except for ethnicity, no differences in effect size and direction were identified. No evidence is available on nirmatrelvir/ritonavir to treat hospitalized people with COVID-19 and to prevent a SARS-CoV-2 infection. We will continually update our search and make search results available on OSF.

COVID-19 Intensive Care-Evaluation of Public Information Sources and Current Standards of Care in German Intensive Care Units: A Cross Sectional Online Survey on Intensive Care Staff in Germany.

Backround: In February 2021, the first formal evidence and consensus-based (S3) guidelines for the inpatient treatment of patients with COVID-19 were published in Germany and have been updated twice during 2021. The aim of the present study is to re-evaluate the dissemination pathways and strategies for ICU staff (first evaluation in December 2020 when previous versions of consensus-based guidelines (S2k) were published) and question selected aspects of guideline adherence of standard care for patients with COVID-19 in the ICU. Methods: We conducted an anonymous online survey among German intensive care staff from 11 October 2021 to 11 November 2021. We distributed the survey via e-mail in intensive care facilities and requested redirection to additional intensive care staff (snowball sampling). Results: There was a difference between the professional groups in the number, selection and qualitative assessment of information sources about COVID-19. Standard operating procedures were most frequently used by all occupational groups and received a high quality rating. Physicians preferred sources for active information search (e.g., medical journals), while nurses predominantly used passive consumable sources (e.g., every-day media). Despite differences in usage behaviour, the sources were rated similarly in terms of the quality of the information on COVID-19. The trusted organizations have not changed over time. The use of guidelines was frequently stated and highly recommended. The majority of the participants reported guideline-compliant treatment. Nevertheless, there were certain variations in the use of medication as well as the criteria chosen for discontinuing non-invasive ventilation (NIV) compared to guideline recommendations. Conclusions: An adequate external source of information for nursing staff is lacking, the usual sources of physicians are only appropriate for the minority of nursing staff. The self-reported use of guidelines is high.

Ivermectin for preventing and treating COVID-19.

BACKGROUND: Ivermectin, an antiparasitic agent, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in early stages of infection. Currently, evidence on ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin plus standard of care compared to standard of care plus/minus placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), WHO COVID-19 Global literature on coronavirus disease, and HTA database weekly to identify completed and ongoing trials without language restrictions to 16 December 2021. Additionally, we included trials with > 1000 participants up to April 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  For this review update, we reappraised eligible trials for research integrity: only RCTs prospectively registered in a trial registry according to WHO guidelines for clinical trial registration were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane RoB 2 tool. We used GRADE to rate the certainty of evidence for outcomes in the following settings and populations: 1) to treat inpatients with moderate-to-severe COVID-19, 2) to treat outpatients with mild COVID-19 (outcomes: mortality, clinical worsening or improvement, (serious) adverse events, quality of life, and viral clearance), and 3) to prevent SARS-CoV-2 infection (outcomes: SARS-CoV-2 infection, development of COVID-19 symptoms, admission to hospital, mortality, adverse events and quality of life). MAIN RESULTS: We excluded seven of the 14 trials included in the previous review version; six were not prospectively registered and one was non-randomized. This updated review includes 11 trials with 3409 participants investigating ivermectin plus standard of care compared to standard of care plus/minus placebo. No trial investigated ivermectin for prevention of infection or compared ivermectin to an intervention with proven efficacy. Five trials treated participants with moderate COVID-19 (inpatient settings); six treated mild COVID-19 (outpatient settings). Eight trials were double-blind and placebo-controlled, and three were open-label. We assessed around 50% of the trial results as low risk of bias. We identified 31 ongoing trials. In addition, there are 28 potentially eligible trials without publication of results, or with disparities in the reporting of the methods and results, held in 'awaiting classification' until the trial authors clarify questions upon request. Ivermectin for treating COVID-19 in inpatient settings with moderate-to-severe disease We are uncertain whether ivermectin plus standard of care compared to standard of care plus/minus placebo reduces or increases all-cause mortality at 28 days (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 3 trials, 230 participants; very low-certainty evidence); or clinical worsening, assessed by participants with new need for invasive mechanical ventilation or death at day 28 (RR 0.82, 95% CI 0.33 to 2.04; 2 trials, 118 participants; very low-certainty evidence); or serious adverse events during the trial period (RR 1.55, 95% CI 0.07 to 35.89; 2 trials, 197 participants; very low-certainty evidence). Ivermectin plus standard of care compared to standard of care plus placebo may have little or no effect on clinical improvement, assessed by the number of participants discharged alive at day 28 (RR 1.03, 95% CI 0.78 to 1.35; 1 trial, 73 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.04, 95% CI 0.61 to 1.79; 3 trials, 228 participants; low-certainty evidence); and on viral clearance at 7 days (RR 1.12, 95% CI 0.80 to 1.58; 3 trials, 231 participants; low-certainty evidence). No trial investigated quality of life at any time point. Ivermectin for treating COVID-19 in outpatient settings with asymptomatic or mild disease Ivermectin plus standard of care compared to standard of care plus/minus placebo probably has little or no effect on all-cause mortality at day 28 (RR 0.77, 95% CI 0.47 to 1.25; 6 trials, 2860 participants; moderate-certainty evidence) and little or no effect on quality of life, measured with the PROMIS Global-10 scale (physical component mean difference (MD) 0.00, 95% CI -0.98 to 0.98; and mental component MD 0.00, 95% CI -1.08 to 1.08; 1358 participants; high-certainty evidence). Ivermectin may have little or no effect on clinical worsening, assessed by admission to hospital or death within 28 days (RR 1.09, 95% CI 0.20 to 6.02; 2 trials, 590 participants; low-certainty evidence); on clinical improvement, assessed by the number of participants with all initial symptoms resolved up to 14 days (RR 0.90, 95% CI 0.60 to 1.36; 2 trials, 478 participants; low-certainty evidence); on serious adverse events (RR 2.27, 95% CI 0.62 to 8.31; 5 trials, 1502 participants; low-certainty evidence); on any adverse events during the trial period (RR 1.24, 95% CI 0.87 to 1.76; 5 trials, 1502 participants; low-certainty evidence); and on viral clearance at day 7 compared to placebo (RR 1.01, 95% CI 0.69 to 1.48; 2 trials, 331 participants; low-certainty evidence). None of the trials reporting duration of symptoms were eligible for meta-analysis. AUTHORS' CONCLUSIONS: For outpatients, there is currently low- to high-certainty evidence that ivermectin has no beneficial effect for people with COVID-19. Based on the very low-certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low-certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events. No evidence is available on ivermectin to prevent SARS-CoV-2 infection. In this update, certainty of evidence increased through higher quality trials including more participants. According to this review's living approach, we will continually update our search.

COVID-19 Vaccines: Fear of Side Effects among German Health Care Workers.

(1) Background: Health care workers (HCWs) play a key role in increasing anti-COVID vaccination rates. Fear of potential side effects is one of the main reasons for vaccine hesitancy. We investigated which side effects are of concern to HCWs and how these are associated with vaccine hesitancy. (2) Methods: Data were collected in an online survey in February 2021 among HCWs from across Germany with 4500 included participants. Free-text comments on previously experienced vaccination side effects, and fear of short- and long-term side effects of the COVID-19 vaccination were categorized and analyzed. (3) Results: Most feared short-term side effects were vaccination reactions, allergic reactions, and limitations in daily life. Most feared long-term side effects were (auto-) immune reactions, neurological side effects, and currently unknown long-term consequences. Concerns about serious vaccination side effects were associated with vaccination refusal. There was a clear association between refusal of COVID-19 vaccination in one's personal environment and fear of side effects. (4) Conclusions: Transparent information about vaccine side effects is needed, especially for HCW. Especially when the participants' acquaintances advised against vaccination, they were significantly more likely to fear side effects. Thus, further education of HCW is necessary to achieve good information transfer in clusters as well.

Four Decades of Randomized Clinical Trials Influencing Mortality in Critically Ill and Perioperative Patients.

OBJECTIVES: Randomized clinical trials (RCTs) represent the highest level of scientific evidence. The aim of this review was to map and summarize the main characteristics and publication trends of RCTs with a statistically significant effect on mortality in critically ill and perioperative patients. DESIGN: A mapping review of RCTs published between January 1982 and January 2021. The authors searched PubMed/MEDLINE and EMBASE for RCTs reporting mortality data. A descriptive analysis was conducted, including general and methodologic information of all these RCTs with a statistically significant difference (p < 0.05) in mortality. MEASUREMENTS AND MAIN RESULTS: The authors identified 340 studies published in 115 journals from 42 countries. The most represented clinical areas were ventilatory support (n = 58, 17%) and hemodynamics (n = 56, 16%). A detrimental effect on survival was described in 47 (14%) RCTs. Denmark had the highest number of published trials per million inhabitants. A total of 40 (12%) RCTs were led by a female author. The intention-to-treat principle was applied overall in 60% of RCTs, though this percentage increased up to 75% when the study was published in journals with high impact factor. CONCLUSIONS: In the largest contemporary RCTs database of interventions significantly influencing mortality, the authors found an increase in scientific production. United States, China, France, Italy, and the United Kingdom contributed with 172 (51%) RCTs over 40 years. Only 20% of the studies were multinational collaborations, though this percentage increased over time. The presence of women as first authors was 1 out of 8 RCTs.

[COVID-19 pandemic: preferences and barriers for dissemination of evidence syntheses : Survey of intensive care personnel in Germany]. / COVID-19-Pandemie: Präferenzen und Barrieren für die Disseminierung von Evidenzsynthesen : Befragung des intensivmedizinischen Personals in Deutschland.

BACKGROUND: In the context of COVID-19, the German CEOsys project (COVID-19 Evidenz Ökosystem, www.covid-evidenz.de ) identifies, evaluates and summarizes the results of scientific studies to obtain evidence on this disease. The evidence syntheses are used to derive specific recommendations for clinical practice and to contribute to national guidelines. Besides the necessity of conducting good quality evidence syntheses during a pandemic, just as important is that the dissemination of evidence needs to be quick and efficient, especially in a health crisis. The CEOsys project has set itself this challenge. OBJECTIVE: Preparing the most suitable distribution of evidence syntheses as part of the CEOsys project tasks. METHODS: Intensive care unit (ICU) personnel in Germany were surveyed via categorical and free text questions. The survey focused on the following topics: evidence syntheses, channels and strategies of distribution, possibility of feedback, structure and barriers of dissemination and trustworthiness of various organizations. Profession, qualification, setting and size of the facility were recorded. Questionnaires were pretested throughout the queried professions (physician, nurse, others). The survey was anonymously carried out online through SosciSurvey® and an e­mail was sent directly to 940 addresses. The survey was launched on 3 December, a reminder was sent after 14 days and it ended on 31 December. The survey was also announced via e­mail through DIVI. RESULTS: Of 317 respondents 200 completed the questionnaire. All information was analyzed including the responses from incomplete questionnaires. The most stated barriers were lack of time and access. Especially residents and nurses without specialization in intensive care mentioned uncertainty or insufficient experience in dealing with evidence syntheses as a barrier. Active distribution of evidence syntheses was clearly preferred. More than half of the participants chose websites of public institutions, medical journals, professional societies and e­mail newsletters for drawing attention to new evidence syntheses. Short versions, algorithms and webinars were the most preferred strategies for dissemination. Trust in organizations supplying information on the COVID-19 pandemic was given to professional societies and the Robert Koch Institute (RKI) as the German governmental institute for infections and public health. The respondents' prioritized topics are long-term consequences of the disease, protection of medical personnel against infection and possibilities of ventilation treatment. CONCLUSION: Even though universally valid, evidence syntheses should be actively brought to the target audience, especially during a health crisis such as the COVID-19 pandemic with its exceptional challenges including lack of time and uncertainties in patient care. The contents should be clear, short (short versions, algorithms) and with free access. E­mail newsletters, websites or medical journals should continuously report on new evidence syntheses. Professional societies and the governmental institute for infections and public health should be involved in dissemination due to their obvious trustworthiness.

Antibiotics for the treatment of COVID-19.

BACKGROUND: The effect of antibiotics with potential antiviral and anti-inflammatory properties are being investigated in clinical trials as treatment for COVID-19. The use of antibiotics follows the intention-to-treat the viral disease and not primarily to treat bacterial co-infections of individuals with COVID-19. A thorough understanding of the current evidence regarding effectiveness and safety of antibiotics as anti-viral treatments for COVID-19 based on randomised controlled trials (RCTs) is required. OBJECTIVES: To assess the efficacy and safety of antibiotics compared to each other, no treatment, standard of care alone, placebo, or any other active intervention with proven efficacy for treatment of COVID-19 outpatients and inpatients.  SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv, CENTRAL), Web of Science and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 14 June 2021. SELECTION CRITERIA: RCTs were included that compared antibiotics with each other, no treatment, standard of care alone, placebo, or another proven intervention, for treatment of people with confirmed COVID-19, irrespective of disease severity, treated in the in- or outpatient settings. Co-interventions had to be the same in both study arms. We excluded studies comparing antibiotics to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using the Cochrane risk of bias tool (ROB 2) for RCTs. We used GRADE to rate the certainty of evidence for the following primary outcomes: 1. to treat inpatients with moderate to severe COVID-19: mortality, clinical worsening defined as new need for intubation or death, clinical improvement defined as being discharged alive, quality of life, adverse and serious adverse events, and cardiac arrhythmias; 2. to treat outpatients with asymptomatic or mild COVID-19: mortality, clinical worsening defined as hospital admission or death, clinical improvement defined as symptom resolution, quality of life, adverse and serious adverse events, and cardiac arrhythmias. MAIN RESULTS: We included 11 studies with 11,281 participants with an average age of 54 years investigating antibiotics compared to placebo, standard of care alone or another antibiotic. No study was found comparing antibiotics to an intervention with proven efficacy. All studies investigated azithromycin, two studies investigated other antibiotics compared to azithromycin. Seven studies investigated inpatients with moderate to severe COVID-19 and four investigated mild COVID-19 cases in outpatient settings. Eight studies had an open-label design, two were blinded with a placebo control, and one did not report on blinding. We identified 19 ongoing and 15 studies awaiting classification pending publication of results or clarification of inconsistencies. Of the 30 study results contributing to primary outcomes by included studies, 17 were assessed as overall low risk and 13 as some concerns of bias. Only studies investigating azithromycin reported data eligible for the prioritised primary outcomes. Azithromycin doses and treatment duration varied among included studies.  Azithromycin for the treatment of COVID-19 compared to placebo or standard of care alone in inpatients We are very certain that azithromycin has little or no effect on all-cause mortality at day 28 compared to standard of care alone (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.90 to 1.06; 8600 participants; 4 studies; high-certainty evidence). Azithromycin probably has little or no effect on clinical worsening or death at day 28 (RR 0.95; 95% CI 0.87 to 1.03; 7311 participants; 1 study; moderate-certainty evidence), on clinical improvement at day 28 (RR 0.96; 95% CI 0.84 to 1.11; 8172 participants; 3 studies; moderate-certainty evidence), on serious adverse events during the study period (RR 1.11; 95% CI 0.89 to 1.40; 794 participants; 4 studies; moderate-certainty evidence), and cardiac arrhythmias during the study period (RR 0.92; 95% CI 0.73 to 1.15; 7865 participants; 4 studies; moderate-certainty evidence) compared to placebo or standard of care alone. Azithromycin may increase any adverse events slightly during the study period (RR 1.20; 95% CI 0.92 to 1.57; 355 participants; 3 studies; low-certainty evidence) compared to standard of care alone. No study reported quality of life up to 28 days. Azithromycin for the treatment of COVID-19 compared to placebo or standard of care alone in outpatients Azithromycin may have little or no effect compared to placebo or standard of care alone on all-cause mortality at day 28 (RR 1.00 ; 95% CI 0.06 to 15.69; 876 participants; 3 studies; low-certainty evidence), on admission to hospital or death within 28 days (RR 0.94 ; 95% CI 0.57 to 1.56; 876 participants; 3 studies; low-certainty evidence), and on symptom resolution at day 14 (RR 1.03; 95% CI 0.95 to 1.12; 138 participants; 1 study; low-certainty evidence). We are uncertain whether azithromycin increases or reduces serious adverse events compared to placebo or standard of care alone (0 participants experienced serious adverse events; 454 participants; 2 studies; very low-certainty evidence). No study reported on adverse events, cardiac arrhythmias during the study period or quality of life up to 28 days. Azithromycin for the treatment of COVID-19 compared to any other antibiotics in inpatients and outpatients One study compared azithromycin to lincomycin in inpatients, but did not report any primary outcome. Another study compared azithromycin to clarithromycin in outpatients, but did not report any relevant outcome for this review. AUTHORS' CONCLUSIONS: We are certain that risk of death in hospitalised COVID-19 patients is not reduced by treatment with azithromycin after 28 days. Further, based on moderate-certainty evidence, patients in the inpatient setting with moderate and severe disease probably do not benefit from azithromycin used as potential antiviral and anti-inflammatory treatment for COVID-19 regarding clinical worsening or improvement. For the outpatient setting, there is currently low-certainty evidence that azithromycin may have no beneficial effect for COVID-19 individuals. There is no evidence from RCTs available for other antibiotics as antiviral and anti-inflammatory treatment of COVID-19. With accordance to the living approach of this review, we will continually update our search and include eligible trials to fill this evidence gap. However, in relation to the evidence for azithromycin and in the context of antimicrobial resistance, antibiotics should not be used for treatment of COVID-19 outside well-designed RCTs.