Barotrauma in patients with severe coronavirus disease 2019-retrospective observational study.

Background: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Although it is known that the COVID-19 acute respiratory distress syndrome (ARDS) is associated with higher incidence of pulmonary barotrauma, unique mechanisms causing the aforementioned complication are still to be investigated. The goal of this research was to investigate the incidence of barotrauma among COVID-19 patients treated in the intensive care unit (ICU) and to examine different clinical outcomes among those subjects. Methods: This retrospective observational cohort study included adult COVID-19 patients admitted to ICU from September 1, 2020, to February 28, 2022. All admitted subjects received invasive respiratory support. Subjects were divided into two groups based on occurrence of pulmonary barotrauma. Data were collected from available electronical medical records. Results: In the study period, a total of 900 subjects met inclusion criteria. Pulmonary barotrauma occurred in 88 (9.8%) of them. Subcutaneous emphysema developed in 73 (83%), pneumomediastinum in 68 (77.3%) and pneumothorax in 54 (61.4%) subjects. A small group of subjects developed less common complications like pneumoperitoneum (8 subjects, 9.1%) and pneumopericardium (2 subjects, 2.3%). Survival rate was higher in control than in barotrauma group [396 (48.8%) vs. 22 (25.0%), P<0.05]. There was also a significant difference between two groups in PaO2/FiO2 ratio on admission, duration of non-invasive respiratory support before mechanical ventilation, duration of mechanical ventilation and duration of ICU and hospital stay, all in favour of control group. Conclusions: Development of barotrauma in patients with severe forms of COVID-19 disease and in need of respiratory support is associated with longer ICU and hospital stay as well as lower survival rates at hospital discharge. Further efforts are needed in understanding mechanism in developing barotrauma and finding new prevention and treatment options.

Consumption of psychotropic drugs in Croatia before and during the COVID-19 pandemic: a 10-year longitudinal study (2012-2021).

PURPOSE: This longitudinal study aimed to examine the trends in antipsychotics, antidepressants, anxiolytics, and hypnotics/sedatives consumption in Croatia over a 10-year period (2012-2021). The study also assessed whether the COVID-19 pandemic had an impact on the yearly consumption of psychotropic drugs. METHODS: Data were collected from Croatian Agency for Medicinal Products and Medical Devices (HALMED) and presented as defined daily doses per 1000 inhabitants per day (DDD/TID). The consumption before (2012-2019) and during the COVID-19 pandemic (2020-2021) was compared with interrupted time series analysis. RESULTS: There was an increase in total consumption of analyzed psychotropic drugs in Croatia between the years 2012 and 2021, from 115.47 DDD/TID in 2012 to 155.50 DDD/TID in 2021. An increasing trend was observed in the consumption of all 4 analyzed groups of medicines (antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants). Anxiolytics accounted for 59% (68.29/115.47 DDD/TID), and hypnotics and sedatives for 8.5% (9.76/115.47 DDD/TID) of total consumption in 2012. At the end of a 10-year period, hypnotics and sedatives represented 12% (19.05/155.50 DDD/TID) and anxiolytics 54% (83.53/155.50 DDD/TID) of psychotropic drugs consumption. The total consumption of psychotropic drugs was not significantly different before and during COVID-19 pandemic (estimate ± standard error = 5.029 ± 6.899, t = 0.729, P = 0.490). CONCLUSION: Croatia had a high, continuously increasing consumption of psychotropic drugs. National anxiolytics consumption was one of the highest globally, while consumption of antidepressants was rather low compared to other high-income countries. The COVID-19 pandemic did not seem to influence the yearly utilization of psychotropic drugs in Croatia.

Vitamin D Supplementation and Clinical Outcomes in Severe COVID-19 Patients-Randomized Controlled Trial.

COVID-19 symptoms vary from asymptomatic cases to moderate and severe illness with patients needing hospitalization and intensive care treatment. Vitamin D is associated with severity of viral infections and has an immune-modulatory effect in immune response. Observational studies showed a negative association of low vitamin D levels and COVID-19 severity and mortality outcomes. In this study, we aimed to determine whether daily supplementation of vitamin D during intensive care unit (ICU) stay in COVID-19 patients with severe illness affects clinically relevant outcomes. Patients with COVID-19 disease in need of respiratory support admitted to the ICU were eligible for inclusion. Patients with low vitamin D levels were randomized into one of two groups: the intervention group received daily supplementation of vitamin D and the control group did not receive vitamin D supplementation. In total, 155 patients were randomized: 78 into the intervention group and 77 into the control group. There was no statistically significant difference in number of days spent on respiratory support, although the trial was underpowered for the main outcome. There was no difference in any of the secondary outcomes analyzed between two groups. Our study suggests no benefit in vitamin D supplementation to patients with severe COVID-19 disease admitted to the ICU and in need of respiratory support in any of the analyzed outcomes.

Health-Related Quality of Life of COVID-19 Survivors Treated in Intensive Care Unit-Prospective Observational Study.

Purpose: To investigate the quality of life (QoL) of survivors from severe forms of COVID-19 treated in the ICU. Methods: In this study, we investigated the QoL of patients with severe COVID-19 treated in the ICU from November 2021 to February 2022. In the study period, 288 patients were treated in ICU and 162 were alive at the time of analysis. Of those, 113 patients were included in this study. QoL was analyzed 4 months after ICU admission using the EQ-5D-5L questionnaire administered by telephone. Results: Of the 162 surviving patients, 46% reported moderate to severe problems in the anxiety/depression domain, 37% had moderate to severe problems in usual activities, and 29% in the mobility domain. Older patients had lower QoL in mobility, self-care and usual activities domains. Female patients had lower QoL in usual activities, while male patients had lower QoL in the self-care domain. Patients who spent longer time on invasive respiratory support and those with longer hospital lengths of stay had lower QoL in all domains. Conclusion: Severe COVID-19 reduces HRQoL in a significant number of survivors 4 months after ICU admission. Early recognition of patients at increased risk for reduced QoL could lead to early focused rehabilitation and improved QoL of these patients.

Characteristics, completion and publication of PROSPERO records in regional anesthesia for acute perioperative pain.

Aim: We analyzed characteristics and completion status of Systematic Reviews (SRs) about regional anesthesia for acute perioperative pain relief registered in PROSPERO. Materials & methods: PROSPERO was searched on 5 January 2022. Characteristics of PROSPERO records, completion status and publication information were extracted. PubMed and Google Scholar were searched by 31 May 2022, for additional published SRs. The inconsistency of PROSPERO records' status was analyzed by comparing the most recent PROSPERO status with subsequent publication of completed SR. Time-to-publication was calculated. Results: Almost half of 174 included PROSPERO records (49%) were registered in 2021. A median of 3 (IQR: 2-4.75) authors, and a search of 4 information sources (IQR: 3-5) was planned. At first registration, 51 (29%) records had already started or completed formal screening. PROSPERO records included mostly adults (48%) undergoing trunk blocks (56%), with pain intensity (74%) as a main outcome. 147 (84%) PROSPERO records had a status "ongoing". Yet, 71 (41%) PROSPERO records were completed SRs, published after a median of 291 days. Inconsistency in status was found in 34% of PROSPERO records. Conclusion: Despite an increase in PROSPERO registrations about regional anesthesia, most were not published, and a third had inaccurate status.

Effects of Different Inhalation Therapy on Ventilator-Associated Pneumonia in Ventilated COVID-19 Patients: A Randomized Controlled Trial.

The effect of routine inhalation therapy on ventilator-associated pneumonia (VAP) in mechanically ventilated patients with the coronavirus disease (COVID-19) has not been well-defined. This randomized controlled trial included 175 eligible adult patients with COVID-19 who were treated with mechanical ventilation at the University Hospital of Split between October 2020 and June 2021. Patients were randomized and allocated to a control group (no routine inhalation) or one of the treatment arms (inhalation of N-acetylcysteine; 5% saline solution; or 8.4% sodium bicarbonate). The primary outcome was the incidence of VAP, while secondary outcomes included all-cause mortality. Routine inhalation therapy had no effect on the incidence of bacterial or fungal VAP nor on all-cause mortality (p > 0.05). Secondary analyses revealed a significant reduction of Gram-positive and methicillin-resistant Staphylococcus aureus (MRSA) VAP in the treatment groups. Specifically, the bicarbonate group had a statistically significantly lower incidence of Gram-positive bacterial VAP (4.8%), followed by the N-acetylcysteine group (10.3%), 5% saline group (19.0%), and control group (34.6%; p = 0.001). This difference was driven by a lower incidence of MRSA VAP in the bicarbonate group (2.4%), followed by the N-acetylcysteine group (7.7%), 5% saline group (14.3%), and control group (34.6%; p < 0.001). Longer duration of ventilator therapy was the only significant, independent predictor of any bacterial or fungal VAP in the multivariate analysis (aOR 1.14, 95% CI 1.01−1.29, p = 0.038 and aOR 1.05, 95% CI 1.01−1.10, p = 0.028, respectively). In conclusion, inhalation therapy had no effect on the overall VAP incidence or all-cause mortality. Further studies should explore the secondary findings of this study such as the reduction of Gram-positive or MRSA-caused VAP in treated patients.

Assessing the risk of performance and detection bias in Cochrane reviews as a joint domain is less accurate compared to two separate domains.

BACKGROUND: Initially, the Cochrane risk of bias (RoB) tool had a domain for "blinding of participants, personnel and outcome assessors". In the 2011 tool, the assessment of blinding was split into two domains: blinding of participants and personnel (performance bias) and blinding of outcome assessors (detection bias). The aims of this study were twofold; first, to analyze the frequency of usage of the joint blinding domain (a single domain for performance and detection bias), and second, to assess the proportion of adequate assessments made in the joint versus single RoB domains for blinding by comparing whether authors' RoB judgments were supported by explanatory comments in line with the Cochrane Handbook recommendations. METHODS: We extracted information about the assessment of blinding from RoB tables (judgment, comment, and whether it was specified which outcome type; e.g., objective, subjective) of 729 Cochrane reviews published in 2015-2016. In the Cochrane RoB tool, judgment (low, unclear or high risk) needs to be accompanied by a transparent comment, in which authors provide a summary justifying RoB judgment, to ensure transparency in how these judgments were reached. We reassessed RoB based on the supporting comments reported in Cochrane RoB tables, in line with instructions from the Cochrane Handbook. Then, we compared our new assessments to judgments made by Cochrane authors. We compared the frequency of adequate judgments in reviews with two separate domains for blinding versus those with a joint domain for blinding. RESULTS: The total number of assessments for performance bias was 6918, with 8656 for detection bias and 3169 for the joint domain. The frequency of adequate assessments was 74% for performance bias, 78% for detection bias, and 59% for the joint domain. The lowest frequency of adequate assessments was found when Cochrane authors judged low risk - 47% in performance bias, 62% in detection bias, and 31% in the joint domain. The joint domain and detection bias domain had a similar proportion of specified outcome types (17% and 18%, respectively). CONCLUSIONS: Splitting joint RoB assessment about blinding into two domains was justified because the frequency of adequate judgments was higher in separate domains. Specification of outcome types in RoB domains should be further scrutinized.

Pain assessment in clinical trials: a narrative review.

Pain is a symptom measured in many clinical trials. For pain as an outcome domain, trialists need to choose adequate outcome measure(s), as there are myriad outcome measures for pain to choose from. To ensure consistency and uniformity in clinical trials and systematic reviews, core outcome sets (COS) have been defined; COS includes a predefined minimal list of core outcomes that should be measured within a trial, to ensure their consistency and comparability. COS is defined via consensus procedure, which includes relevant stakeholders such as experts from a specific field and patients. Along with outcomes, outcome measures for each outcome need to be defined to make sure that the outcomes will be measured consistently and uniformly. Hereby we reviewed studies that have examined use of recommended core outcome domains and outcome measures in clinical trials that would be expected to measure pain. Despite the existence of COS and defined core outcome measures (COMs), multiple studies have shown that these are not necessarily used in clinical trials, or in the relevant systematic reviews, which further increases heterogeneity of existing evidence, hinders evidence synthesis and trial comparability, and assessment of comparative effectiveness of interventions. Trialists are encouraged to use COS and COMs when designing clinical trials. Research community is encouraged to design interventions that will help with identifying barriers for using COS and COMs and interventions to foster their uptake. Use of consistent pain outcomes and pain outcome measures is in the interest of patients, research community, healthcare workers and decision-makers. For clinical conditions for which there are no COS and COMs, efforts to design them would be beneficial.

Reasons and factors associated with inconclusiveness of systematic reviews about interventions for neuropathic pain.

Aim: Systematic reviews (SRs) are frequently inconclusive. The aim of this study was to analyze factors associated with conclusiveness of SRs about efficacy and safety of interventions for neuropathic pain (NeuP). Materials & methods: The study protocol was registered in the PROSPERO database (No. CRD42015025831). Five electronic databases (Medical Literature Analysis and Retrieval System Online, Cochrane Database of Systematic Reviews, Cumulative Index for Nursing and Allied Health Literature, Database of Abstracts of Reviews of Effects and Psychological Information Database) were searched until July 2018 for SRs about NeuP management. Conclusion statements for efficacy and safety, and characteristics of SRs were analyzed. Conclusiveness was defined as explicit statement by the SR authors that one intervention is better/similar to the other in terms of efficacy and safety. Methodological quality of SRs was assessed with the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) tool. Results: Of 160 SRs, 37 (23%) were conclusive for efficacy and/or safety. In the SRs, conclusions about safety were missing in half of the analyzed abstracts, and a third of the full texts. Conclusive SRs included significantly more trials and participants, searched more databases, had more authors, conducted meta-analysis, analyzed quality of evidence, and had lower methodological quality than inconclusive SRs. The most common reasons for the lack of conclusiveness indicated by the SR authors were the small number of participants and trials, and the high heterogeneity of included studies. Conclusion: Most SRs about NeuP treatment were inconclusive. Sources of inconclusiveness of NeuP reviews need to be further studied, and SR authors need to provide conclusions about both safety and efficacy of interventions.

Adequacy of risk of bias assessment in surgical vs non-surgical trials in Cochrane reviews: a methodological study.

BACKGROUND: Bias in randomized controlled trials (RCTs) can lead to underestimation or overestimation of the true effects of interventions. Surgical RCTs may suffer from the risk of bias (RoB) that is avoidable in trials of other interventions, and vice versa. We aimed to compare the adequacy of RoB assessments in surgical versus non-surgical RCTs included in Cochrane reviews and to assess the most common differences in those RoB assessments. Due to specificities of surgical trials, i.e. difficulties associated with blinding of surgical interventions, we hypothesized that assessments of surgical trials may be more adequate, compared to RCTs of non-surgical interventions. METHODS: This was a methodological study, analyzing methods of published Cochrane systematic reviews. Data were extracted from RoB tables in Cochrane reviews (judgments and accompanying explanatory comment) for the following four RoB domains used in the 2011 Cochrane RoB tool: randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessors. We defined adequate assessments as those that were in line with instructions from the Cochrane Handbook for Systematic Reviews of Interventions. The prevalence of adequate assessments was compared in surgical versus non-surgical trials. The most common differences in both groups of reviews were presented. RESULTS: In 729 analyzed Cochrane reviews, there were 10,537 included trials. The prevalence of adequate RoB judgments made by Cochrane authors ranged from 87.9, 95%CI (87.3 to 88.6%) for randomization to 70.7, 95%CI (69.8 to 71.5%) for blinding of participants and personnel. For all analyzed RoB domains, the prevalence of adequate RoB domains was higher in surgical trials than in non-surgical trials. For two RoB domains assessing blinding, this difference between surgical and non-surgical trials was statistically significant (P < 0.001), while the difference was not significant for the RoB domain regarding randomization (P = 0.124) and allocation concealment (P = 0.039, ß < 0.8). CONCLUSIONS: RoB judgments were more in line with instructions from the Cochrane Handbook when Cochrane reviews assessed surgical trials, compared to those that analyzed non-surgical interventions. However, further steps are warranted to scrutinize RoB assessment in trials of both surgical and non-surgical interventions.

Efficacy and Safety of Pulsed Radiofrequency as a Method of Dorsal Root Ganglia Stimulation in Patients with Neuropathic Pain: A Systematic Review.

OBJECTIVE: Pulsed radiofrequency (PRF) is a nonablative pain treatment that uses radiofrequency current in short high-voltage bursts, resulting in interruption of nociceptive afferent pathways. We conducted a systematic review with the aim to create a synthesis of evidence about the efficacy and safety of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization. All study designs were eligible. We assessed risk of bias using the Cochrane tool for randomized controlled trials and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). We assessed level of evidence using the Oxford tool and quality of evidence with GRADE. RESULTS: We included 28 studies with participants suffering from lumbosacral, cervical, or thoracic radicular pain, post-herpetic neuralgia, neuropathicbone pain in cancer patients, or carpal tunnel syndrome. Only five studies were randomized controlled trials (RCTs), while others were of nonrandomized designs, predominantly before and after comparisons. A total of 991 participants were included, with a median number (range) of 31 (1-101) participants. Only 204 participants were included in the RCTs, with a median number (range) of 38 (23-62) participants. The overall quality of evidence was low, as the majority of the included studies were rated as evidence level 4 or 5. The quality of evidence was very low. CONCLUSIONS: Evidence about the efficacy and safety of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality. Current research results about the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of participants.

Efficacy and safety of pulsed radiofrequency as a method of dorsal root ganglia stimulation for treatment of non-neuropathic pain: a systematic review.

BACKGROUND: We systematically reviewed the evidence on the efficacy and safety of dorsal root ganglion (DRG) targeted pulsed radiofrequency (PRF) versus any comparator for treatment of non-neuropathic pain. METHODS: We searched MEDLINE, CINAHL, Embase, PsycINFO, clinicaltrials.gov and WHO clinical trial register until January 8, 2019. All study designs were eligible. Two authors independently conducted literature screening. Primary outcomes were pain intensity and serious adverse events (SAEs). Secondary outcomes were any other pain-related outcome and any other safety outcome that was reported. We assessed the risk of bias using the Cochrane tool and Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I). We conducted narrative evidence synthesis and assessed the conclusiveness of included studies regarding efficacy and safety. RESULTS: We included 17 studies with 599 participants, which analyzed various pain syndromes. Two studies were randomized controlled trials; both included participants with low back pain (LBP). Non-randomized studies included patients with the following indications: LBP, postsurgical pain, pain associated with herpes zoster, cervicogenic headache, complex regional pain syndrome type 1, intractable vertebral metastatic pain, chronic scrotal and inguinal pain, occipital radiating pain in rheumatoid arthritis and chronic migraine. In these studies, the PRF was usually initiated after other treatments have failed. Eleven studies had positive conclusive statements (11/17) about efficacy; the remaining had positive inconclusive statements. Only three studies provided conclusiveness of evidence statements regarding safety - two indicated that the evidence was positive conclusive, and one positive inconclusive. The risk of bias was predominantly unclear in randomized and serious in non-randomized studies. CONCLUSION: Poor quality and few participants characterize evidence about benefits and harms of DRG PRF in patients with non-neuropathic pain. Results from available studies should only be considered preliminary. Not all studies have reported data regarding the safety of the intervention, but those that did, indicate that the intervention is relatively safe. As the procedure is non-destructive and early results are promising, further comparative studies about PRF in non-neuropathic pain syndromes would be welcomed.

Assessing risk of bias judgments for blinding of outcome assessors in Cochrane reviews.

Aim: Adequate judging of risk of bias (RoB) for blinding of outcome assessors (detection bias) is important for supporting highest level of evidence. Materials & methods: Judgments and supporting comments for detection bias were retrieved from RoB tables reported in Cochrane reviews. We categorized comments, and then compared judgment and supporting comment with instructions from the Cochrane Handbook. Results: We analyzed 8656 judgments for detection bias from 7626 trials included in 575 reviews. Overall, 1909 judgments (22%) were not in line with the Cochrane Handbook. In 9% of trials, the authors split the detection bias domain according to outcomes. Here, prevalence of inadequate judgments was 19%. Conclusion: Interventions to improve RoB assessments in systematic reviews should be explored.

Biomedical conferences' author instructions rarely mention guidelines for reporting abstracts of trials and systematic reviews.

Aim: To analyze whether instructions for authors of biomedical conference abstracts mention guidelines for writing randomized controlled trial and systematic review abstracts and to evaluate reasons for their absence from instructions. Materials & methods: We analyzed instructions for authors of biomedical conferences advertized in 2019 and assessed whether they mentioned Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Abstracts and Consolidated Standards of Reporting Trials for Abstracts guidelines. We surveyed contact persons from abstract/publication committees of selected conferences to analyze why relevant guidelines were missing. Results: Instructions for abstracts were available for 819 conferences. Only two (0.2%) had reporting instructions for randomized controlled trial/systematic review authors. Almost half of the contacted conference organizers whose response we received were not aware of Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Abstracts and Consolidated Standards of Reporting Trials for Abstracts guidelines. Conclusion: Conference organizers do not require and are not familiar enough with reporting guidelines.

Conference abstracts describing systematic reviews on pain were selectively published, not reliable, and poorly reported.

OBJECTIVE: The objective of the study was to determine the reporting quality of systematic review (SR) abstracts presented at World Congresses on Pain (WCPs) and to quantify agreement in results presented in those abstracts with their corresponding full-length publications. STUDY DESIGN AND SETTING: We screened abstracts of five WCPs held from 2008 to 2016 to find abstracts describing SRs. Two authors searched for corresponding full publications using PubMed and Google Scholar in April 2018. Methods and outcomes extracted from abstracts were compared with their corresponding full publications. The reporting quality of abstracts was evaluated against the PRISMA for Abstracts (PRISMA-A) checklist. RESULTS: We identified 143 conference abstracts describing SRs. Of these, 90 (63%) were published as full-length articles in peer-reviewed journals by April 2018, with a median time from conference presentation to publication of 5 months (interquartile range: -0.25 to 14 months). Among 79 abstract-publication pairs evaluable for discordance, there was some form of discordance in 40% of pairs. Qualitative discordance (different direction of the effect) was found in 13 analyzed pairs (16%). The median adherence by abstracts to each PRISMA-A checklist item was 33% (interquartile range: 29% to 42%). CONCLUSION: Conference abstracts of pain SRs are selectively published, not reliable, and poorly reported.

Outcome Domains, Outcome Measures, and Characteristics of Randomized Controlled Trials Testing Nonsurgical Interventions for Osteoarthritis.

OBJECTIVE: Core outcome set (COS) is the minimum set of outcome domains that should be measured and reported in clinical trials. We analyzed outcome domains, prevalence of use of COS published by Outcome Measures in Rheumatology (OMERACT) initiative, outcome measures for outcome domains recommended by OMERACT COS, duration and size of randomized controlled trials (RCT) testing nonsurgical interventions for osteoarthritis (OA). METHODS: We searched PubMed and analyzed RCT about nonsurgical interventions for OA published from June 2012 to June 2017. We extracted data about trial type, use of OMERACT COS, efficacy outcome domains, safety outcome domains, outcome measures used for COS assessment, duration, and sample size. RESULTS: Among 334 analyzed trials, complete OMERACT-recommended COS was used by 14% of trials. Higher median prevalence of using OMERACT COS was found in trials explicitly described as phase III, and trials of pharmacological interventions with followup ≥ 1 year, but both with wide range of COS usage. Trialists used numerous different outcome measures for analyzing core outcome domains: 50 different outcome measures for pain, 74 for physical function, 9 for patient's global assessment, and 5 for imaging. CONCLUSION: Suboptimal use of recommended COS and heterogeneity of outcome measures is reducing quality and comparability of OA trials and hinders conclusions about efficacy and comparative efficacy of nonsurgical interventions. Interventions for improving study design of trials in this field would be beneficial.

Selective reporting bias due to discrepancies between registered and published outcomes in osteoarthritis trials.

Aim: Outcome reporting bias (ORB) occurs when outcomes planned in a study protocol are subsequently not reported or are partially reported. Our aim was to analyze ORB in randomized controlled trials (RCTs) about conservative interventions for osteoarthritis (OA) by comparing registered protocols and published manuscripts, as well as association between study funding type and intervention type, and ORB in those RCTs. Materials & methods: We analyzed RCTs that were published in a peer-review journal and analyzed any type of conservative intervention for treatment of OA in humans that reported in the manuscript registration in a public clinical trial registry and provided unique registration identifier. We extracted data indicating ORB by comparing outcomes in protocol and published article, and characteristics of trials. Results: In 190 (57%) of 334 included RCTs, it was indicated in the manuscript that a trial was registered. In 48% of trials we found discrepancies in number, type or time point of primary efficacy outcome between protocol and manuscript. Significantly less discrepancies in primary efficacy outcomes between protocols and published articles were found in trials funded by a commercial sponsor (p = 0.0062) and trials of pharmacological interventions (p = 0.0016). Conclusion: Trials about conservative therapies for OA have high prevalence of discrepancies between protocol and publication, and frequent ORB. This may mislead readers of published results because it has been shown that ORB can lead to both overestimation and underestimation of effects of interventions, depending on the intervention and outcome. Efforts to prevent nonregistration of protocols and selective reporting are needed.

Efficacy and safety of modified-release paracetamol for acute and chronic pain: a systematic review protocol.

INTRODUCTION: Paracetamol (acetaminophen) is widely used for management of mild-to-moderate pain and reduction of fever. It is available as immediate release (IR) and modified-release (MR) formulation. In 2017, European Medicines Agency recommended a suspension of marketing of MR paracetamol in the European Union. Benefit-risk balance of these products has been assessed as negative as data showed that existing procedures for overdose management may not be efficient. Since MR paracetamol is still available in other countries (Australia and USA) and there is no available systematic review (SR) of efficacy and safety of MR paracetamol in the literature, we have decided to perform one to evaluate available data from randomised clinical trials (RCTs). METHODS AND ANALYSIS: Using predefined search criteria, we will search EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform to identify RCTs evaluating efficacy and safety of MR paracetamol alone in any dose or duration for any pain. Participants are defined as adults and adolescents (over 12 years). Primary efficacy outcomes will be pain intensity, pain relief and sleep. Primary safety outcomes will be the number of patients experiencing any (serious) adverse event, the number of patients withdrawn due to adverse events and the number of patients with gastrointestinal and hepatic adverse events. Data analysis will be subdivided based on different clinical syndromes. Meta-analysis will be conducted if possible. Cochrane risk of bias (RoB) tool with seven dimensions will be used to assess RoB of individual studies. ETHICS AND DISSEMINATION: This SR will include only data collected from trial reports; therefore, an ethical approval will not be sought. We will publish the protocol and our findings in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42018115769.

Risk of bias judgments for random sequence generation in Cochrane systematic reviews were frequently not in line with Cochrane Handbook.

BACKGROUND: Assessing the risk of bias (RoB) in included studies is one of the key methodological aspects of systematic reviews. Cochrane systematic reviews appraise RoB of randomised controlled trials (RCTs) with the Cochrane RoB tool. Detailed instructions for using the Cochrane RoB tool are provided in the Cochrane Handbook for Systematic Reviews of Interventions (The Cochrane Handbook). The purpose of this study was to analyse whether Cochrane authors use adequate judgments about the RoB for random sequence generation of RCTs included in Cochrane reviews. METHODS: We extracted authors' judgments (high, low or unclear RoB) and supports for judgments (comments accompanying judgments which explain the rationale for a judgment) for random sequence generation of included RCTs from RoB tables of Cochrane reviews using automated data scraping. We categorised all supporting comments, analysed the number and type of various supporting comments and assessed adequacy of RoB judgment for randomisation in line with recommendations from the Cochrane Handbook. RESULTS: We analysed 10,103 RCTs that were included in 704 Cochrane reviews. For 5,706 RCTs, randomisation was not described, but for the remaining RCTs, it was indicated that randomisation was performed using computer/software/internet (N = 2,850), random number table (N = 883), mechanical method (N = 359) or it was incomplete/inappropriate (N = 305). Overall, 1,220/10,103 trials (12%) did not have a RoB judgment in line with Cochrane Handbook guidance about randomisation. The highest proportion of misjudgements was found for trials with high RoB (28%), followed by those with low (20%) or unclear (3%). Therefore, one in eight judgments for the analysed domain in Cochrane reviews was not in line with Cochrane Handbook, and one in four if the judgment was "high risk". CONCLUSION: Authors of Cochrane reviews often make judgments about the RoB related to random sequence generation that are not in line with instructions given in the Cochrane Handbook, which compromises the reliability of the systematic reviews. Our results can help authors of both Cochrane and non-Cochrane reviews which use Cochrane RoB tool to avoid making common mistakes when assessing RoB in included trials.

Awareness and acceptability of Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials core outcome set for chronic pain among surveyed neuropathic pain authors.

Aim: We assessed the knowledge and adoption of Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT)-recommended core outcome set (COS) and core outcome measures (COM) among authors of systematic reviews (SR) and randomized controlled trials (RCT) about interventions for neuropathic pain (NeuP). Methods: NeuP SR and RCT authors identified via a systematic literature search were surveyed. Results: The response rate was low. Although majority of respondents were familiar with the IMMPACT COS, only 61% of SR authors and 40% of RCT authors used the COS. The main perceived obstacle that prevented the adoption of the COS was the lack of awareness of the full IMMPACT COS. Conclusion: The adoption of IMMPACT-recommended COS and COM among NeuP authors was inadequate and their appropriateness needs to be further evaluated.