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.

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.

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.

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.

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.

Comparison of methodological quality rating of systematic reviews on neuropathic pain using AMSTAR and R-AMSTAR.

BACKGROUND: Systematic reviews (SRs) in the field of neuropathic pain (NeuP) are increasingly important for decision-making. However, methodological flaws in SRs can reduce the validity of conclusions. Hence, it is important to assess the methodological quality of NeuP SRs critically. Additionally, it remains unclear which assessment tool should be used. We studied the methodological quality of SRs published in the field of NeuP and compared two assessment tools. METHODS: We systematically searched 5 electronic databases to identify SRs of randomized controlled trials of interventions for NeuP available up to March 2015. Two independent reviewers assessed the methodological quality of the studies using the Assessment of Multiple Systematic Reviews (AMSTAR) and the revised AMSTAR (R-AMSTAR) tools. The scores were converted to percentiles and ranked into 4 grades to allow comparison between the two checklists. Gwet's AC1 coefficient was used for interrater reliability assessment. RESULTS: The 97 included SRs had a wide range of methodological quality scores (AMSTAR median (IQR): 6 (5-8) vs. R-AMSTAR median (IQR): 30 (26-35)). The overall agreement score between the 2 raters was 0.62 (95% CI 0.39-0.86) for AMSTAR and 0.62 (95% CI 0.53-0.70) for R-AMSTAR. The 31 Cochrane systematic reviews (CSRs) were consistently ranked higher than the 66 non-Cochrane systematic reviews (NCSRs). The analysis of individual domains showed the best compliance in a comprehensive literature search (item 3) on both checklists. The results for the domain that was the least compliant differed: conflict of interest (item 11) was the item most poorly reported on AMSTAR vs. publication bias assessment (item 10) on R-AMSTAR. A high positive correlation between the total AMSTAR and R-AMSTAR scores for all SRs, as well as for CSRs and NCSRs, was observed. CONCLUSIONS: The methodological quality of analyzed SRs in the field of NeuP was not optimal, and CSRs had a higher quality than NCSRs. Both AMSTAR and R-AMSTAR tools produced comparable quality ratings. Our results point out to weaknesses in the methodology of existing SRs on interventions for the management NeuP and call for future improvement by better adherence to analyzed quality checklists, either AMSTAR or R-AMSTAR.

Efficacy and Safety Outcomes in Systematic Reviews of Interventions for Postoperative Pain in Children: Comparison Against the Recommended Core Outcome Set.

Objective: To investigate the range of efficacy and safety outcomes used in systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions for postoperative pain in children and compare them with outcome domains recommended in the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT). Methods: Five electronic databases were searched: MEDLINE, Cochrane Database of Systematic Reviews, DARE, CINAHL, and PsycINFO. Two review authors extracted outcome data independently. Efficacy and safety outcomes were extracted and categorized. The type and number of outcomes were analyzed and compared against the outcomes recommended by PedIMMPACT. The study protocol was registered in PROSPERO (CRD42015029654). Results: We included 48 systematic reviews with data from 816 trials. The median number of all outcomes was 4, while the median number of the PedIMMPACT core outcomes was three out of six. The most commonly reported outcome of the PedIMMPACT Core Outcome set (COS) was "symptoms and adverse events," followed by pain intensity, which was reported in 75% of the included SRs. Just over half of the SRs that included a pain intensity outcome also indicated the specific pain assessment tool used in the methods section. Conclusions: Systematic reviews in the field of pediatric pain do not use the recommended COS. Nor do they consistently include pain as an outcome. This makes comparisons of efficacy and safety across interventions very difficult. Future studies should explore whether the authors are aware of the COS and whether the recommended COS is appropriate.

Interventions for Neuropathic Pain: An Overview of Systematic Reviews.

Numerous interventions for neuropathic pain (NeuP) are available, but its treatment remains unsatisfactory. We systematically summarized evidence from systematic reviews (SRs) of randomized controlled trials on interventions for NeuP. Five electronic databases were searched up to March 2015. Study quality was analyzed using A Measurement Tool to Assess Systematic Reviews. The most common interventions in 97 included SRs were pharmacologic (59%) and surgical (15%). The majority of analyzed SRs were of medium quality. More than 50% of conclusions from abstracts on efficacy and approximately 80% on safety were inconclusive. Effective interventions were described for painful diabetic neuropathy (pregabalin, gabapentin, certain tricyclic antidepressants [TCAs], opioids, antidepressants, and anticonvulsants), postherpetic neuralgia (gabapentin, pregabalin, certain TCAs, antidepressants and anticonvulsants, opioids, sodium valproate, topical capsaicin, and lidocaine), lumbar radicular pain (epidural corticosteroids, repetitive transcranial magnetic stimulation [rTMS], and discectomy), cervical radicular pain (rTMS), carpal tunnel syndrome (carpal tunnel release), cubital tunnel syndrome (simple decompression and ulnar nerve transposition), trigeminal neuralgia (carbamazepine, lamotrigine, and pimozide for refractory cases, rTMS), HIV-related neuropathy (topical capsaicin), and central NeuP (certain TCAs, pregabalin, cannabinoids, and rTMS). Evidence about interventions for NeuP is frequently inconclusive or completely lacking. New randomized controlled trials about interventions for NeuP are necessary; they should address safety and use clear diagnostic criteria.

Methodological and Reporting Quality of Systematic Reviews Published in the Highest Ranking Journals in the Field of Pain.

BACKGROUND: Systematic reviews (SRs) are important for making clinical recommendations and guidelines. We analyzed methodological and reporting quality of pain-related SRs published in the top-ranking anesthesiology journals. METHODS: This was a cross-sectional meta-epidemiological study. SRs published from 2005 to 2015 in the first quartile journals within the Journal Citation Reports category Anesthesiology were analyzed based on the Journal Citation Reports impact factor for year 2014. Each SR was assessed by 2 independent authors using Assessment of Multiple Systematic Reviews (AMSTAR) and Preferred Reporting Items of Systematic reviews and Meta-Analyses (PRISMA) tools. Total score (median and interquartile range, IQR) on checklists, temporal trends in total score, correlation in total scores between the 2 checklists, and variability of those results between journals were analyzed. RESULTS: A total of 446 SRs were included. Median total score of AMSTAR was 6/11 (IQR: 4-7) and of PRISMA 18.5/27 (IQR: 15-22). High compliance (reported in over 90% SRs) was found in only 1 of 11 AMSTAR and 5 of 27 PRISMA items. Low compliance was found for the majority of AMSTAR and PRISMA individual items. Linear regression indicated that there was no improvement in the methodological and reporting quality of SRs before and after the publication of the 2 checklists (AMSTAR: F(1,8) = 0.22; P = .65, PRISMA: F(1,7) = 0.22; P = .47). Total scores of AMSTAR and PRISMA had positive association (R = 0.71; P < .0001). CONCLUSIONS: Endorsement of PRISMA in instructions for authors was not a guarantee of compliance. Methodological and reporting quality of pain-related SRs should be improved using relevant checklists. This can be remedied by a joint effort of authors, editors, and peer reviewers.

Interventions for postoperative pain in children: An overview of systematic reviews.

The aim of this study was to conduct an overview of systematic reviews that summarizes the results about efficacy and safety from randomized controlled trials involving the various strategies used for postoperative pain management in children. We searched the Cochrane Database of Systematic Reviews, CINAHL, Database of Reviews of Effect, Embase, MEDLINE, and PsycINFO from the earliest date to January 24, 2016. This overview included 45 systematic reviews that evaluated interventions for postoperative pain in children. Out of 45 systematic reviews that investigated various interventions for postoperative pain in children, 19 systematic reviews (42%) presented conclusive evidence of efficacy. Positive conclusive evidence was reported in 18 systematic reviews (40%) for the efficacy of diclofenac, ketamine, caudal analgesia, dexmedetomidine, music therapy, corticosteroid, epidural analgesia, paracetamol, and/or nonsteroidal anti-inflammatory drugs and transversus abdominis plane block. Only one systematic review reported conclusive evidence of equal efficacy that involved a comparison of dexmedetomidine vs morphine and fentanyl. Safety of interventions was reported as conclusive in 14 systematic reviews (31%), with positive conclusive evidence for dexmedetomidine, corticosteroid, epidural analgesia, transversus abdominis plane block, and clonidine. Seven systematic reviews reported equal conclusive safety for epidural infusion, diclofenac intravenous vs ketamine added to opioid analgesia, bupivacaine, ketamine, paracetamol, and dexmedetomidine vs intravenous infusions of various opioid analgesics, oral suspension and suppository of diclofenac, only opioid, normal saline, no treatment, placebo, and midazolam. Negative conclusive statement for safety was reported in one systematic review for caudal analgesia vs noncaudal regional analgesia. More than half of systematic reviews included in this overview were rated as having medium methodological quality. Of 45 included systematic reviews, 10 were Cochrane reviews and they had higher methodological quality than non-Cochrane reviews. As evidence concerning efficacy and safety is inconclusive for most of the analyzed interventions, our review points out the need for more rigorous trials concerning pain management in children.

Proliferative injection therapy for osteoarthritis: a systematic review.

PURPOSE: To systematically analyse randomised controlled trials (RCTs) about efficacy and safety of proliferative injection therapy (prolotherapy) for treatment of osteoarthritis (OA). METHODS: CENTRAL, Embase and MEDLINE were searched. Two reviewers independently conducted screening and data extraction. RCTs were assessed with the Cochrane risk of bias tool. Type of treatment, study design, dosing, efficacy outcomes and safety outcomes were analysed. The protocol was registered in PROSPERO (CRD42016035258). RESULTS: Seven RCTs were included, with 393 participants aged 40-75 years and mean OA pain duration from three months to eight years. Follow-up was 12 weeks to 12 months. Studies analysed OA of the knee joint (n = 5), first carpometacarpal joint (n = 1) and finger joints (n = 1). Various types of prolotherapy were used; dextrose was the most commonly used irritant agent. All studies concluded that prolotherapy was effective treatment for OA. No serious adverse events were reported. The studies had considerable methodological limitations. DISCUSSION: Limited evidence from low-quality studies indicates a beneficial effect of prolotherapy for OA management. The number of participants in these studies was too small to provide reliable evidence. CONCLUSIONS: Current data from trials about prolotherapy for OA should be considered preliminary, and future high-quality trials on this topic are warranted.

Cochrane plain language summaries are highly heterogeneous with low adherence to the standards.

BACKGROUND: The aim of this study was to analyze whether Cochrane plain language summaries (PLSs) adhere to the Standards for the reporting of Plain Language Summaries in new Cochrane Intervention Reviews (PLEACS). METHODS: A systematic analysis of adherence to the measurable PLEACS items was performed for Cochrane PLSs published from March 2013 to the end of January 2015. Duplicate independent data extraction was performed. An adherence score was calculated for each PLS and for the Cochrane Review Groups (CRGs) that published them. RESULTS: Of the 1738 analyzed PLSs, not a single one adhered fully to the measured PLEACS items. The highest adherence was found for absence of details of the search strategy (99 % adherence), and the lowest adherence for an item mandating to address quality according to the GRADE system (0.7 % adherence). Overall adherence percentage of PLSs reporting reviews with included studies was 57 %. Different CRGs had a wide range of adherence scores. CONCLUSIONS: Cochrane plain language summaries are highly heterogeneous with a low adherence to the PLEACS standards. Therefore, there is much room for improving the content and consistency of the PLS. A standardization of PLSs is necessary to ensure delivery of proper and consistent information for consumers.

Cdk1, PKCδ and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death.

Myocardial ischemia-reperfusion (I/R) injury is one of the leading causes of death and disability worldwide. Mitochondrial fission has been shown to be involved in cardiomyocyte death. However, molecular machinery involved in mitochondrial fission during I/R injury has not yet been completely understood. In this study we aimed to investigate molecular mechanisms of controlling activation of dynamin-related protein 1 (Drp1, a key protein in mitochondrial fission) during anoxia-reoxygenation (A/R) injury of HL1 cardiomyocytes. A/R injury induced cardiomyocyte death accompanied by the increases of mitochondrial fission, reactive oxygen species (ROS) production and activated Drp1 (pSer616 Drp1), and decrease of inactivated Drp1 (pSer637 Drp1) while mitochondrial fusion protein levels were not significantly changed. Blocking Drp1 activity with mitochondrial division inhibitor mdivi1 attenuated cell death, mitochondrial fission, and Drp1 activation after A/R. Trolox, a ROS scavenger, decreased pSer616 Drp1 level and mitochondrial fission after A/R. Immunoprecipitation assay further indicates that cyclin dependent kinase 1 (Cdk1) and protein kinase C isoform delta (PKCδ) bind Drp1, thus increasing mitochondrial fission. Inhibiting Cdk1 and PKCδ attenuated the increases in pSer616 Drp1, mitochondrial fission, and cardiomyocyte death. FK506, a calcineurin inhibitor, blocked the decrease in expression of inactivated pSer637 Drp1 and mitochondrial fission. Our findings reveal the following novel molecular mechanisms controlling mitochondrial fission during A/R injury of cardiomyocytes: (1) ROS are upstream initiators of mitochondrial fission; and (2) the increased mitochondrial fission is resulted from both increased activation and decreased inactivation of Drp1 through Cdk1, PKCδ, and calcineurin-mediated pathways, respectively.

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.

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.

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.

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.

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.