Glucocorticoid use in acute respiratory failure from pulmonary causes and association with early changes in the systemic host immune response.

BACKGROUND: Glucocorticoids are commonly used in patients with or at-risk for acute respiratory distress syndrome (ARDS), but optimal use remains unclear despite well-conducted clinical trials. We performed a secondary analysis in patients previously enrolled in the Acute Lung Injury and Biospecimen Repository at the University of Pittsburgh. The primary aim of our study was to investigate early changes in host response biomarkers in response to real-world use of glucocorticoids in patients with acute respiratory failure due to ARDS or at-risk due to a pulmonary insult. Participants had baseline plasma samples obtained on study enrollment and on follow-up 3 to 5 days later to measure markers of innate immunity (IL-6, IL-8, IL-10, TNFr1, ST2, fractalkine), epithelial injury (sRAGE), endothelial injury (angiopoietin-2), and host response to bacterial infections (procalcitonin, pentraxin-3). In our primary analyses, we investigated the effect of receiving glucocorticoids between baseline and follow-up samples on host response biomarkers measured at follow-up by doubly robust inverse probability weighting analysis. In exploratory analyses, we examined associations between glucocorticoid use and previously characterized host response subphenotypes (hyperinflammatory and hypoinflammatory). RESULTS: 67 of 148 participants (45%) received glucocorticoids between baseline and follow-up samples. Dose and type of glucocorticoids varied. Regimens that used hydrocortisone alone were most common (37%), and median daily dose was equivalent to 40 mg methylprednisolone (interquartile range: 21, 67). Participants who received glucocorticoids were more likely to be female, to be on immunosuppressive therapy at baseline, and to have higher baseline levels of ST-2, fractalkine, IL-10, pentraxin-3, sRAGE, and TNFr1. Glucocorticoid use was associated with decreases in IL-6 and increases in fractalkine. In exploratory analyses, glucocorticoid use was more frequent in participants in the hyperinflammatory subphenotype (58% vs 40%, p = 0.05), and was not associated with subphenotype classification at the follow-up time point (p = 0.16). CONCLUSIONS: Glucocorticoid use varied in a cohort of patients with or at-risk for ARDS and was associated with early changes in the systemic host immune response.

Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reanalyzed. We used mouse models of hemorrhagic acute lung injury mediated by Pseudomonas aeruginosa exoproducts in wild-type mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral. In critically ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in nonsurvivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, and lower respiratory tract GDF15 levels were higher in coronavirus disease (COVID-19) nonsurvivors. In mice, intratracheal P. aeruginosa type II secretion system exoproducts were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and an altered lung transcriptional profile during injury induced by P. aeruginosa type II secretion system exoproducts, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which is associated with plasma levels in humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway.

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA.

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes.

The upper and lower respiratory tract microbiome in severe aspiration pneumonia.

Uncertainty persists whether anaerobic bacteria represent important pathogens in aspiration pneumonia. In a nested case-control study of mechanically ventilated patients classified as macro-aspiration pneumonia (MAsP, n = 56), non-macro-aspiration pneumonia (NonMAsP, n = 91), and uninfected controls (n = 11), we profiled upper (URT) and lower respiratory tract (LRT) microbiota with bacterial 16S rRNA gene sequencing, measured plasma host-response biomarkers, analyzed bacterial communities by diversity and oxygen requirements, and performed unsupervised clustering with Dirichlet Multinomial Models (DMM). MAsP and NonMAsP patients had indistinguishable microbiota profiles by alpha diversity and oxygen requirements with similar host-response profiles and 60-day survival. Unsupervised DMM clusters revealed distinct bacterial clusters in the URT and LRT, with low-diversity clusters enriched for facultative anaerobes and typical pathogens, associated with higher plasma levels of SPD and sCD14 and worse 60-day survival. The predictive inter-patient variability in these bacterial profiles highlights the importance of microbiome study in patient sub-phenotyping and precision medicine approaches for severe pneumonia.

Inter-rater reliability and prognostic value of baseline Radiographic Assessment of Lung Edema (RALE) scores in observational cohort studies of inpatients with COVID-19.

OBJECTIVES: To reliably quantify the radiographic severity of COVID-19 pneumonia with the Radiographic Assessment of Lung Edema (RALE) score on clinical chest X-rays among inpatients and examine the prognostic value of baseline RALE scores on COVID-19 clinical outcomes. SETTING: Hospitalised patients with COVID-19 in dedicated wards and intensive care units from two different hospital systems. PARTICIPANTS: 425 patients with COVID-19 in a discovery data set and 415 patients in a validation data set. PRIMARY AND SECONDARY OUTCOMES: We measured inter-rater reliability for RALE score annotations by different reviewers and examined for associations of consensus RALE scores with the level of respiratory support, demographics, physiologic variables, applied therapies, plasma host-response biomarkers, SARS-CoV-2 RNA load and clinical outcomes. RESULTS: Inter-rater agreement for RALE scores improved from fair to excellent following reviewer training and feedback (intraclass correlation coefficient of 0.85 vs 0.93, respectively). In the discovery cohort, the required level of respiratory support at the time of CXR acquisition (supplemental oxygen or non-invasive ventilation (n=178); invasive-mechanical ventilation (n=234), extracorporeal membrane oxygenation (n=13)) was significantly associated with RALE scores (median (IQR): 20.0 (14.1-26.7), 26.0 (20.5-34.0) and 44.5 (34.5-48.0), respectively, p<0.0001). Among invasively ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, soluble receptor of advanced glycation end-products and soluble tumour necrosis factor receptor 1 (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted HR 1.04 (1.02-1.07), p=0.002). We replicated the significant associations of RALE scores with baseline disease severity and mortality in the independent validation data set. CONCLUSIONS: With a reproducible method to measure radiographic severity in COVID-19, we found significant associations with clinical and physiologic severity, host inflammation and clinical outcomes. The incorporation of radiographic severity assessments in clinical decision-making may provide important guidance for prognostication and treatment allocation in COVID-19.

Self-Management Programs for Chronic Non-Cancer Pain: A Rapid Review of Randomized Trials.

BACKGROUND: The body of evidence regarding self-management programs (SMPs) for adult chronic non-cancer pain (CNCP) is steadily growing, and regular updates are needed for effective decision-making. OBJECTIVES: To systematically identify, critically appraise, and summarize the findings from randomized controlled trials (RCTs) of SMPs for CNCP. METHODS: We searched relevant databases from 2009 to August 2021 and included English-language RCT publications of SMPs compared with usual care for CNCP among adults (18+ years old). The primary outcome was health-related quality of life (HR-QoL). We conducted meta-analysis using an inverse variance, random-effects model and calculated the standardized mean difference (SMD) and associated 95% confidence interval (CI) and statistical heterogeneity using the I2 statistic. RESULTS: From 8538 citations, we included 28 RCTs with varying patient populations, standards for SMPs, and usual care. No RCTs were classified as having a low risk of bias. There was no evidence of a significant improvement in overall HR-QoL, irrespective of pain type, immediately post-intervention (SMD 0.01, 95%CI -0.21 to 0.24; I2 57%; 11 RCTs; 979 participants), 1-4 months post-intervention (SMD 0.02, 95%CI -0.16 to 0.20; I2 48.7%; 12 RCTs; 1160 participants), and 6-12 months post-intervention (SMD 0.07, 95%CI -0.06 to 0.21; I2 26.1%; 9 RCTs; 1404 participants). Similar findings were made for physical and mental HR-QoL, and for specific QoL assessment scales (e.g., SF-36). CONCLUSIONS: There is a lack of evidence that SMPs are efficacious for CNCP compared with usual care. Standardization of SMPs for CNCP and better planned/conducted RCTs are needed to confirm these conclusions.

Radiographic Assessment of Lung Edema (RALE) Scores are Highly Reproducible and Prognostic of Clinical Outcomes for Inpatients with COVID-19.

INTRODUCTION: Chest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs). METHODS: We performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens. RESULTS: We found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, p<0.0001). Among invasively-ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, sRAGE and TNFR1 levels (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted hazard ratio 1.04[1.02-1.07], p=0.002). We validated significant associations of RALE scores with baseline severity and mortality in an independent dataset of 415 COVID-19 inpatients. CONCLUSION: Reproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

Impact of employing primary healthcare professionals in emergency department triage on patient flow outcomes: a systematic review and meta-analysis.

OBJECTIVES: To identify, critically appraise and summarise evidence on the impact of employing primary healthcare professionals (PHCPs: family physicians/general practitioners (GPs), nurse practitioners (NP) and nurses with increased authority) in the emergency department (ED) triage, on patient flow outcomes. METHODS: We searched Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley) and CINAHL (EBSCO) (inception to January 2020). Our primary outcome was the time to provider initial assessment (PIA). Secondary outcomes included time to triage, proportion of patients leaving without being seen (LWBS), length of stay (ED LOS), proportion of patients leaving against medical advice (LAMA), number of repeat ED visits and patient satisfaction. Two independent reviewers selected studies, extracted data and assessed study quality using the National Institute for Health and Care Excellence quality assessment tool. RESULTS: From 23 973 records, 40 comparative studies including 10 randomised controlled trials (RCTs) and 13 pre-post studies were included. PHCP interventions were led by NP (n=14), GP (n=3) or nurses with increased authority (n=23) at triage. In all studies, PHCP-led intervention effectiveness was compared with the traditional nurse-led triage model. Median duration of the interventions was 6 months. Study quality was generally low (confounding bias); 7 RCTs were classified as moderate quality. Most studies reported that PHCP-led triage interventions decreased the PIA (13/14), ED LOS (29/30), proportion of patients LWBS (8/10), time to triage (3/3) and repeat ED visits (5/6), and increased the patient satisfaction (8/10). The proportion of patients LAMA did not differ between groups (3/3). Evidence from RCTs (n=8) as well as other study designs showed a significant decrease in ED LOS favouring the PHCP-led interventions. CONCLUSIONS: Overall, PHCP-led triage interventions improved ED patient flow metrics. There was a significant decrease in ED LOS irrespective of the study design, favouring the PHCP-led interventions. Evidence from well-designed high-quality RCTs is required prior to widespread implementation. PROSPERO REGISTRATION NUMBER: CRD42020148053.

A Pilot Double-Blind Placebo-Controlled Randomized Clinical Trial to Investigate the Effects of Early Enteral Nutrients in Sepsis.

Preclinical studies from our laboratory demonstrated therapeutic effects of enteral dextrose administration in the acute phase of sepsis, mediated by the intestine-derived incretin hormone glucose-dependent insulinotropic peptide. The current study investigated the effects of an early enteral dextrose infusion on systemic inflammation and glucose metabolism in critically ill septic patients. DESIGN: Single-center, double-blind, placebo-controlled randomized pilot clinical trial (NCT03454087). SETTING: Tertiary-care medical center in Pittsburgh, PA. PATIENTS: Critically ill adult patients within 48 hours of sepsis diagnosis and with established enteral access. INTERVENTIONS: Participants were randomized 1:1 to receive a continuous water (placebo) or enteral dextrose infusion (50% dextrose; 0.5 g/mL) at 10 mL per hour for 24 hours. MEASUREMENTS AND MAIN RESULTS: We randomized 58 participants between June 2018 and January 2020 (placebo: n = 29, dextrose: n = 29). Protocol adherence was high with similar duration of study infusion in the placebo (median duration, 24 hr [interquartile range, 20.9-24 hr]) and dextrose (23.9 hr [23-24 hr]) groups (p = 0.59). The primary outcome of circulating interleukin-6 at end-infusion did not differ between the dextrose (median, 32 pg/mL [19-79 pg/mL]) and placebo groups (24 pg/mL [9-59 pg/mL]; p = 0.13) with similar results in other measures of the systemic host immune response. Enteral dextrose increased circulating glucose-dependent insulinotropic peptide (76% increase; 95% CI [35-119]; p < 0.01) and insulin (53% [17-88]; p < 0.01) compared with placebo consistent with preclinical studies, but also increased blood glucose during the 24-hour infusion period (153 mg/dL [119-223] vs 116 mg/dL [91-140]; p < 0.01). Occurrence of emesis, ICU and hospital length of stay, and 30-day mortality did not differ between the placebo and enteral dextrose groups. CONCLUSIONS: Early infusion of low-level enteral dextrose in critically ill septic patients increased circulating levels of insulin and the incretin hormone glucose-dependent insulinotropic peptide without decreasing systemic inflammation.

Customized guidance/training improved the psychometric properties of methodologically rigorous risk of bias instruments for non-randomized studies.

OBJECTIVES: To evaluate the impact of guidance and training on the inter-rater reliability (IRR), inter-consensus reliability (ICR) and evaluator burden of the Risk of Bias (RoB) in Non-randomized Studies (NRS) of Interventions (ROBINS-I) tool, and the RoB instrument for NRS of Exposures (ROB-NRSE). STUDY DESIGN AND SETTING: In a before-and-after study, seven reviewers appraised the RoB using ROBINS-I (n = 44) and ROB-NRSE (n = 44), before and after guidance and training. We used Gwet's AC1 statistic to calculate IRR and ICR. RESULTS: After guidance and training, the IRR and ICR of the overall bias domain of ROBINS-I and ROB-NRSE improved significantly; with many individual domains showing either a significant (IRR and ICR of ROB-NRSE; ICR of ROBINS-I), or nonsignificant improvement (IRR of ROBINS-I). Evaluator burden significantly decreased after guidance and training for ROBINS-I, whereas for ROB-NRSE there was a slight nonsignificant increase. CONCLUSION: Overall, there was benefit for guidance and training for both tools. We highly recommend guidance and training to reviewers prior to RoB assessments and that future research investigate aspects of guidance and training that are most effective.

Interventions and strategies involving primary healthcare professionals to manage emergency department overcrowding: a scoping review.

OBJECTIVES: To conduct a scoping review to identify and summarise the existing literature on interventions involving primary healthcare professionals to manage emergency department (ED) overcrowding. DESIGN: A scoping review. DATA SOURCES: A comprehensive database search of Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley) and CINAHL (EBSCO) databases was conducted (inception until January 2020) using peer-reviewed search strategies, complemented by a search of grey literature sources. ELIGIBILITY CRITERIA: Interventions and strategies involving primary healthcare professionals (PHCPs: general practitioners (GPs), nurse practitioners (NPs) or nurses with expanded role) to manage ED overcrowding. METHODS: We engaged and collaborated, with 13 patient partners during the design and conduct stages of this review. We conducted this review using the JBI guidelines. Two reviewers independently selected studies and extracted data. We conducted descriptive analysis of the included studies (frequencies and percentages). RESULTS: From 23 947 records identified, we included 268 studies published between 1981 and 2020. The majority (58%) of studies were conducted in North America and were predominantly cohort studies (42%). The reported interventions were either 'within ED' (48%) interventions (eg, PHCP-led ED triage or fast track) or 'outside ED' interventions (52%) (eg, after-hours GP clinic and GP cooperatives). PHCPs involved in the interventions were: GP (32%), NP (26%), nurses with expanded role (16%) and combinations of the PHCPs (42%). The 'within ED' and 'outside ED' interventions reported outcomes on patient flow and ED utilisation, respectively. CONCLUSIONS: We identified many interventions involving PHCPs that predominantly reported a positive impact on ED utilisation/patient flow metrics. Future research needs to focus on conducting well-designed randomized controlled trials (RCTs) and systematic reviews to evaluate the effectiveness of specific interventions involving PHCPs to critically appraise and summarise evidence on this topic.

Circulating microbial cell-free DNA is associated with inflammatory host-responses in severe pneumonia.

Host inflammatory responses predict worse outcome in severe pneumonia, yet little is known about what drives dysregulated inflammation. We performed metagenomic sequencing of microbial cell-free DNA (mcfDNA) in 83 mechanically ventilated patients (26 culture-positive, 41 culture-negative pneumonia, 16 uninfected controls). Culture-positive patients had higher levels of mcfDNA than those with culture-negative pneumonia and uninfected controls (p<0.005). Plasma levels of inflammatory biomarkers (fractalkine, procalcitonin, pentraxin-3 and suppression of tumorigenicity-2) were independently associated with mcfDNA levels (adjusted p<0.05) among all patients with pneumonia. Such host-microbe interactions in the systemic circulation of patients with severe pneumonia warrant further large-scale clinical and mechanistic investigations.

Endogenous Glucose Production in Critical Illness.

Regulation of endogenous glucose production (EGP) by hormonal, neuronal, and metabolic signaling pathways contributes to the maintenance of euglycemia under normal physiologic conditions. EGP is defined by the generation of glucose from substrates through glycogenolysis and gluconeogenesis, usually in fasted states, for local and systemic use. Abnormal increases in EGP are noted in patients with diabetes mellitus type 2, and elevated EGP may also impact the pathogenesis of nonalcoholic fatty liver disease and congestive heart failure. In this narrative review, we performed a literature search in PubMed to identify recently published English language articles characterizing EGP in critical illness. Evidence from preclinical and clinical studies demonstrates that critical illness can disrupt EGP through multiple mechanisms including increased systemic inflammation, counterregulatory hormone and catecholamine release, alterations in the hypothalamic-pituitary axis, insulin resistance, lactic acidosis, and iatrogenic insults such as vasopressors and glucocorticoids administered as part of clinical care. EGP contributes to hyperglycemia in critical illness when abnormally elevated and to hypoglycemia when abnormally depressed, each of which has been independently associated with increased mortality. Increased EGP may also promote protein catabolism that could worsen critical illness myopathy and impede recovery. Better understanding of the mechanisms and factors contributing to dysregulated EGP in critical illness may help in the development of therapeutic strategies that promote euglycemia, reduce intensive care unit-associated catabolism, and improve patient outcomes.

COVID-19 versus Non-COVID-19 Acute Respiratory Distress Syndrome: Comparison of Demographics, Physiologic Parameters, Inflammatory Biomarkers, and Clinical Outcomes.

Rationale: There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to coronavirus disease (COVID-19).Objectives: To compare key demographic and physiologic parameters, biomarkers, and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia.Methods: We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study and compared them with a historical, pre-COVID-19 cohort of patients with viral ARDS (n = 14), bacterial ARDS (n = 21), and ARDS due to culture-negative pneumonia (n = 30). We recorded clinical demographics; measured respiratory mechanical parameters; collected serial peripheral blood specimens for measurement of plasma interleukin (IL)-6, IL-8, and IL-10; and followed patients prospectively for patient-centered outcomes. We conducted between-group comparisons with nonparametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models.Results: Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared with those with non-COVID-19 ARDS (P < 0.05). Patients with COVID-19 had lower delivered minute ventilation compared with bacterial and culture-negative ARDS (post hoc P < 0.01) but not compared with viral ARDS. We found no differences in static compliance, hypoxemic indices, or carbon dioxide clearance between groups. Patients with COVID-19 had lower IL-6 levels compared with bacterial and culture-negative ARDS at early time points after intubation but no differences in IL-6 levels compared with viral ARDS. Patients with COVID-19 had longer duration of mechanical ventilation but similar 60-day mortality in both unadjusted and adjusted analyses.Conclusions: COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared with bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared with non-COVID-19 ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.

Methodologically rigorous risk of bias tools for nonrandomized studies had low reliability and high evaluator burden.

OBJECTIVE: To assess the real-world interrater reliability (IRR), interconsensus reliability (ICR), and evaluator burden of the Risk of Bias (RoB) in Nonrandomized Studies (NRS) of Interventions (ROBINS-I), and the ROB Instrument for NRS of Exposures (ROB-NRSE) tools. STUDY DESIGN AND SETTING: A six-center cross-sectional study with seven reviewers (2 reviewer pairs) assessing the RoB using ROBINS-I (n = 44 NRS) or ROB-NRSE (n = 44 NRS). We used Gwet's AC1 statistic to calculate the IRR and ICR. To measure the evaluator burden, we assessed the total time taken to apply the tool and reach a consensus. RESULTS: For ROBINS-I, both IRR and ICR for individual domains ranged from poor to substantial agreement. IRR and ICR on overall RoB were poor. The evaluator burden was 48.45 min (95% CI 45.61 to 51.29). For ROB-NRSE, the IRR and ICR for the majority of domains were poor, while the rest ranged from fair to perfect agreement. IRR and ICR on overall RoB were slight and poor, respectively. The evaluator burden was 36.98 min (95% CI 34.80 to 39.16). CONCLUSIONS: We found both tools to have low reliability, although ROBINS-I was slightly higher. Measures to increase agreement between raters (e.g., detailed training, supportive guidance material) may improve reliability and decrease evaluator burden.

Inter-rater reliability and validity of risk of bias instrument for non-randomized studies of exposures: a study protocol.

BACKGROUND: A new tool, "risk of bias (ROB) instrument for non-randomized studies of exposures (ROB-NRSE)," was recently developed. It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability in the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of the new ROB-NRSE tool. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus-evaluator burden). METHODS: Reviewers from four participating centers will apprise the ROB of a sample of NRSE publications using ROB-NRSE tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSE publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet's AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSE publications using both the Newcastle-Ottawa Scale (NOS) and ROB-NRSE tool. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall's tau coefficient. To measure evaluator burden, we will assess the time taken to apply ROB-NRSE tool (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4, to manage and analyze study data, respectively. DISCUSSION: The quality of evidence from systematic reviews that include NRSE depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of ROB-NRSE and how best to use it.

Resveratrol for adults with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic disorder that is characterised by insulin resistance and hyperglycaemia, which over time may give rise to vascular complications. Resveratrol is a plant-derived nutritional supplement shown to have anti-diabetic properties in many animal models. Less evidence is available on its safety and efficacy in the management of T2DM in humans. OBJECTIVES: To assess the efficacy and safety of resveratrol formulations for adults with type 2 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and International Pharmaceutical Abstracts, as well as the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. The date of the last search was December 2018 for all databases. No language restrictions were applied. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing effects of oral resveratrol (any dose or formulation, duration, or frequency of administration) with placebo, no treatment, other anti-diabetic medications, or diet or exercise, in adults with a diagnosis of T2DM. DATA COLLECTION AND ANALYSIS: Two review authors independently identified and included RCTs, assessed risk of bias, and extracted study-level data. Study authors were contacted for any missing information or for clarification of reported data. We assessed studies for certainty of the evidence using the GRADE instrument. MAIN RESULTS: We identified three RCTs with a total of 50 participants. Oral resveratrol not combined with other plant polyphenols was administered at 10 mg, 150 mg, or 1000 mg daily for a period ranging from four weeks to five weeks. The comparator intervention was placebo. Overall, all three included studies had low risk of bias. None of the three included studies reported long-term, patient-relevant outcomes such as all-cause mortality, diabetes-related complications, diabetes-related mortality, health-related quality of life, or socioeconomic effects. All three included studies reported that no adverse events were observed, indicating that no deaths occurred (very low-quality evidence for adverse events, all-cause mortality, and diabetes-related mortality). Resveratrol versus placebo showed neutral effects for glycosylated haemoglobin A1c (HbA1c) levels (mean difference (MD) 0.1%, 95% confidence interval (CI) -0.02 to 0.2; P = 0.09; 2 studies; 31 participants; very low-certainty evidence). Due to the short follow-up period, HbA1c results have to be interpreted cautiously. Similarly, resveratrol versus placebo showed neutral effects for fasting blood glucose levels (MD 2 mg/dL, 95% CI -2 to 7; P = 0.29; 2 studies; 31 participants), and resveratrol versus placebo showed neutral effects for insulin resistance (MD -0.35, 95% CI -0.99 to 0.28; P = 0.27; 2 studies; 36 participants). We found eight ongoing RCTs with approximately 800 participants and two studies awaiting assessment, which, when published, could contribute to the findings of this review. AUTHORS' CONCLUSIONS: Currently, research is insufficient for review authors to evaluate the safety and efficacy of resveratrol supplementation for treatment of adults with T2DM. The limited available research does not provide sufficient evidence to support any effect, beneficial or adverse, of four to five weeks of 10 mg to 1000 mg of resveratrol in adults with T2DM. Adequately powered RCTs reporting patient-relevant outcomes with long-term follow-up periods are needed to further evaluate the efficacy and safety of resveratrol supplementation in the treatment of T2DM.

Inter-rater reliability and concurrent validity of ROBINS-I: protocol for a cross-sectional study.

BACKGROUND: The Cochrane Bias Methods Group recently developed the "Risk of Bias (ROB) in Non-randomized Studies of Interventions" (ROBINS-I) tool to assess ROB for non-randomized studies of interventions (NRSI). It is important to establish consistency in its application and interpretation across review teams. In addition, it is important to understand if specialized training and guidance will improve the reliability of the results of the assessments. Therefore, the objective of this cross-sectional study is to establish the inter-rater reliability (IRR), inter-consensus reliability (ICR), and concurrent validity of ROBINS-I. Furthermore, as this is a relatively new tool, it is important to understand the barriers to using this tool (e.g., time to conduct assessments and reach consensus-evaluator burden). METHODS: Reviewers from four participating centers will appraise the ROB of a sample of NRSI publications using the ROBINS-I tool in two stages. For IRR and ICR, two pairs of reviewers will assess the ROB for each NRSI publication. In the first stage, reviewers will assess the ROB without any formal guidance. In the second stage, reviewers will be provided customized training and guidance. At each stage, each pair of reviewers will resolve conflicts and arrive at a consensus. To calculate the IRR and ICR, we will use Gwet's AC1 statistic. For concurrent validity, reviewers will appraise a sample of NRSI publications using both the New-castle Ottawa Scale (NOS) and ROBINS-I. We will analyze the concordance between the two tools for similar domains and for the overall judgments using Kendall's tau coefficient. To measure the evaluator burden, we will assess the time taken to apply the ROBINS-I (without and with guidance), and the NOS. To assess the impact of customized training and guidance on the evaluator burden, we will use the generalized linear models. We will use Microsoft Excel and SAS 9.4 to manage and analyze study data, respectively. DISCUSSION: The quality of evidence from systematic reviews that include NRS depends partly on the study-level ROB assessments. The findings of this study will contribute to an improved understanding of the ROBINS-I tool and how best to use it.