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Alison Dillman,1 Michael J Zoratti,2 Jay JH Park,3 Grace Hsu,2 Louis Dron,2 Gerald Smith,2 Ofir Harari,2 Craig R Rayner,4 Noor-E Zannat,2 Alind Gupta,2 Eric Mackay,5 Paul Arora,6 Zelyn Lee,7 Edward J Mills2 1School of Public Health, Faculty of Medicine, Imperial College London, London, England; 2Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; 3Department of Experimental Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 4Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia; 5Department of Statistical Sciences, University of Toronto, Toronto, Canada; 6Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; 7Department of Physiology & Department of Neuroscience, University of Toronto, Toronto, CanadaCorrespondence: Jay JH Park Tel +1 604 294-3823Email jayhpark1@alumni.ubc.caPurpose: A multitude of randomized controlled trials (RCTs) have emerged in response to the novel coronavirus disease (COVID-19) pandemic. Understanding the distribution of trials among various settings is important to guide future research priorities and efforts. The purpose of this review was to describe the emerging evidence base of COVID-19 RCTs by stages of disease progression, from pre-exposure to hospitalization.Methods: We collated trial data across international registries: ClinicalTrials.gov; International Standard Randomised Controlled Trial Number Registry; Chinese Clinical Trial Registry; Clinical Research Information Service; EU Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; German Clinical Trials Register (up to 7 October 2020). Active COVID-19 RCTs in international registries were eligible for inclusion. We extracted trial status, intervention(s), control, sample size, and clinical context to generate descriptive frequencies, network diagram illustrations, and statistical analyses including odds ratios and the Mann–Whitney U-test.Results: Our search identified 11503 clinical trials registered for COVID-19 and identified 2388 RCTs. After excluding 45 suspended RCTs and 480 trials with unclear or unreported disease stages, 1863 active RCTs were included and categorized into four broad disease stages: pre-exposure (n=107); post-exposure (n=208); outpatient treatment (n=266); hospitalization, including the intensive care unit (n=1376). Across all disease stages, most trials had two arms (n=1500/1863, 80.52%), most often included (hydroxy)chloroquine (n=271/1863, 14.55%) and were US-based (n=408/1863, 21.90%). US-based trials had lower odds of including (hydroxy)chloroquine than trials in other countries (OR: 0.63, 95% CI: 0.45– 0.90) and similar odds of having two arms compared to other geographic regions (OR: 1.05, 95% CI: 0.80– 1.38).Conclusion: There is a marked difference in the number of trials across settings, with limited studies on non-hospitalized persons. Focus on pre- and post-exposure, and outpatients, is worthwhile as a means of reducing infections and lessening the health, social, and economic burden of COVID-19.Keywords: COVID-19, novel coronavirus 2019, systematic review, randomized controlled trials

Introduction: Frailty is in an increasing focus for acute care systems due to its association with adverse health outcomes. The Clinical Frailty Scale (CFS) is a judgement-based frailty assessment tool, which classifies the frailty status of older adults, but more research involving general medicine inpatients is necessary. The objectives of this study were to describe the predictive ability of CFS, administered by geriatric medicine trained nurses, for adverse outcomes including the following: acute unit and total length of stay (LOS), new nursing home (NH) admission, 12-month mortality and readmission within 30-day., Methods: Design Retrospective study. Participants Patients admitted under general medicine unit and seen by the geriatric medicine liaison team in one general hospital. Main Measure CFS., Results: Of 394 patients included, 60% were mild-moderately frail, and 21% severely frail. In a multivariable analysis, patients classified as severely frail (CFS 7-9) had significantly high odds of death during admission (OR = 13.64), new NH admission (OR = 34.97) and acute LOS (OR = 1.74), compared to non-frail patients (CFS1-4). Mild-moderately frail (CFS 5-6) patients had significantly higher odds for new NH admission (OR = 4.36), acute unit LOS (OR = 1.49) and total LOS (OR = 1.61) compared to non-frail patients. In a Cox regression multivariable survival analysis, the severely frail had a sixfold significantly higher likelihood (HR = 6.19) of 12-month mortality, and the mild-moderately frail had a doubled likelihood (HR = 2.13), compared to the non-frail., Conclusions: The CFS has clinical utility for identifying general medicine older inpatients at-risk of various adverse outcomes., (© 2024 The Author(s). Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Background: Axial spondyloarthritis (axSpA) can limit work participation. Our objective was to characterise productivity in patients with axSpA, including changes after 12-16 weeks of treatment with biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs)., Methods: A systematic literature review identified studies published from 1 January 2010 to 21 October 2021 reporting work productivity using the Work Productivity and Activity Impairment (WPAI) questionnaire in patients with axSpA initiating b/tsDMARDs. Baseline and Week 12-16 overall work productivity, absenteeism, presenteeism and activity impairment scores were used in a random-effects meta-analysis to calculate absolute mean change from baseline for each WPAI-domain., Results: Eleven studies in patients with axSpA who received either placebo (n=727) or treatment with adalimumab, bimekizumab, etanercept, ixekizumab, secukinumab or tofacitinib (n=994) were included. In working patients initiating a b/tsDMARD, mean baseline overall work productivity impairment, absenteeism and presenteeism scores were 52.1% (N=7 studies), 11.0% and 48.8% (N=6 studies), respectively. At Week 12-16, the pooled mean change from baseline in overall work impairment for b/tsDMARDs or placebo was -21.6% and -12.3%. When results were extrapolated to 1 year, the potential annual reductions in cost of paid and unpaid productivity loss per patient ranged from €11 962.88 to €14 293.54., Conclusions: Over 50% of employed patients with active axSpA experienced work impairment, primarily due to presenteeism. Overall work productivity improved at Weeks 12-16 to a greater extent for patients who received b/tsDMARDs than placebo. Work productivity loss was associated with a substantial cost burden, which was reduced with improvements in impairment., Competing Interests: Competing interests: MR: Consultant to UCB Pharma; Speakers bureau from AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, Pfizer and UCB Pharma; consultant of AbbVie, Eli Lilly, Novartis and UCB Pharma. MFM: Employee of UCB Pharma. DW and VT: Employees and stockholders of UCB Pharma. BH and N-EZ: Employees of Cytel, which served as a consultant on the project (at the time of research). AB: Received departmental research grants from AbbVie and consulting fees or honorarium from Galapagos, Hy2Care and Novartis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The novel coronavirus 2019 (COVID-19) pandemic has mobilized global research at an unprecedented scale. While challenges associated with the COVID-19 trial landscape have been discussed previously, no comprehensive reviews have been conducted to assess the reporting, design, and data sharing practices of randomized controlled trials (RCTs)., Purpose: The purpose of this review was to gain insight into the current landscape of reporting, methodological design, and data sharing practices for COVID-19 RCTs., Data Sources: We conducted three searches to identify registered clinical trials, peer-reviewed publications, and pre-print publications., Study Selection: After screening eight major trial registries and 7844 records, we identified 178 registered trials and 38 publications describing 35 trials, including 25 peer-reviewed publications and 13 pre-prints., Data Extraction: Trial ID, registry, location, population, intervention, control, study design, recruitment target, actual recruitment, outcomes, data sharing statement, and time of data sharing were extracted., Data Synthesis: Of 178 registered trials, 112 (62.92%) were in hospital settings, median planned recruitment was 100 participants (IQR: 60, 168), and the majority (n = 166, 93.26%) did not report results in their respective registries. Of 35 published trials, 31 (88.57%) were in hospital settings, median actual recruitment was 86 participants (IQR: 55.5, 218), 10 (28.57%) did not reach recruitment targets, and 27 trials (77.14%) reported plans to share data., Conclusions: The findings of our study highlight limitations in the design and reporting practices of COVID-19 RCTs and provide guidance towards more efficient reporting of trial results, greater diversity in patient settings, and more robust data sharing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) is critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness are currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child's linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th , 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care.   Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Improving the health of pregnant women is important to prevent adverse birth outcomes, such as preterm birth and low birthweight. We evaluated the comparative effectiveness of interventions under the domains of micronutrient, balanced energy protein, deworming, maternal education, and water sanitation and hygiene (WASH) for their effects on these adverse birth outcomes. Methods: For this network meta-analysis, we searched for randomized clinical trials (RCTs) of interventions provided to pregnant women in low- and middle-income countries (LMICs). We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We extracted data from eligible studies for study characteristics, interventions, participants' characteristics at baseline, and birth outcomes. We compared effects on preterm birth (<37 gestational week), low birthweight (LBW; <2500 g), and birthweight (continuous) using studies conducted in LMICs. Results: Our network meta-analyses were based on 101 RCTs (132 papers) pertaining to 206,531 participants. Several micronutrients and balanced energy food supplement interventions demonstrated effectiveness over standard-of-care. For instance, versus standard-of-care, micronutrient supplements for pregnant women, such as iron and calcium, decreased risks of preterm birth (iron: RR=0.70, 95% credible interval [Crl] 0.47, 1.01; calcium: RR=0.76, 95%Crl 0.56, 0.99). Daily intake of 1500kcal of local food decreased the risks of preterm birth (RR=0.36, 95%Crl 0.16, 0.77) and LBW (RR=0.17, 95%Crl 0.09, 0.29), respectively when compared to standard-of-care. Educational and deworming interventions did not show improvements in birth outcomes, and no WASH intervention trials reported on these adverse birth outcomes. Conclusion: We found several pregnancy interventions that improve birth outcomes. However, most clinical trials have only evaluated interventions under a single domain (e.g. micronutrients) even though the causes of adverse birth outcomes are multi-faceted. There is a need to combine interventions that of different domains as packages and test for their effectiveness. Registration: PROSPERO CRD42018110446; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child's linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th , 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care.   Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)

Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) are critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness is currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)

Background: Improving the health of pregnant women is important to prevent adverse birth outcomes, such as preterm birth and low birthweight. We evaluated the comparative effectiveness of interventions under the domains of micronutrient, balanced energy protein, deworming, maternal education, and water sanitation and hygiene (WASH) for their effects on these adverse birth outcomes. Methods: For this network meta-analysis, we searched for randomized clinical trials (RCTs) of interventions provided to pregnant women in low- and middle-income countries (LMICs). We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We extracted data from eligible studies for study characteristics, interventions, participants' characteristics at baseline, and birth outcomes. We compared effects on preterm birth (<37 gestational week), low birthweight (LBW; <2500 g), and birthweight (continuous) using studies conducted in LMICs. Results: Our network meta-analyses were based on 101 RCTs (132 papers) pertaining to 206,531 participants. Several micronutrients and balanced energy food supplement interventions demonstrated effectiveness over standard-of-care. For instance, versus standard-of-care, micronutrient supplements for pregnant women, such as iron and calcium, decreased risks of preterm birth (iron: RR=0.70, 95% credible interval [Crl] 0.47, 1.01; calcium: RR=0.76, 95%Crl 0.56, 0.99). Daily intake of 1500kcal of local food decreased the risks of preterm birth (RR=0.36, 95%Crl 0.16, 0.77) and LBW (RR=0.17, 95%Crl 0.09, 0.29), respectively when compared to standard-of-care. Educational and deworming interventions did not show improvements in birth outcomes, and no WASH intervention trials reported on these adverse birth outcomes. Conclusion: We found several pregnancy interventions that improve birth outcomes. However, most clinical trials have only evaluated interventions under a single domain (e.g. micronutrients) even though the causes of adverse birth outcomes are multi-faceted. There is a need to combine interventions that of different domains as packages and test for their effectiveness. Registration: PROSPERO CRD42018110446; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)