Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis.

BACKGROUND: Physical exercise is effective in managing Parkinson's disease (PD), but the relative benefit of different exercise types remains unclear. OBJECTIVES: To compare the effects of different types of physical exercise in adults with PD on the severity of motor signs, quality of life (QoL), and the occurrence of adverse events, and to generate a clinically meaningful treatment ranking using network meta-analyses (NMAs). SEARCH METHODS: An experienced information specialist performed a systematic search for relevant articles in CENTRAL, MEDLINE, Embase, and five other databases to 17 May 2021. We also searched trial registries, conference proceedings, and reference lists of identified studies up to this date. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing one type of physical exercise for adults with PD to another type of exercise, a control group, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. A third author was involved in case of disagreements. We categorized the interventions and analyzed their effects on the severity of motor signs, QoL, freezing of gait, and functional mobility and balance up to six weeks after the intervention using NMAs. Two review authors independently assessed the risk of bias using the risk of bias 2 (RoB 2) tool and rated the confidence in the evidence using the CINeMA approach for results on the severity of motor signs and QoL. We consulted a third review author to resolve any disagreements. Due to heterogeneous reporting of adverse events, we summarized safety data narratively and rated our confidence in the evidence using the GRADE approach. MAIN RESULTS: We included 154 RCTs with a total of 7837 participants with mostly mild to moderate disease and no major cognitive impairment. The number of participants per study was small (mean 51, range from 10 to 474). The NMAs on the severity of motor signs and QoL included data from 60 (2721 participants), and 48 (3029 participants) trials, respectively. Eighty-five studies (5192 participants) provided safety data. Here, we present the main results. We observed evidence of beneficial effects for most types of physical exercise included in our review compared to a passive control group. The effects on the severity of motor signs and QoL are expressed as scores on the motor scale of the Unified Parkinson's Disease Rating Scale (UPDRS-M) and the Parkinson's Disease Questionnaire 39 (PDQ-39), respectively. For both scales, higher scores denote higher symptom burden. Therefore, negative estimates reflect improvement (minimum clinically important difference: -2.5 for UPDRS-M and -4.72 for PDQ-39). Severity of motor signs The evidence from the NMA (60 studies; 2721 participants) suggests that dance and gait/balance/functional training probably have a moderate beneficial effect on the severity of motor signs (dance: mean difference (MD) -10.18, 95% confidence interval (CI) -14.87 to -5.36; gait/balance/functional training: MD -7.50, 95% CI -11.39 to -3.48; moderate confidence), and multi-domain training probably has a small beneficial effect on the severity of motor signs (MD -5.90, 95% CI -9.11 to -2.68; moderate confidence). The evidence also suggests that endurance, aqua-based, strength/resistance, and mind-body training might have a small beneficial effect on the severity of motor signs (endurance training: MD -5.76, 95% CI -9.78 to -1.74; aqua-based training: MD -5.09, 95% CI -10.45 to 0.40; strength/resistance training: MD -4.96, 95% CI -9.51 to -0.40; mind-body training: MD -3.62, 95% CI -7.24 to 0.00; low confidence). The evidence is very uncertain about the effects of "Lee Silverman Voice training BIG" (LSVT BIG) and flexibility training on the severity of motor signs (LSVT BIG: MD -6.70, 95% CI -16.48 to 3.08; flexibility training: MD 4.20, 95% CI -1.61 to 9.92; very low confidence). Quality of life The evidence from the NMA (48 studies; 3029 participants) suggests that aqua-based training probably has a large beneficial effect on QoL (MD -15.15, 95% CI -23.43 to -6.87; moderate confidence). The evidence also suggests that mind-body, gait/balance/functional, and multi-domain training and dance might have a small beneficial effect on QoL (mind-body training: MD -7.22, 95% CI -13.57 to -0.70; gait/balance/functional training: MD -6.17, 95% CI -10.75 to -1.59; multi-domain training: MD -5.29, 95% CI -9.51 to -1.06; dance: MD -3.88, 95% CI -10.92 to 3.00; low confidence). The evidence is very uncertain about the effects of gaming, strength/resistance, endurance, and flexibility training on QoL (gaming: MD -8.99, 95% CI -23.43 to 5.46; strength/resistance training: MD -6.70, 95% CI -12.86 to -0.35; endurance training: MD -6.52, 95% CI -13.74 to 0.88; flexibility training: MD 1.94, 95% CI -10.40 to 14.27; very low confidence). Adverse events Only 85 studies (5192 participants) provided some kind of safety data, mostly only for the intervention groups. No adverse events (AEs) occurred in 40 studies and no serious AEs occurred in four studies. AEs occurred in 28 studies. The most frequently reported events were falls (18 studies) and pain (10 studies). The evidence is very uncertain about the effect of physical exercise on the risk of adverse events (very low confidence). Across outcomes, we observed little evidence of differences between exercise types. AUTHORS' CONCLUSIONS: We found evidence of beneficial effects on the severity of motor signs and QoL for most types of physical exercise for people with PD included in this review, but little evidence of differences between these interventions. Thus, our review highlights the importance of physical exercise regarding our primary outcomes severity of motor signs and QoL, while the exact exercise type might be secondary. Notably, this conclusion is consistent with the possibility that specific motor symptoms may be treated most effectively by PD-specific programs. Although the evidence is very uncertain about the effect of exercise on the risk of adverse events, the interventions included in our review were described as relatively safe. Larger, well-conducted studies are needed to increase confidence in the evidence. Additional studies recruiting people with advanced disease severity and cognitive impairment might help extend the generalizability of our findings to a broader range of people with PD.

Can Physical Exercise Be Considered as a Promising Enhancer of Global Cognition in People with Parkinson's Disease? Results of a Systematic Review and Meta-Analysis.

Background: Physical exercise interventions are known to improve quality of life, motor and non-motor symptoms in people with Parkinson's disease (PD). However, systematic reviews and meta-analyses on cognitive outcomes are rare. Objective: To perform a systematic review and meta-analysis of physical exercise intervention effects compared with passive and active control groups (CGs) on global cognition in people with PD. Methods: A literature search was performed for randomized controlled trials (RCTs) on physical exercise interventions in PD using nine databases. We included RCTs reporting global cognition outcomes. A meta-analysis was performed using random-effects models and standardized mean differences (SMDs) with 95% confidence intervals (CIs). Bias was assessed with the revised Cochrane Risk of Bias tool and the certainty of evidence was rated using the GRADE approach. Results: Seventeen studies (ten with passive, seven with active CGs) were included in the systematic review. Exercise interventions varied considerably between studies. The meta-analysis included nine studies with 236 people with PD (seven with passive, two with active CGs). The SMD was 0.33 (95% CI 0.00; 0.65) demonstrating a small effect (p = 0.05) in favor of physical exercise. Compared with passive CGs, physical exercise had a small non-significant effect (SMD = 0.22, 95% CI -0.14;0.58, p = 0.24). Compared with active CGs, physical exercise had a medium significant effect (SMD = 0.72, 95% CI 0.12;1.33, p = 0.02). Conclusions: Physical exercise may increase global cognition in people with PD, but the evidence is very uncertain. Further large-scale RCTs are needed to confirm this finding and to identify the most effective type of physical exercise for improving cognition.

Patient-reported outcomes in Hodgkin lymphoma trials: a systematic review.

Background: Lymphoma treatment can lead to long-term consequences such as fatigue, infertility and organ damage. In clinical trials, survival outcomes, clinical response and toxicity are extensively reported while the assessment of treatment on quality of life (QoL) and symptoms is often lacking. Objective: We evaluated the use and frequency of patient-reported outcome (PRO) instruments used in randomized controlled trials (RCTs) for Hodgkin lymphoma (HL) and their consistency of reporting. Methods: MEDLINE, CENTRAL and trial registries for RCTs investigating HL were systematically searched from 01/01/2016 to 31/05/2022. Following trial selection, trial, patient characteristics and outcome data on the use of PRO measures (PROMs) and reporting of PROs using a pre-defined extraction form were extracted. To assess reporting consistency, trial registries, protocols and publications were compared. Results: We identified 4,222 records. Following screening, a total of 317 reports were eligible for full-text evaluation. One hundred sixty-six reports of 51 ongoing/completed trials were included, of which 41% of trials were completed and 49% were ongoing based on registry entries. Full-text or abstract were available for 33 trials. Seventy percent of trials were conducted in the newly diagnosed disease setting, the majority with advanced HL. In 32 trials with published follow-up data, the median follow-up was 5.2 years. Eighteen (35%) completed/ongoing trials had mentioned PRO assessment in registry entries, protocol or publications. Twelve trials (67%) had published results and only 6 trials (50%) reported on PROs in part with the exception of 1 trial where PROs were evaluated as secondary/exploratory outcome. The most referenced global PROM was the EORTC-QLQ-C30 (12 studies), the EQ-5D (3 studies) and the FACT-Neurotoxicity (3 studies). FACT-Lymphoma, a disease-specific PROM for non-HL was mentioned in one ongoing trial. None of the trials referenced the EORTC QLQ-HL27, another disease-specific PROM developed specifically for HL patient's QoL assessment. Discussions: Only one-third of RCTs in HL report PROs as an outcome and only half present the outcome in subsequent publications, showcasing the underreporting of PROs in trials. Disease-specific PROMs are underutilized in the assessment of QoL in HL patients. Guidance on the assessment of PROs is needed to inform on comprehensive outcomes important to patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=391552, identifier CRD42023391552.

Higher Risk of Many Physical Health Conditions in Sexual Minority Men: Comprehensive Systematic Review and Meta-Analysis in Gay- and Bisexual-Identified Compared with Heterosexual-Identified Men.

Purpose: The purpose of this study was to provide a systematic review and, where possible, meta-analysis on the prevalence of physical health conditions in sexual minority men (SMM, i.e., gay- and bisexual-identified men) compared with heterosexual-identified men. Methods: A systematic literature search in the databases MEDLINE, Embase, CENTRAL, CINAHL, and Web of Science was conducted on epidemiological studies on physical health conditions, classified in the Global Burden of Disease project and published between 2000 and 2021. Meta-analyses comparing odds ratios were calculated. Results: In total, 23,649 abstracts were screened, and 32 studies were included in the systematic review. Main findings were that (1) Largest differences in prevalence by sexual identity were found for chronic respiratory diseases, particularly asthma: overall, SMM were significantly almost 50% more likely to suffer from asthma than heterosexual men. (2) Evidence of higher prevalence was also found for chronic kidney diseases and headache disorders in gay men and for hepatitis B/C in both gay and bisexual men. (3) We found an overall trend that bisexual men were more affected by some of the physical health conditions compared with gay men (e.g., cardiovascular diseases, asthma). However, regarding cancer, headache disorders, and hepatitis, gay men were more affected. Conclusion: We found evidence of physical health disparities by sexual identity, suggesting more health issues in SMM. Since some of these findings rely on few comparisons or small samples of SMM only, this review is intended to be a vehement plea for routinely including sexual identity assessment in health research and clinical practice.

Comprehensive systematic review and meta-analysis on physical health conditions in lesbian- and bisexual-identified women compared with heterosexual-identified women.

BACKGROUND: Sexual minority individuals experience discrimination, leading to mental health disparities. Physical health disparities have not been examined to the same extent in systematic reviews so far. OBJECTIVES: To provide a systematic review and, where possible, meta-analyses on the prevalence of physical health conditions in sexual minority women (i.e. lesbian- and bisexual-identified women) compared to heterosexual-identified women. DESIGN: The study design is a systematic review with meta-analyses. DATA SOURCES AND METHODS: A systematic literature search in MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science databases was conducted on epidemiologic studies on physical health conditions, classified in the Global Burden of Disease project, published between 2000 and 2021. Meta-analyses pooling odds ratios were calculated. RESULTS: In total, 23,649 abstracts were screened and 44 studies were included in the systematic review. Meta-analyses were run for arthritis, asthma, back pain, cancer, chronic kidney diseases, diabetes, headache disorders, heart attacks, hepatitis, hypertension, and stroke. Most significant differences in prevalence by sexual identity were found for chronic respiratory conditions, especially asthma. Overall, sexual minority women were significantly 1.5-2 times more likely to have asthma than heterosexual women. Furthermore, evidence of higher prevalence in sexual minority compared to heterosexual women was found for back pain, headaches/migraines, hepatitis B/C, periodontitis, urinary tract infections, and acne. In contrast, bisexual women had lower cancer rates. Overall, sexual minority women had lower odds of heart attacks, diabetes, and hypertension than heterosexual women (in terms of diabetes and hypertension possibly due to non-consideration of pregnancy-related conditions). CONCLUSION: We found evidence for physical health disparities by sexual identity. Since some of these findings rely on few comparisons only, this review emphasizes the need for routinely including sexual identity assessment in health research and clinical practice. Providing a more detailed picture of the prevalence of physical health conditions in sexual minority women may ultimately contribute to reducing health disparities.

Interventions for improving health literacy in migrants.

BACKGROUND: Health literacy (HL) is a determinant of health and important for autonomous decision-making. Migrants are at high risk for limited HL. Improving HL is important for equitable promotion of migrants' health. OBJECTIVES: To assess the effectiveness of interventions for improving HL in migrants. To assess whether female or male migrants respond differently to the identified interventions. SEARCH METHODS: We ran electronic searches to 2 February 2022 in CENTRAL, MEDLINE, Embase, PsycInfo and CINAHL. We also searched trial registries. We used a study filter for randomised controlled trials (RCTs) (RCT classifier). SELECTION CRITERIA: We included RCTs and cluster-RCTs addressing HL either as a concept or its components (access, understand, appraise, apply health information). DATA COLLECTION AND ANALYSIS: We used the methodological procedures recommended by Cochrane and followed the PRISMA-E guidelines. Outcome categories were: a) HL, b) quality of life (QoL), c) knowledge, d) health outcomes, e) health behaviour, f) self-efficacy, g) health service use and h) adverse events. We conducted meta-analysis where possible, and reported the remaining results as a narrative synthesis. MAIN RESULTS: We included 28 RCTs and six cluster-RCTs (8249 participants), all conducted in high-income countries. Participants were migrants with a wide range of conditions. All interventions were adapted to culture, language and literacy. We did not find evidence that HL interventions cause harm, but only two studies assessed adverse events (e.g. anxiety). Many studies reported results for short-term assessments (less than six weeks after total programme completion), reported here. For several comparisons, there were also findings at later time points, which are presented in the review text. Compared with no HL intervention (standard care/no intervention) or an unrelated HL intervention (similar intervention but different information topic) Self-management programmes (SMP) probably improve self-efficacy slightly (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.50; 2 studies, 333 participants; moderate certainty). SMP may improve HIV-related HL (understanding (mean difference (MD) 4.25, 95% CI 1.32 to 7.18); recognition of HIV terms (MD 3.32, 95% CI 1.28 to 5.36)) (1 study, 69 participants). SMP may slightly improve health behaviours (3 studies, 514 participants), but may have little or no effect on knowledge (2 studies, 321 participants) or subjective health status (MD 0.38, 95% CI -0.13 to 0.89; 1 study, 69 participants) (low certainty). We are uncertain of the effects of SMP on QoL, health service use or adverse events due to a lack of evidence. HL skills building courses (HLSBC) may improve knowledge (MD 10.87, 95% CI 5.69 to 16.06; 2 studies, 111 participants) and any generic HL (SMD 0.48, 95% CI 0.20 to 0.75; 2 studies, 229 participants), but may have little or no effect on depression literacy (MD 0.17, 95% CI -1.28 to 1.62) or any health behaviour (2 studies, 229 participants) (low certainty). We are uncertain if HLSBC improve QoL, health outcomes, health service use, self-efficacy or adverse events, due to very low-certainty or a lack of evidence. Audio-/visual education without personal feedback (AVE) probably improves depression literacy (MD 8.62, 95% CI 7.51 to 9.73; 1 study, 202 participants) and health service use (MD -0.59, 95% CI -1.11 to -0.07; 1 study, 157 participants), but probably has little or no effect on health behaviour (risk ratio (RR) 1.07, 95% CI 0.91 to 1.25; 1 study, 135 participants) (moderate certainty). AVE may improve self-efficacy (MD 3.51, 95% CI 2.53 to 4.49; 1 study, 133 participants) and may slightly improve knowledge (MD 8.44, 95% CI -2.56 to 19.44; 2 studies, 293 participants) and intention to seek depression treatment (MD 1.8, 95% CI 0.43 to 3.17), with little or no effect on depression (SMD -0.15, 95% CI -0.40 to 0.10) (low certainty). No evidence was found for QoL and adverse events. Adapted medical instruction may improve understanding of health information (3 studies, 478 participants), with little or no effect on medication adherence (MD 0.5, 95% CI -0.1 to 1.1; 1 study, 200 participants) (low certainty). No evidence was found for QoL, health outcomes, knowledge, health service use, self-efficacy or adverse events. Compared with written information on the same topic SMP probably improves health numeracy slightly (MD 0.7, 95% CI 0.15 to 1.25) and probably improves print literacy (MD 9, 95% CI 2.9 to 15.1; 1 study, 209 participants) and self-efficacy (SMD 0.47, 95% CI 0.3 to 0.64; 4 studies, 552 participants) (moderate certainty). SMP may improve any disease-specific HL (SMD 0.67, 95% CI 0.27 to 1.07; 4 studies, 955 participants), knowledge (MD 11.45, 95% CI 4.75 to 18.15; 6 studies, 1101 participants) and some health behaviours (4 studies, 797 participants), with little or no effect on health information appraisal (MD 1.15, 95% CI -0.23 to 2.53; 1 study, 329 participants) (low certainty). We are uncertain whether SMP improves QoL, health outcomes, health service use or adverse events, due to a lack of evidence or low/very low-certainty evidence. AVE probably has little or no effect on diabetes HL (MD 2, 95% CI -0.15 to 4.15; 1 study, 240 participants), but probably improves information appraisal (MD -9.88, 95% CI -12.87 to -6.89) and application (RR 1.51, 95% CI 1.29 to 1.77) (1 study, 608 participants; moderate certainty). AVE may slightly improve knowledge (MD 8.35, 95% CI -0.32 to 17.02; low certainty). No short-term evidence was found for QoL, depression, health behaviour, self-efficacy, health service use or adverse events. AVE compared with another AVE We are uncertain whether narrative videos are superior to factual knowledge videos as the evidence is of very low certainty. Gender differences Female migrants' diabetes HL may improve slightly more than that of males, when receiving AVE (MD 5.00, 95% CI 0.62 to 9.38; 1 study, 118 participants), but we do not know whether female or male migrants benefit differently from other interventions due to very low-certainty or a lack of evidence. AUTHORS' CONCLUSIONS: Adequately powered studies measuring long-term effects (more than six months) of HL interventions in female and male migrants are needed, using well-validated tools and representing various healthcare systems.

Early versus late tracheostomy in critically ill COVID-19 patients.

BACKGROUND: The role of early tracheostomy as an intervention for critically ill COVID-19 patients is unclear. Previous reports have described prolonged intensive care stays and difficulty weaning from mechanical ventilation in critically ill COVID-19 patients, particularly in those developing acute respiratory distress syndrome. Pre-pandemic evidence on the benefits of early tracheostomy is conflicting but suggests shorter hospital stays and lower mortality rates compared to late tracheostomy. OBJECTIVES: To assess the benefits and harms of early tracheostomy compared to late tracheostomy in critically ill COVID-19 patients. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, which comprises CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv, as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 14 June 2022. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) evaluating early tracheostomy compared to late tracheostomy during SARS-CoV-2 infection in critically ill adults irrespective of gender, ethnicity, or setting. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs and the ROBINS-I tool for NRSIs. We used the GRADE approach to assess the certainty of evidence for outcomes of our prioritized categories: mortality, clinical status, and intensive care unit (ICU) length of stay. As the timing of tracheostomy was very heterogeneous among the included studies, we applied GRADE only to studies that defined early tracheostomy as 10 days or less, which was chosen according to clinical relevance. MAIN RESULTS: We included one RCT with 150 participants diagnosed with SARS-CoV-2 infection and 24 NRSIs with 6372 participants diagnosed with SARS-CoV-2 infection. All participants were admitted to the ICU, orally intubated and mechanically ventilated. The RCT was a multicenter, parallel, single-blinded study conducted in Sweden. Of the 24 NRSIs, which were mostly conducted in high- and middle-income countries, eight had a prospective design and 16 a retrospective design. We did not find any ongoing studies. RCT-based evidence We judged risk of bias for the RCT to be of low or some concerns regarding randomization and measurement of the outcome. Early tracheostomy may result in little to no difference in overall mortality (RR 0.82, 95% CI 0.52 to 1.29; RD 67 fewer per 1000, 95% CI 178 fewer to 108 more; 1 study, 150 participants; low-certainty evidence). As an indicator of improvement of clinical status, early tracheostomy may result in little to no difference in duration to liberation from invasive mechanical ventilation (MD 1.50 days fewer, 95%, CI 5.74 days fewer to 2.74 days more; 1 study, 150 participants; low-certainty evidence). As an indicator of worsening clinical status, early tracheostomy may result in little to no difference in the incidence of adverse events of any grade (RR 0.94, 95% CI 0.79 to 1.13; RD 47 fewer per 1000, 95% CI 164 fewer to 102 more; 1 study, 150 participants; low-certainty evidence); little to no difference in the incidence of ventilator-associated pneumonia (RR 1.08, 95% CI 0.23 to 5.20; RD 3 more per 1000, 95% CI 30 fewer to 162 more; 1 study, 150 participants; low-certainty evidence). None of the studies reported need for renal replacement therapy. Early tracheostomy may result in little benefit to no difference in ICU length of stay (MD 0.5 days fewer, 95% CI 5.34 days fewer to 4.34 days more; 1 study, 150 participants; low-certainty evidence). NRSI-based evidence We considered risk of bias for NRSIs to be critical because of possible confounding, study participant enrollment into the studies, intervention classification and potentially systematic errors in the measurement of outcomes. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases overall mortality (RR 1.47, 95% CI 0.43 to 5.00; RD 143 more per 1000, 95% CI 174 less to 1218 more; I2 = 79%; 2 studies, 719 participants) or duration to liberation from mechanical ventilation (MD 1.98 days fewer, 95% CI 0.16 days fewer to 4.12 more; 1 study, 50 participants), because we graded the certainty of evidence as very low. Three NRSIs reported ICU length of stay for 519 patients with early tracheostomy (≤ 10 days) as a median value, which we could not include in the meta-analyses. We are uncertain whether early tracheostomy (≤ 10 days) increases or decreases the ICU length of stay, because we graded the certainty of evidence as very low. AUTHORS' CONCLUSIONS: We found low-certainty evidence that early tracheostomy may result in little to no difference in overall mortality in critically ill COVID-19 patients requiring prolonged mechanical ventilation compared with late tracheostomy. In terms of clinical improvement, early tracheostomy may result in little to no difference in duration to liberation from mechanical ventilation compared with late tracheostomy. We are not certain about the impact of early tracheostomy on clinical worsening in terms of the incidence of adverse events, need for renal replacement therapy, ventilator-associated pneumonia, or the length of stay in the ICU. Future RCTs should provide additional data on the benefits and harms of early tracheostomy for defined main outcomes of COVID-19 research, as well as of comparable diseases, especially for different population subgroups to reduce clinical heterogeneity, and report a longer observation period. Then it would be possible to draw conclusions regarding which patient groups might benefit from early intervention. Furthermore, validated scoring systems for more accurate predictions of the need for prolonged mechanical ventilation should be developed and used in new RCTs to ensure safer indication and patient safety. High-quality (prospectively registered) NRSIs should be conducted in the future to provide valuable answers to clinical questions. This could enable us to draw more reliable conclusions about the potential benefits and harms of early tracheostomy in critically ill COVID-19 patients.

Antiplatelet agents for the treatment of adults with COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) can cause thrombotic events that lead to severe complications or death. Antiplatelet agents, such as acetylsalicylic acid, have been shown to effectively reduce thrombotic events in other diseases: they could influence the course of COVID-19 in general. OBJECTIVES: To assess the efficacy and safety of antiplatelets given with standard care compared to no treatment or standard care (with/without placebo) for adults with COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which comprises MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv, CENTRAL), Web of Science, WHO COVID-19 Global literature on coronavirus disease and the Epistemonikos COVID-19 L*OVE Platform to identify completed and ongoing studies without language restrictions to December 2022. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating antiplatelet agents for the treatment of COVID-19 in adults with COVID-19, irrespective of disease severity, gender or ethnicity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (RoB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the outcomes. MAIN RESULTS: Antiplatelets plus standard care versus standard care (with/without placebo) Adults with a confirmed diagnosis of moderate to severe COVID-19 We included four studies (17,541 participants) that recruited hospitalised people with a confirmed diagnosis of moderate to severe COVID-19. A total of 8964 participants were analysed in the antiplatelet arm (either with cyclooxygenase inhibitors or P2Y12 inhibitors) and 8577 participants in the control arm. Most people were older than 50 years and had comorbidities such as hypertension, lung disease or diabetes. The studies were conducted in high- to lower middle-income countries prior to wide-scale vaccination programmes. Antiplatelets compared to standard care: - probably result in little to no difference in 28-day mortality (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.05; 3 studies, 17,249 participants; moderate-certainty evidence). In absolute terms, this means that for every 177 deaths per 1000 people not receiving antiplatelets, there were 168 deaths per 1000 people who did receive the intervention (95% CI 151 to 186 per 1000 people); - probably result in little to no difference in worsening (new need for invasive mechanical ventilation or death up to day 28) (RR 0.95, 95% CI 0.90 to 1.01; 2 studies, 15,266 participants; moderate-certainty evidence); - probably result in little to no difference in improvement (participants discharged alive up to day 28) (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 15,454 participants; moderate-certainty evidence); - probably result in a slight reduction of thrombotic events at longest follow-up (RR 0.90, 95% CI 0.80 to 1.02; 4 studies, 17,518 participants; moderate-certainty evidence); - may result in a slight increase in serious adverse events at longest follow-up (Peto odds ratio (OR) 1.57, 95% CI 0.48 to 5.14; 1 study, 1815 participants; low-certainty evidence), but non-serious adverse events during study treatment were not reported; - probably increase the occurrence of major bleeding events at longest follow-up (Peto OR 1.68, 95% CI 1.29 to 2.19; 4 studies, 17,527 participants; moderate-certainty evidence). Adults with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included two RCTs allocating participants, of whom 4209 had confirmed mild COVID-19 and were not hospitalised. A total of 2109 participants were analysed in the antiplatelet arm (treated with acetylsalicylic acid) and 2100 participants in the control arm. No study included people with asymptomatic SARS-CoV-2 infection. Antiplatelets compared to standard care: - may result in little to no difference in all-cause mortality at day 45 (Peto OR 1.00, 95% CI 0.45 to 2.22; 2 studies, 4209 participants; low-certainty evidence); - may slightly decrease the incidence of new thrombotic events up to day 45 (Peto OR 0.37, 95% CI 0.09 to 1.46; 2 studies, 4209 participants; low-certainty evidence); - may make little or no difference to the incidence of serious adverse events up to day 45 (Peto OR 1.00, 95% CI 0.60 to 1.64; 1 study, 3881 participants; low-certainty evidence), but non-serious adverse events were not reported. The evidence is very uncertain about the effect of antiplatelets on the following outcomes (compared to standard care plus placebo): - admission to hospital or death up to day 45 (Peto OR 0.79, 95% CI 0.57 to 1.10; 2 studies, 4209 participants; very low-certainty evidence); - major bleeding events up to longest follow-up (no event occurred in 328 participants; very low-certainty evidence). Quality of life and adverse events during study treatment were not reported. AUTHORS' CONCLUSIONS: In people with confirmed or suspected COVID-19 and moderate to severe disease, we found moderate-certainty evidence that antiplatelets probably result in little to no difference in 28-day mortality, clinical worsening or improvement, but probably result in a slight reduction in thrombotic events. They probably increase the occurrence of major bleeding events. Low-certainty evidence suggests that antiplatelets may result in a slight increase in serious adverse events. In people with confirmed COVID-19 and mild symptoms, we found low-certainty evidence that antiplatelets may result in little to no difference in 45-day mortality and serious adverse events, and may slightly reduce thrombotic events. The effects on the combined outcome admission to hospital or death up to day 45 and major bleeding events are very uncertain. Quality of life was not reported. Included studies were conducted in high- to lower middle-income settings using antiplatelets prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, adverse events and people with asymptomatic infection. The 14 ongoing and three completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review.

Physical Exercise as a Potential Treatment for Fatigue in Parkinson's Disease? A Systematic Review and Meta-Analysis of Pharmacological and Non-Pharmacological Interventions.

BACKGROUND: Fatigue is one of the most common and debilitating non-motor symptoms among patients with Parkinson's disease (PD) and significantly impacts quality of life. Therefore, effective treatment options are needed. OBJECTIVE: To provide an update on randomized controlled trials (RCTs) including pharmacological and non-pharmacological (but non-surgical) treatments that examine the effects of fatigue on PD patients. METHODS: We searched the MEDLINE, EMBASE, PsycINFO, CENTRAL, and CINAHL databases for (cross-over) RCTs on pharmacological and non-pharmacological interventions for treating fatigue in PD patients until May 2021. Meta-analyses for random-effects models were calculated when two or more studies on the same treatment option were available using standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: Fourteen pharmacological and 16 non-pharmacological intervention RCTs were identified. For pharmacological approaches, a meta-analysis could only be performed for modafinil compared to placebo (n = 2) revealing a non-significant effect on fatigue (SMD = - 0.21, 95% CI - 0.74-0.31, p = 0.43). Regarding non-pharmacological approaches, physical exercise (n = 8) following different training approaches versus passive or placebo control groups showed a small significant effect (SMD = - 0.37, 95% CI - 0.69- - 0.05, p = 0.02) which could not be demonstrated for acupuncture vs. sham-acupuncture (SMD = 0.16, 95% CI - 0.19-0.50, p = 0.37). CONCLUSION: Physical exercise may be a promising strategy to treat fatigue in PD patients. Further research is required to examine the efficacy of this treatment strategy and further interventions. Future studies should differentiate treatment effects on physical and mental fatigue as the different underlying mechanisms of these symptoms may lead to different treatment responses. More effort is required to develop, evaluate, and implement holistic fatigue management strategies for PD patients.

Meta-epidemiological review identified variable reporting and handling of time-to-event analyses in publications of trials included in meta-analyses of systematic reviews.

OBJECTIVES: Previous findings indicate limited reporting of systematic reviews with meta-analyses of time-to-event (TTE) outcomes. We assessed corresponding available information in trial publications included in such meta-analyses. STUDY DESIGN AND SETTING: We extracted data from all randomized trials in pairwise, hazard ratio (HR)-based meta-analyses of primary outcomes and overall survival of 50 systematic reviews systematically identified from the Cochrane Database and Core Clinical Journals. Data on methods and characteristics relevant for TTE analysis of reviews, trials, and outcomes were extracted. RESULTS: Meta-analyses included 235 trials with 315 trial analyses. Most prominently assessed was overall survival (91%). Definitions (61%), censoring reasons (41%), and follow-up specifications (56%) for trial outcomes were often missing. Available TTE data per trial were most frequently survival curves (83%), log-rank P values (76%), and HRs (72%). When trial TTE data recalculation was reported, reviews mostly specified HRs or P values (each 5%). Reviews primarily included intention-to-treat analyses (64%) and analyses not adjusted for covariates (25%). Except for missing outcome data, TTE-relevant trial characteristics, for example, informative censoring, treatment switching, and proportional hazards, were sporadically addressed in trial publications. Reporting limitations in trial publications translate to the review level. CONCLUSION: TTE (meta)-analyses, in trial and review publications, need clear reporting standards.

First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.

Convalescent plasma for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma may reduce mortality in patients with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of this intervention is required. OBJECTIVES: To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID-19; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at up to day 28, worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID-19 symptoms resolution (for individuals with mild disease), quality of life, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 participants; high-certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS: For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have very-low to low certainty evidence for most primary outcomes and moderate certainty for hospital admission or death. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

The effectiveness of clinical guideline implementation strategies in oncology-a systematic review.

IMPORTANCE: Guideline recommendations do not necessarily translate into changes in clinical practice behaviour or better patient outcomes. OBJECTIVE: This systematic review aims to identify recent clinical guideline implementation strategies in oncology and to determine their effect primarily on patient-relevant outcomes and secondarily on healthcare professionals' adherence. METHODS: A systematic search of five electronic databases (PubMed, Web of Science, GIN, CENTRAL, CINAHL) was conducted on 16 december 2022. Randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) assessing the effectiveness of guideline implementation strategies on patient-relevant outcomes (overall survival, quality of life, adverse events) and healthcare professionals' adherence outcomes (screening, referral, prescribing, attitudes, knowledge) in the oncological setting were targeted. The Cochrane risk-of-bias tool and the ROBINS-I tool were used for assessing the risk of bias. Certainty in the evidence was evaluated according to GRADE recommendations. This review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number CRD42021268593. FINDINGS: Of 1326 records identified, nine studies, five cluster RCTs and four controlled before-and after studies, were included in the narrative synthesis. All nine studies assess the effect of multi-component interventions in 3577 cancer patients and more than 450 oncologists, nurses and medical staff. PATIENT-LEVEL: Educational meetings combined with materials, opinion leaders, audit and feedback, a tailored intervention or academic detailing may have little to no effect on overall survival, quality of life and adverse events of cancer patients compared to no intervention, however, the evidence is either uncertain or very uncertain. PROVIDER-LEVEL: Multi-component interventions may increase or slightly increase guideline adherence regarding screening, referral and prescribing behaviour of healthcare professionals according to guidelines, but the certainty in evidence is low. The interventions may have little to no effect on attitudes and knowledge of healthcare professionals, still, the evidence is very uncertain. CONCLUSIONS AND RELEVANCE: Knowledge and skill accumulation through team-oriented or online educational training and dissemination of materials embedded in multi-component interventions seem to be the most frequently researched guideline implementation strategies in oncology recently. This systematic review provides an overview of recent guideline implementation strategies in oncology, encourages future implementation research in this area and informs policymakers and professional organisations on the development and adoption of implementation strategies.

Effectiveness, Immunogenicity and Harms of Additional SARS-CoV-2 Vaccine Doses in Kidney Transplant Recipients: A Systematic Review.

BACKGROUND: Kidney transplant recipients (KTRs) who have a highly impaired immune response are in need of intensified and safe vaccination strategies to achieve seroconversion and prevent severe disease. METHODS: We searched the Web of Science Core Collection, the Cochrane COVID-19 Study Register and the WHO COVID-19 global literature on coronavirus disease from January 2020 to 22 July 2022 for prospective studies that assessed immunogenicity and efficacy after three or more SARS-CoV-2 vaccine doses. RESULTS: In 37 studies on 3429 patients, de novo seroconversion after three and four vaccine doses ranged from 32 to 60% and 25 to 37%. Variant-specific neutralization was 59 to 70% for Delta and 12 to 52% for Omicron. Severe disease after infection was rarely reported but all concerned KTRs lacked immune responses after vaccination. Studies investigating the clinical course of COVID-19 found remarkably higher rates of severe disease than in the general population. Serious adverse events and acute graft rejections were very rare. Substantial heterogeneity between the studies limited their comparability and summary. CONCLUSION: Additional SARS-CoV-2 vaccine doses are potent and safe in general terms as well as regarding transplant-specific outcomes whilst the Omicron wave remains a significant threat to KTRs without adequate immune responses.

Survival and immunotoxicities in association with sex-specific body composition patterns of cancer patients undergoing immune-checkpoint inhibitor therapy - A systematic review and meta-analysis.

BACKGROUND: Imbalanced body composition is mechanistically connected to dysregulated immune activities. Whether overweight/obesity or sarcopenia has an impact on treatment results in cancer patients undergoing immune checkpoint inhibitor (ICI) therapy is currently under debate. We aimed to answer if survival rates and occurrence of immune-related adverse events (irAEs) were different in obese or sarcopenic patients. METHODS: A systematic search was conducted in PubMed, Embase and CENTRAL for all records published until July 2022 using specific search terms for body composition in combination with terms for ICI regimens. Two authors screened independently. All studies that reported on body mass index or sarcopenia measures were selected for further analysis. RESULTS: 48 studies reporting on overweight/obesity comprising of 19,767 patients, and 32 studies reporting on sarcopenia comprising of 3193 patients fulfilled the inclusion criteria. In the entire cohort, overweight/obesity was significantly associated with better progression-free survival (PFS; p = 0.009) and overall survival (OS; p <0.00001). Subgroup analyses stratified by sex revealed that overweight/obese males had the strongest survival benefit (PFS: p = 0.05; OS: p = 0.0005), and overweight/obese female patients did not show any. However, overweight/obese patients of both sexes had a higher risk to develop irAEs grade ≥3 (p = 0.0009). Sarcopenic patients showed significantly shorter PFS (p <0.0001) and OS (p <0.0001). The frequency of irAEs did not differ between sarcopenic and non-sarcopenic patients. CONCLUSION: This meta-analysis suggests that body composition is associated in a sex-specific manner with survival and irAEs in cancer patients undergoing ICI treatment.

Convalescent plasma for people with COVID-19: a living systematic review.

BACKGROUND: Convalescent plasma may reduce mortality in patients with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of this intervention is required. OBJECTIVES: To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID-19; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at up to day 28, worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID-19 symptoms resolution (for individuals with mild disease), quality of life, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 participants; high-certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS: For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have low certainty evidence for our primary outcomes. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

ANTECEDENTES: El plasma de convaleciente podría reducir la mortalidad en pacientes con enfermedades respiratorias víricas, y se está investigando como posible tratamiento para la enfermedad por coronavirus 2019 (covid­19). Se requiere un profundo conocimiento del conjunto de evidencia actual sobre los beneficios y riesgos de esta intervención. OBJETIVOS: Evaluar la efectividad y seguridad de la transfusión de plasma de convaleciente en el tratamiento de las personas con covid­19; y mantener la vigencia de la evidencia con un enfoque de revisión sistemática continua. MÉTODOS DE BÚSQUEDA: Para identificar estudios en curso y completados, se realizaron búsquedas en la base de datos COVID­19 de la OMS: literatura global sobre la enfermedad por coronavirus, MEDLINE, Embase, el Registro Cochrane de Estudios de covid­19 y la Plataforma COVID­19 L*OVE de Epistemonikos. Se realizaron búsquedas mensuales hasta el 3 de marzo de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados (ECA) que evaluaron el plasma de convaleciente para la covid­19, independientemente de la gravedad de la enfermedad, la edad, el sexo o el origen étnico. Se excluyeron los estudios que incluyeron poblaciones con otras enfermedades por coronavirus, como el síndrome respiratorio agudo grave (SARS) o el síndrome respiratorio de Oriente Medio (MERS), así como los estudios que evaluaron la inmunoglobulina estándar. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se siguió la metodología estándar de Cochrane. Para evaluar el sesgo en los estudios incluidos se utilizó la herramienta RoB 2. Se utilizó el método GRADE para evaluar la certeza de la evidencia para los siguientes desenlaces: mortalidad por todas las causas hasta el día 28, empeoramiento y mejoría del estado clínico (para personas con enfermedad moderada a grave), ingreso hospitalario o muerte, resolución de los síntomas de covid­19 (para personas con enfermedad leve), calidad de vida, eventos adversos de grado 3 o 4 y eventos adversos graves. RESULTADOS PRINCIPALES: En esta cuarta versión actualizada de la revisión se incluyeron 33 ECA con 24 861 participantes, de los cuales 11 432 recibieron plasma de convaleciente. De ellos, 9 estudios son unicéntricos y 24 multicéntricos. Se realizaron 14 estudios en América, 8 en Europa, 3 en el Sudeste Asiático, 2 en África, 2 en el Pacífico occidental, 3 en el Mediterráneo oriental y 1 en varias regiones. Se identificaron otros 49 estudios en curso que evaluaron el plasma de convaleciente, y 33 estudios que informaban de que se habían completado. Personas con un diagnóstico confirmado de covid­19 y enfermedad de moderada a grave El uso de plasma de convaleciente se investigó en 29 ECA con 22 728 participantes con enfermedad moderada a grave. En 23 ECA con 22 020 participantes se comparó el plasma de convaleciente con el placebo o la atención habitual sola, en 5 se comparó con plasma estándar y en 1, con inmunoglobulina humana. Se evalúan subgrupos sobre detección de anticuerpos, aparición de síntomas, grupos de ingresos de países y varias comorbilidades en el texto completo. Plasma de convaleciente versus placebo o atención habitual sola El plasma de convaleciente no reduce la mortalidad por todas las causas hasta el día 28 (razón de riesgos [RR] 0,98; intervalo de confianza [IC] del 95%: 0,92 a 1,03; 220 por cada 1000; 21 ECA, 19 021 participantes; evidencia de certeza alta). Tiene poca o ninguna repercusión en la necesidad de ventilación mecánica invasiva o la muerte (RR 1,03; IC del 95%: 0,97 a 1,11; 296 por cada 1000; seis ECA, 14 477 participantes; evidencia de certeza alta) y no tiene ningún efecto en si los participantes reciben el alta hospitalaria (RR 1,00; IC de 95%: 0,97 a 1,02; 665 por cada 1000; seis ECA, 12 721 participantes; evidencia de certeza alta). El plasma de convaleciente podría tener poca o ninguna repercusión en la calidad de vida (DM 1,00; IC del 95%: ­2,14 a 4,14; un ECA, 483 participantes; evidencia de certeza baja). El plasma de convaleciente podría tener poco o ningún efecto en el riesgo de eventos adversos de grado 3 y 4 (RR 1,17; IC del 95%: 0,96 a 1,42; 212 por cada 1000; seis ECA, 2392 participantes; evidencia de certeza baja). Es probable que tenga poco o ningún efecto sobre el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,91 a 1,44; 135 por cada 1000; seis ECA, 3901 participantes; evidencia de certeza moderada). Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce o aumenta la mortalidad por cualquier causa hasta el día 28 (RR 0,73; IC del 95%: 0,45 a 1,19; 129 por cada 1000; cuatro ECA, 484 participantes; evidencia de certeza muy baja). No se sabe si el plasma de convaleciente reduce o aumenta la necesidad de ventilación mecánica invasiva o la muerte (RR 5,59; IC del 95%: 0,29 a 108,38; 311 por cada 1000; un estudio, 34 participantes; evidencia de certeza muy baja) ni si reduce o aumenta el riesgo de eventos adversos graves (RR 0,80; IC 95%: 0,55 a 1,15; 236 por cada 1000; tres ECA, 327 participantes; evidencia de certeza muy baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus inmunoglobulina humana El plasma de convaleciente podría tener poco o ningún efecto sobre la mortalidad por cualquier causa hasta el día 28 (RR 1,07; IC del 95%: 0,76 a 1,50; 464 por cada 1000; un estudio, 190 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Personas con un diagnóstico confirmado de infección por SARS­CoV­2 y enfermedad leve Se identificaron dos ECA, con 536 participantes, que compararon el plasma de convaleciente con placebo o atención habitual sola y dos ECA, con 1597 participantes con enfermedad leve, que compararon el plasma de convaleciente con plasma estándar. Plasma de convaleciente versus placebo o atención habitual sola No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (odds ratio [OR] 0,36; IC del 95%: 0,09 a 1,46; 8 por cada 1000; dos ECA, 536 participantes; evidencia de certeza muy baja). Podría tener poco o ningún efecto en el ingreso hospitalario o la muerte a los 28 días (RR 1,05; IC del 95%: 0,60 a 1,84; 117 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el tiempo hasta la resolución de los síntomas de covid­19 (cociente de riesgos instantáneos [CRI] 1,05; IC del 95%: 0,85 a 1,30; 483 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja), en el riesgo de eventos adversos de grados 3 y 4 (RR 1,29; IC del 95%: 0,75 a 2,19; 144 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja) y en el riesgo de eventos adversos graves (RR 1,14; IC del 95%: 0,66 a 1,94; 133 por cada 1000; un ECA, 376 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Plasma de convaleciente versus plasma estándar No se sabe si el plasma de convaleciente reduce la mortalidad por cualquier causa hasta el día 28 (OR 0,30; IC del 95%: 0,05 a 1,75; 2 por cada 1000; dos ECA, 1597 participantes; evidencia de certeza muy baja). Es probable que reduzca el ingreso hospitalario o la muerte a los 28 días (RR 0,49; IC del 95%: 0,31 a 0,75; 36 por cada 1000; dos ECA, 1595 participantes; evidencia de certeza moderada). El plasma de convaleciente podría tener poco o ningún efecto sobre la resolución inicial de los síntomas hasta el día 28 (RR 1,12; IC del 95%: 0,98 a 1,27; un ECA, 416 participantes; evidencia de certeza baja). No se identificó ningún estudio que informara sobre otros desenlaces clave. Esta es una revisión sistemática continua. Cada mes se busca nueva evidencia y se actualiza la revisión cuando se identifica evidencia nueva relevante. CONCLUSIONES DE LOS AUTORES: Para la comparación del plasma de convaleciente versus placebo o la atención habitual sola, existe evidencia de certeza alta de que el plasma de convaleciente para personas con enfermedad moderada a grave no reduce la mortalidad y tiene poco o ningún efecto en la mejoría o el empeoramiento clínico. Es probable que tenga poco o ningún efecto en los eventos adversos graves. Para las personas con enfermedad leve, existe evidencia de certeza baja para los desenlaces principales. Hay 49 estudios en curso y 33 estudios que declaran estar completados en un registro de ensayos. La publicación de los estudios en curso podría resolver algunas de las incertidumbres en torno al tratamiento con plasma de convaleciente para personas con enfermedad asintomática o leve.

Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis.

BACKGROUND: Physical exercise is effective in managing Parkinson's disease (PD), but the relative benefit of different exercise types remains unclear. OBJECTIVES: To compare the effects of different types of physical exercise in adults with PD on the severity of motor signs, quality of life (QoL), and the occurrence of adverse events, and to generate a clinically meaningful treatment ranking using network meta-analyses (NMAs). SEARCH METHODS: An experienced information specialist performed a systematic search for relevant articles in CENTRAL, MEDLINE, Embase, and five other databases to 17 May 2021. We also searched trial registries, conference proceedings, and reference lists of identified studies up to this date. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing one type of physical exercise for adults with PD to another type of exercise, a control group, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. A third author was involved in case of disagreements.  We categorized the interventions and analyzed their effects on the severity of motor signs, QoL, freezing of gait, and functional mobility and balance up to six weeks after the intervention using NMAs. Two review authors independently assessed the risk of bias using the risk of bias 2 (RoB 2) tool and rated the confidence in the evidence using the CINeMA approach for results on the severity of motor signs and QoL. We consulted a third review author to resolve any disagreements. Due to heterogeneous reporting of adverse events, we summarized safety data narratively and rated our confidence in the evidence using the GRADE approach. MAIN RESULTS: We included 156 RCTs with a total of 7939 participants with mostly mild to moderate disease and no major cognitive impairment. The number of participants per study was small (mean 51, range from 10 to 474). The NMAs on the severity of motor signs and QoL included data from 71 (3196 participants), and 55 (3283 participants) trials, respectively. Eighty-five studies (5192 participants) provided safety data. Here, we present the main results. We observed evidence of beneficial effects for most types of physical exercise included in our review compared to a passive control group. The effects on the severity of motor signs and QoL are expressed as scores on the motor scale of the Unified Parkinson Disease Rating Scale (UPDRS-M) and the Parkinson's Disease Questionnaire 39 (PDQ-39), respectively. For both scales, higher scores denote higher symptom burden. Therefore, negative estimates reflect improvement (minimum clinically important difference: -2.5 for UPDRS-M and -4.72 for PDQ-39). Severity of motor signs The evidence from the NMA (71 studies; 3196 participants) suggests that dance has a moderate beneficial effect on the severity of motor signs (mean difference (MD) -10.32, 95% confidence interval (CI) -15.54 to -4.96; high confidence), and aqua-based, gait/balance/functional, and multi-domain training might have a moderate beneficial effect on the severity of motor signs (aqua-based: MD -7.77, 95% CI -13.27 to -2.28; gait/balance/functional: MD -7.37, 95% CI -11.39 to -3.35; multi-domain: MD -6.97, 95% CI -10.32 to -3.62; low confidence). The evidence also suggests that mind-body training and endurance training might have a small beneficial effect on the severity of motor signs (mind-body: MD -6.57, 95% CI -10.18 to -2.81; endurance: MD -6.43, 95% CI -10.72 to -2.28; low confidence). Flexibility training might have a trivial or no effect on the severity of motor signs (MD 2.01, 95% CI -4.82 to 8.98; low confidence). The evidence is very uncertain about the effects of strength/resistance training and "Lee Silverman Voice training BIG" (LSVT BIG) on the severity of motor signs (strength/resistance: MD -6.97, 95% CI -11.93 to -2.01; LSVT BIG: MD -5.49, 95% CI -14.74 to 3.62; very low confidence). Quality of life The evidence from the NMA (55 studies; 3283 participants) suggests that aqua-based training probably has a large beneficial effect on QoL (MD -14.98, 95% CI -23.26 to -6.52; moderate confidence). The evidence also suggests that endurance training might have a moderate beneficial effect, and that gait/balance/functional and multi-domain training might have a small beneficial effect on QoL (endurance: MD -9.16, 95% CI -15.68 to -2.82; gait/balance/functional: MD -5.64, 95% CI -10.04 to -1.23; multi-domain: MD -5.29, 95% CI -9.34 to -1.06; low confidence). The evidence is very uncertain about the effects of mind-body training, gaming, strength/resistance training, dance, LSVT BIG, and flexibility training on QoL (mind-body: MD -8.81, 95% CI -14.62 to -3.00; gaming: MD -7.05, 95% CI -18.50 to 4.41; strength/resistance: MD -6.34, 95% CI -12.33 to -0.35; dance: MD -4.05, 95% CI -11.28 to 3.00; LSVT BIG: MD 2.29, 95% CI -16.03 to 20.44; flexibility: MD 1.23, 95% CI -11.45 to 13.92; very low confidence). Adverse events Only 85 studies (5192 participants) provided some kind of safety data, mostly only for the intervention groups. No adverse events (AEs) occurred in 40 studies and no serious AEs occurred in four studies. AEs occurred in 28 studies. The most frequently reported events were falls (18 studies) and pain (10 studies). The evidence is very uncertain about the effect of physical exercise on the risk of adverse events (very low confidence). Across outcomes, we observed little evidence of differences between exercise types. AUTHORS' CONCLUSIONS: We found evidence of beneficial effects on the severity of motor signs and QoL for most types of physical exercise for people with PD included in this review, but little evidence of differences between these interventions. Thus, our review highlights the importance of physical exercise regarding our primary outcomes severity of motor signs and QoL, while the exact exercise type might be secondary. Notably, this conclusion is consistent with the possibility that specific motor symptoms may be treated most effectively by PD-specific programs. Although the evidence is very uncertain about the effect of exercise on the risk of adverse events, the interventions included in our review were described as relatively safe. Larger, well-conducted studies are needed to increase confidence in the evidence. Additional studies recruiting people with advanced disease severity and cognitive impairment might help extend the generalizability of our findings to a broader range of people with PD.

Hyperimmune immunoglobulin for people with COVID-19.

BACKGROUND: Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID-19 and was split to address hIVIG and convalescent plasma separately. OBJECTIVES: To assess the benefits and harms of hIVIG therapy for the treatment of people with COVID-19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Research Database, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated hIVIG for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies that evaluated standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events. MAIN RESULTS: We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco-humanised polyclonal antibody, and 241 received equine-derived processed and purified F(ab')2 fragments. All participants were hospitalised with moderate-to-severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern. There are no data for people with COVID-19 with no symptoms (asymptomatic) or people with mild COVID-19. We identified a further 10 ongoing studies evaluating hIVIG. Benefits of hIVIG prepared from humans We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all-cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low-certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low-certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if hIVIG has any impact on quality of life. Harms of hIVIG prepared from humans hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low-certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3-4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate-certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate-certainty evidence). We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables. Benefits of animal-derived polyclonal antibodies We included data on one RCT (241 participants) to assess the benefits and harms of receptor-binding domain-specific polyclonal F(ab´)2 fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all-cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low-certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low-certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if EpAbs have any impact on quality of life. Harms of animal-derived polyclonal antibodies EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low-certainty evidence). Adverse events at grade 3-4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low-certainty evidence). We also identified additional results on the benefits and harms of other animal-derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables. AUTHORS' CONCLUSIONS: We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate-to-severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3-4 adverse events. Studies did not evaluate quality of life. RBD-specific polyclonal F(ab´)2 fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern and prior to widespread vaccine rollout. As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.

Fluvoxamine for the treatment of COVID-19.

BACKGROUND: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been approved for the treatment of depression, obsessive-compulsive disorder, and a variety of anxiety disorders; it is available as an oral preparation. Fluvoxamine has not been approved for the treatment of infections, but has been used in the early treatment of people with mild to moderate COVID-19. As there are only a few effective therapies for people with COVID-19 in the community, a thorough understanding of the current evidence regarding the efficacy and safety of fluvoxamine as an anti-inflammatory and possible anti-viral treatment for COVID-19, based on randomised controlled trials (RCTs), is needed. OBJECTIVES: To assess the efficacy and safety of fluvoxamine in addition to standard care, compared to standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy for the treatment of COVID-19 outpatients and inpatients. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv), Web of Science and WHO COVID-19 Global literature on COVID-19 to identify completed and ongoing studies up to 1 February 2022. SELECTION CRITERIA: We included RCTs that compared fluvoxamine in addition to standard care (also including no intervention), with standard care (alone or with placebo), or any other active pharmacological comparator with proven efficacy in clinical trials for the treatment of people with confirmed COVID-19, irrespective of disease severity, in both inpatients and outpatients. Co-interventions needed to be the same in both study arms. We excluded studies comparing fluvoxamine to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using the Cochrane Risk of Bias 2 tool for RCTs. We used GRADE to rate the certainty of evidence to treat people with asymptomatic to severe COVID-19 for the primary outcomes including mortality, clinical deterioration, clinical improvement, quality of life, serious adverse events, adverse events of any grade, and suicide or suicide attempt. MAIN RESULTS: We identified two completed studies with a total of 1649 symptomatic participants. One study was conducted in the USA (study with 152 participants, 80 and 72 participants per study arm) and the other study in Brazil (study with 1497 high-risk participants for progression to severe disease, 741 and 756 participants per study arm) among outpatients with mild COVID-19. Both studies were double-blind, placebo-controlled trials in which participants were prescribed 100 mg fluvoxamine two or three times daily for a maximum of 15 days. We identified five ongoing studies and two studies awaiting classification (due to translation issues, and due to missing published data). We found no published studies comparing fluvoxamine to other pharmacological interventions of proven efficacy. We assessed both included studies to have an overall high risk of bias. Fluvoxamine for the treatment of COVID-19 in inpatients We did not identify any completed studies of inpatients. Fluvoxamine for the treatment of COVID-19 in outpatients Fluvoxamine in addition to standard care may slightly reduce all-cause mortality at day 28 (RR 0.69, 95% CI 0.38 to 1.27; risk difference (RD) 9 per 1000; 2 studies, 1649 participants; low-certainty evidence), and may reduce clinical deterioration defined as all-cause hospital admission or death before hospital admission (RR 0.55, 95% CI 0.16 to 1.89; RD 57 per 1000; 2 studies, 1649 participants; low-certainty evidence). We are very uncertain regarding the effect of fluvoxamine on serious adverse events (RR 0.56, 95% CI 0.15 to 2.03; RD 54 per 1000; 2 studies, 1649 participants; very low-certainty evidence) or adverse events of any grade (RR 1.06, 95% CI 0.82 to 1.37; RD 7 per 1000; 2 studies, 1649 participants; very low-certainty evidence). Neither of the studies reported on symptom resolution (clinical improvement), quality of life or suicide/suicide attempt. AUTHORS' CONCLUSIONS: Based on a low-certainty evidence, fluvoxamine may slightly reduce all-cause mortality at day 28, and may reduce the risk of admission to hospital or death in outpatients with mild COVID-19. However, we are very uncertain regarding the effect of fluvoxamine on serious adverse events, or any adverse events. In accordance with the living approach of this review, we will continually update our search and include eligible trials as they arise, to complete any gaps in the evidence.

Interventions to increase COVID-19 vaccine uptake: a scoping review.

BACKGROUND: Vaccines are effective in preventing severe COVID-19, a disease for which few treatments are available and which can lead to disability or death. Widespread vaccination against COVID-19 may help protect those not yet able to get vaccinated. In addition, new and vaccine-resistant mutations of SARS-CoV-2 may be less likely to develop if the spread of COVID-19 is limited. Different vaccines are now widely available in many settings. However, vaccine hesitancy is a serious threat to the goal of nationwide vaccination in many countries and poses a substantial threat to population health. This scoping review maps interventions aimed at increasing COVID-19 vaccine uptake and decreasing COVID-19 vaccine hesitancy. OBJECTIVES: To scope the existing research landscape on interventions to enhance the willingness of different populations to be vaccinated against COVID-19, increase COVID-19 vaccine uptake, or decrease COVID-19 vaccine hesitancy, and to map the evidence according to addressed populations and intervention categories. SEARCH METHODS: We searched Cochrane COVID-19 Study Register, Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index), WHO COVID-19 Global literature on coronavirus disease, PsycINFO, and CINAHL to 11 October 2021. SELECTION CRITERIA: We included studies that assess the impact of interventions implemented to enhance the willingness of different populations to be vaccinated against COVID-19, increase vaccine uptake, or decrease COVID-19 vaccine hesitancy. We included randomised controlled trials (RCTs), non-randomised studies of intervention (NRSIs), observational studies and case studies with more than 100 participants. Furthermore, we included systematic reviews and meta-analyses. We did not limit the scope of the review to a specific population or to specific outcomes assessed. We excluded interventions addressing hesitancy towards vaccines for diseases other than COVID-19. DATA COLLECTION AND ANALYSIS: Data were analysed according to a protocol uploaded to the Open Science Framework. We used an interactive scoping map to visualise the results of our scoping review. We mapped the identified interventions according to pre-specified intervention categories, that were adapted to better fit the evidence. The intervention categories were: communication interventions, policy interventions, educational interventions, incentives (both financial and non-financial), interventions to improve access, and multidimensional interventions. The study outcomes were also included in the mapping. Furthermore, we mapped the country in which the study was conducted, the addressed population, and whether the design was randomised-controlled or not. MAIN RESULTS: We included 96 studies in the scoping review, 35 of which are ongoing and 61 studies with published results. We did not identify any relevant systematic reviews. For an overview, please see the interactive scoping map (https://tinyurl.com/2p9jmx24) STUDIES WITH PUBLISHED RESULTS Of the 61 studies with published results, 46 studies were RCTs and 15 NRSIs. The interventions investigated in the studies were heterogeneous with most studies testing communication strategies to enhance COVID-19 vaccine uptake. Most studies assessed the willingness to get vaccinated as an outcome. The majority of studies were conducted in English-speaking high-income countries. Moreover, most studies investigated digital interventions in an online setting. Populations that were addressed were diverse. For example, studies targeted healthcare workers, ethnic minorities in the USA, students, soldiers, at-risk patients, or the general population.  ONGOING STUDIES Of the 35 ongoing studies, 29 studies are RCTs and six NRSIs. Educational and communication interventions were the most used types of interventions. The majority of ongoing studies plan to assess vaccine uptake as an outcome. Again, the majority of studies are being conducted in English-speaking high-income countries. In contrast to the studies with published results, most ongoing studies will not be conducted online. Addressed populations range from minority populations in the USA to healthcare workers or students. Eleven ongoing studies have estimated completion dates in 2022.   AUTHORS' CONCLUSIONS: We were able to identify and map a variety of heterogeneous interventions for increasing COVID-19 vaccine uptake or decreasing vaccine hesitancy. Our results demonstrate that this is an active field of research with 61 published studies and 35 studies still ongoing. This review gives a comprehensive overview of interventions to increase COVID-19 vaccine uptake and can be the foundation for subsequent systematic reviews on the effectiveness of interventions to increase COVID-19 vaccine uptake.  A research gap was shown for studies conducted in low and middle-income countries and studies investigating policy interventions and improved access, as well as for interventions addressing children and adolescents. As COVID-19 vaccines become more widely available, these populations and interventions should not be neglected in research. AUTHORS CONCLUSIONS: We were able to identify and map a variety of heterogeneous interventions for increasing COVID-19 vaccine uptake or decreasing vaccine hesitancy. Our results demonstrate that this is an active field of research with 61 published studies and 35 studies still ongoing. This review gives a comprehensive overview of interventions to increase COVID-19 vaccine uptake and can be the foundation for subsequent systematic reviews on the effectiveness of interventions to increase COVID-19 vaccine uptake.  A research gap was shown for studies conducted in low and middle-income countries and studies investigating policy interventions and improved access, as well as for interventions addressing children and adolescents. As COVID-19 vaccines become more widely available, these populations and interventions should not be neglected in research.