Effect of BCG Vaccination against SARS-CoV-2 Infection

Very low-certainty evidence suggested that it is unclear whether gluten intake is associated with all-cause mortality. Our findings also indicate that low-certainty evidence may show little or no association between gluten intake and cardiovascular mortality and non-fatal myocardial infarction. Low-certainty evidence suggested that a lower compared with a higher gluten intake may be associated with a slightly increased risk to develop type 2 diabetes - a major cardiovascular risk factor. For other cardiovascular risk factors it is unclear whether there is a difference between a gluten-free and normal diet. Given the limited findings from this review predominantly based on observational studies, no recommendations for practice can be made.

Introduction: The Risk Of Bias in Non-randomized Studies – of Interventions (ROBINS-I) tool evaluates internal validity (risk of bias) in non-randomized studies of interventions in comparison to an ideal (hypothetical) randomized trial. The use of ROBINS-I in studies dealing with exposures or interventions in environmental health has not yet been explored. This study evaluated the usability and applicability of ROBINS-I in studies of environmental health (EH) exposure. Methods: Three researchers in sequential rounds applied ROBINS-I to three systematic reviews of EH exposures: bisphenol-A and obesity; perfluorooctanoic acid and birth weight; and polybrominated diphenyl ethers and thyroid function. We began by providing instructions for application of ROBINS-I to EH studies, including possible confounders and co-exposures specific to the exposures considered in the three reviews. For the first two rounds of testing, two reviewers independently applied ROBINS-I and provided feedback on usability of the tool. Barriers and facilitators to the appropriateness of ROBINS-I for environmental health were identified and modifications made to the tool, as necessary. For the third round of testing, three reviewers independently applied the tool and came to consensus on item-level and overall study risk of bias. Results: Suggested modifications ranged from syntax and wording to conceptual changes to the tool. The term "intervention" was replaced with "exposure" throughout the document. Additional instructions were provided to address assessment of cross-sectional studies. Fields to collect information on measurement of exposures and outcomes of interest was added to the project protocol. Additional granularity was added to the measurement of interventions/exposure domain. Conclusion: Modifications made to the risk of bias tool to tailor it to studies of EH exposure increased understanding and application of the tool, as well as consistency in responses.

BackgroundPostpartum fatigue is the most common issue among postnatal women and it could not only seriously affect the health of mothers but also bring about adverse impacts on their offspring. This meta-analysis aims to synthesize nonpharmacological evidence and evaluate the effectiveness of interventions for reducing postpartum fatigue among puerperae.MethodsThe Cochrane Library, PubMed, Embase, Web of Science, PsycINFO, CINAHL and ProQuest databases were searched for papers published from inception until June 2021. Grey literature was searched using OpenGrey. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) evaluating nonpharmacological interventions conducted during 0 ~ 78 weeks postpartum for fatigue reduction were eligible for inclusion. The methodological quality of the included studies was independently assessed by two reviewers using the Cochrane risk-of-bias tool and the risk of bias in nonrandomized studies of interventions. Cohen’s kappa coefficient was used to measure inter-rater agreement. The meta-analysis was conducted using Review Manager 5.3.ResultsSeventeen published clinical trials matched the eligibility criteria and ten studies involving 1194 participants were included in this meta-analysis. The intervention start time varied from immediately postpartum care to 1 year after delivery, and duration ranged from 1 day to 3 months. The results revealed that exercise (SMD = − 1.74, 95% CI = -2.61 to − 0.88) and drinking tea (MD = − 3.12, 95% CI = -5.44 to − 0.80) resulted in significant improvements in women’s postpartum fatigue at postintervention. Drinking tea may have beneficial effects on depression (MD = − 2.89, 95% CI = -4.30 to − 1.49). Positive effects of psychoeducational interventions on postpartum fatigue or depression were not observed. Physical therapies including mother-infant skin-to-skin contact, taking warm showers and breathing lavender oil aroma were used for reducing postpartum fatigue. No significant risk of publication bias was found. Small number of included studies and sample sizes, not time-matched conditions of control groups, high heterogeneity and the risk of bias within the included studies were the main limitations of our review.ConclusionsThis review provides evidence that exercise and drinking tea may be effective nonpharmacological interventions for relieving postpartum fatigue. More effective and targeted exercise programs need to be further studied. Rigorous RCTs of drinking tea are needed. Caution is required when interpreting the findings due to the limitations of our study. Further studies are still needed to validate our findings and increase confidence in the results.

Analysis of the effectiveness of the fiber-reinforced composite lingual retainer: A systematic review and meta-analysis

We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformations syndrome caused by defective cholesterol biosynthesis. Affected individuals show cholesterol deficiency and accumulation of various precursor molecules, mainly 7-dehydrocholesterol and 8-dehydrocholesterol. There is currently no cure for SLOS, with cholesterol supplementation being primarily a biochemical therapy of limited evidence. However, several anecdotal reports and preclinical studies have highlighted statins as a potential therapy for SLOS. To evaluate the effects of statins, either alone or in combination with other non-statin therapies (e.g. cholesterol, bile acid, or vitamin co-supplementation), compared to cholesterol supplementation alone or in combination with other non-statin therapies (e.g. bile acid or vitamin supplementation) on several important outcomes including overall survival, neurobehavioral features, and adverse effects in individuals with SLOS. We searched CENTRAL, MEDLINE, Embase, five other databases and three trials registers on 15 February 2022, together with reference checking, citation searching and contact with study authors to identify additional studies. Randomized controlled trials (RCTs) and quasi-RCTs with parallel or cross-over designs, and non-randomized studies of interventions (NRSIs) including non-randomized trials, cohort studies, and controlled before-and-after studies, were eligible for inclusion in this review if they met our prespecified inclusion criteria, i.e. involved human participants with biochemically or genetically diagnosed SLOS receiving statin therapy or cholesterol supplementation, or both. Two authors screened titles and abstracts and subsequently full-texts for all potentially-relevant references. Both authors independently extracted relevant data from included studies and assessed the risks of bias. We analyzed the data extracted from the included NRSIs and cohort studies separately from the data extracted from the single included RCT. We used a random-effects model to account for the inherent heterogeneity and methodological variation between these different study designs. We used GRADE to assess the certainty of evidence. We included six studies (61 participants with SLOS); one RCT (N = 18), three prospective NRSIs (N = 20), and two retrospective NRSIs (N = 22). Five studies included only children, and two limited their participant inclusion by disease severity. Overall, there were nearly twice as many males as females. All six studies compared add-on statin therapy to cholesterol supplementation alone. However, the dosages, formulations, and durations of treatment were highly variable across studies. We judged the RCT as having a high risk of bias due to missing data and selective reporting. All included NRSIs had a serious or critical overall risk of bias assessed by the Risk Of Bias In Non-randomized Studies of Interventions tool (ROBINS-I). None of the included studies evaluated survival or reported quality of life (QoL). Only the included RCT formally assessed changes in the neurobehavioral manifestations of SLOS, and we are uncertain whether statin therapy improves this outcome (very low-certainty evidence). We are also uncertain whether the adverse events reported in the RCT were statin-related (very low-certainty evidence). In contrast, the adverse events reported in the NRSIs seem to be possibly due to statin therapy (risk ratio 13.00, 95% confidence interval 1.85 to 91.49; P = 0.01; low-certainty evidence), with only one of the NRSIs retrospectively mentioning changes in the irritability of two of their participants. We are uncertain whether statins affect growth based on the RCT or NRSI results (very low-certainty evidence). The RCT showed that statins may make little or no difference to plasma biomarker levels (low-certainty evidence), while we are uncertain of their effects on such parameters in the NRSIs (very low-certainty evidence). Currently, there is no evidence on the potential effects of statin therapy in people with SLOS regarding survival or QoL, and very limited evidence on the effects on neurobehavioral manifestations. Likewise, current evidence is insufficient and of very low certainty regarding the effects of statins on growth parameters in children with SLOS and plasma or cerebrospinal fluid (CSF) levels of various disease biomarkers. Despite these limitations, current evidence seemingly suggests that statins may increase the risk of adverse reactions in individuals with SLOS receiving statins compared to those who are not. Given the insufficient evidence on potential benefits of statins in individuals with SLOS, and their potential for causing adverse reactions, anyone considering this therapy should take these findings into consideration. Future studies should address the highlighted gaps in evidence on the use of statins in individuals with SLOS by collecting prospective data on survival and performing serial standardized assessments of neurobehavioral features, QoL, anthropometric measures, and plasma and CSF biomarker levels after statin introduction. Future studies should also attempt to use consistent dosages, formulations and durations of cholesterol and statin therapy.

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AimsThe efficacy and safety of intrawound vancomycin for preventing surgical site infection in primary hip and knee arthroplasty is uncertain.MethodsA systematic review of the literature was conducted, indexed from inception to March 2020 in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases. All studies evaluating the efficacy and/or safety of intrawound vancomycin in patients who underwent primary hip and knee arthroplasty were included. Incidence of periprosthetic joint infection (PJI), superficial infection, aseptic wound complications, acute kidney injury, anaphylactic reaction, and ototoxicity were meta-analyzed. Results were reported as odds ratios (ORs) and 95% confidence intervals (CIs). The quality of included studies was assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) assessment tool.ResultsNine studies involving 4,607 patients were included. Intrawound vancomycin was associated with lower incidence of PJI (30 patients (1.20%) vs 58 control patients (2.75%); OR 0.44, 95% CI 0.28 to 0.69) and simultaneous acute kidney injury (four patients (0.28%) vs four control patients (0.35%), OR 0.71, 95% CI 0.19 to 2.55). However, it did not reduce risk of superficial infection (four patients (0.67%) vs six control patients (1.60%), OR 0.60, 95% CI 0.17 to 2.12) and was associated with higher incidence of aseptic wound complications (23 patients (2.15%) vs eight in control patients (0.96%), OR 2.39, 95% CI 1.09 to 5.23). Four studies reported no anaphylactic reactions and three studies reported no ototoxicity in any patient group.ConclusionThe current literature suggests that intrawound vancomycin used in primary hip and knee arthroplasty may reduce incidence of PJI, but it may also increase risk of aseptic wound complications.Cite this article: Bone Joint Res 2020;9(11):778–788.

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of first aid glucose administration by any route appropriate for use by first aid providers (buccal, sublingual, oral, rectal) for symptomatic hypoglycaemia.

CAN RADIOTHERAPY CAUSE DENTAL PULP NECROSIS? A SYSTEMATIC REVIEW AND META-ANALYSIS

BackgroundMouth breathing is closely related to the facial skeletal development and malocclusion. The purpose of this systematic review and meta-analysis was to assess the effect of mouth breathing on facial skeletal development and malocclusion in children.MethodsAn electronic search in PubMed, the Cochrane Library, Medline, Web of Science, EMBASE and Sigle through February 23rd, 2020, was conducted. Inclusion criteria were children under 18 years of age with maxillofacial deformities due to mouth breathing. The risk of bias in nonrandomized studies of interventions (ROBINS-I) tool for controlled clinical trials. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used for the quality assessment. The included indicators were SNA, SNB, ANB, SN-OP, SN-PP, PP-MP, SNGoGn, MP-H, 1-NA, 1. NA, 1. NB, 1-NB, Overjet, Overbite, SPAS, PAS, and C3-H. Data concerning the mean difference in mesial molar movement and extent of canine retraction were extracted for statistical analysis. The mean differences and 95% confidence intervals were analyzed for continuous data. Review Manager 5.3, was used to synthesize various parameters associated with the impact of mouth breathing on facial skeletal development and malocclusion.ResultsFollowing full-text evaluations for eligibility, 10 studies were included in the final quantitative synthesis. In Sagittal direction, SNA (MD: − 1.63, P < 0.0001), SNB (MD: − 1.96, P < 0.0001) in mouth-breathing children was lower than that in nasal-breathing children. ANB (MD: 0.90, P < 0.0001), 1. NA (MD: 1.96, P = 0.009), 1-NA (MD: 0.66, P = 0.004), and 1-NB (MD: 1.03, P < 0.0001) showed higher values in children with mouth breathing. In vertical direction, SN-PP (MD: 0.68, P = 0.0050), SN-OP (MD: 3.05, P < 0.0001), PP-MP (MD: 4.92, P < 0.0001) and SNGoGn (MD: 4.10, P < 0.0001) were higher in mouth-breathing individuals. In airway, SPAS (MD: − 3.48, P = 0.0009), PAS (MD: − 2.11, P < 0.0001), and C3-H (MD: − 1.34, P < 0.0001) were lower in mouth breathing group.ConclusionsThe results showed that the mandible and maxilla rotated backward and downward, and the occlusal plane was steep. In addition, mouth breathing presented a tendency of labial inclination of the upper anterior teeth. Airway stenosis was common in mouth-breathing children.Trial registration crd-register@york.ac.uk, registration number CRD42019129198.

ObjectivesThis systematic review and meta-analysis aimed to assess the impact of disc repositioning surgeries on condylar bone regeneration.Materials and methodsThe study protocol adhered to the PRISMA 2020 checklist and Cochrane guidelines (CRD42024501867). The study included both randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs) (both observational and clinical trials) that reported radiological outcomes of condylar bone regeneration after disc repositioning surgeries were included. The focus was on joints exhibiting new bone formation and changes in condylar height. A comprehensive search across six databases (Embase, MEDLINE, CENTRAL, PubMed, Web of Science, and Scopus) was conducted to identify relevant studies up to February 2025. Additionally, reference lists of eligible articles were manually reviewed. The methodological quality were evaluated using the Methodological Index for Non-Randomized Studies (MINORS). The risk-of-bias assessment of the included NRSIs was conducted using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. Random-effect meta-analyses were performed using STATA software with the metaprop and metan commands.ResultsSixteen studies with a total of 1,457 patients met the inclusion criteria, including one RCT. Meta-analyses revealed that 89.3% (95% confidence interval (CI): 79.4%-96.5%) of TMJs demonstrated new condylar bone formation post-disc repositioning surgery. For patients under 21 years of age, this figure rose to 95.9% (95% CI: 91.1%-99.2%). On average, disc repositioning surgeries increased condylar height by 1.54 mm (95% CI: 1.18–1.89 mm), with a greater increase of 1.75 mm (95% CI: 1.41–2.10 mm) observed in patients under 21 years. Considerable heterogeneity was found in most meta-analyses.ConclusionsDisc repositioning surgeries appear to promote condylar bone regeneration, with more pronounced benefits observed in younger patients. However, the considerable heterogeneity among included studies and limited quality of current evidence necessitate cautious interpretation and call for future longitudinal studies with standardized protocols and long-term follow-up to confirm these preliminary results and establish more robust conclusions.Clinical relevanceThis systematic review and meta-analysis indicated that restoring the disc position might be beneficial for condylar bone regeneration.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12903-025-07436-7.

Anemia is associated with adverse outcome in a severity-dependent fashion, commencing with slight deviations from normal hemoglobin levels.1, 2 At a certain degree of anemia, known as the transfusion threshold or trigger, allogeneic red cell transfusions are administered with the purpose of reducing the increased morbidity and mortality observed. Over the past 20 years, there has been growing interest in patient outcomes following allogeneic transfusions, particularly in identifying which patients are most likely to benefit from red cell transfusions and at which hemoglobin threshold. To achieve this, numerous randomized controlled trials have compared restrictive and liberal hemoglobin thresholds for red cell transfusion.3 These clinical trials shed some light on patient outcomes in hemoglobin ranges between 70 and 100 g/L. However, they do not reveal outcomes following transfusion below these hemoglobin values nor do they inform about the effects of treatments aimed at preventing patients from reaching the hemoglobin threshold for transfusion,4 an approach taken by patient blood management (PBM). PBM is "the science of optimizing patient outcomes through the judicious use of the patient's own blood as a patient-centered, multidisciplinary and multimodal approach to patient care. The core business of this newly developing specialty consists of managing anaemia, bleeding and coagulopathy".5 There are few data published on outcomes of patients with hemoglobin levels below 70 g/L.6, 7 What is known on the topic is often based on extrapolations from non-comparative studies assessing the relationship of anemia and mortality in the absence of transfusion.8, 9 However, while these studies provide some useful insights, they do not indicate whether transfusion would have modified outcomes. With the advent and growth of PBM programs and initiatives, anemia is increasingly avoided whenever possible and treated even at hemoglobin levels below those considered transfusion thresholds. In these settings, the effects of allogeneic transfusion have to be assessed against an even more complex background, comparing the impact of PBM as a bundle of care in relation to allogeneic transfusions. Such comparisons are difficult to make since the net effect of allogeneic transfusion on outcome is still ill-defined. Having or not having the option to administer allogeneic transfusions usually alters not only the transfusion behavior of clinicians, but also many other aspects of a patient's management. This includes the timing of an elective procedure, the likelihood of providing PBM measures, the order and speed with which hemostasis is attempted in bleeding patients, the extent of surgical hemostasis aimed for, and the extent of laboratory testing. We therefore undertook an effort to search the medical literature for the best available evidence, comparing outcomes of patients that cannot be transfused if deemed necessary (non-transfusable) with those that can be transfused (transfusable). Though the difference may be subtle, this is in contrast to studies comparing patients transfused to patients not transfused as part of their usual course of treatment. Our objective was to systemically review and summarize the literature to investigate whether adult hospitalized patients treated without the possibility of receiving allogeneic blood experience higher mortality or morbidity compared to patients able to receive allogeneic blood transfusions. We registered our protocol on PROSPERO (CRD42020196673) prior to commencing our review. We based our study methodology on recommendations from the Cochrane Handbook10 and reported our results in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.11 Formal ethics approval was not required for this systematic review and meta-analysis as we only analyzed published literature. It is challenging to involve patients or the public in this work as it involved a summary of research already conducted. However, we attempted to involve relevant consumer groups by mapping out potential stakeholders specific to the review question and by contacting patient representatives for populations not wishing to receive transfusions or with exceedingly rare blood types or complex antibody patterns. These and other stakeholders were asked by mail or in form of personal interviews to contribute to the body of relevant literature, to refine the research question, and to add detail to potential subgroup analyses and other relevant questions in the design of the review. Studies were eligible for inclusion if they investigated hospitalized adult patients or mature minors (>14 years) declining or unable to receive blood transfusions. The comparator group selected was patients able to receive allogeneic transfusions. The studies identified needed to measure at least one of the pre-defined outcomes of interest (mortality, morbidity, length of stay), and included more than three patients in the intervention group. To maximize the generalizability of our results, we included all studies irrespective of the setting, country, year of publication, publication status, or language. Our study group of interest was participants considered non-transfusable. We defined non-transfusable as: patients declining allogeneic transfusions (regardless of reason); patients treated under conditions where transfusions were not available (pandemics, disasters, combat settings, resource limited countries); patients with rare blood types or complex antibody patterns for whom no transfusions are available. We defined transfusable patients as those able to receive transfusions regardless of whether they were or were not administered a transfusion. Essentially our intervention of interest compared different bundles of care, namely the treatment non-transfusable and transfusable patients received. We started our search on July 12,020, searching MEDLINE, Embase, PubMed, and The Cochrane Registry. We contacted study authors and experts in the field to ensure relevant articles were not missing. In addition, we searched the reference lists of identified studies, reviews based on similar topics, conference abstracts from the Society for the Advancement of Blood Management (SABM) and the Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis (NATA), and ongoing trials registered in clinicaltrials.gov. We did not restrict our literature search by date. Our search string included terms and combination of terms like bloodless, Jehovah's Witnesses, blood conservation, blood management, transfusion free, refuse, deny, decline, reject, transfusion, blood, red cells, and mapped these to MESH terms where available. Details of our search strategy can be found in the Data S1 (pages 2–4). Two authors (PS, ML) independently screened titles and abstracts returned by the literature search. Studies not meeting the pre-defined eligibility criteria were excluded from our review. More details on the reason for exclusion are available in the Data S1. Disagreements were first resolved through discussion, followed by resolution with a third independent party. Using pre-defined data extraction sheets, two authors (PS, ML) independently extracted data from included studies. All disagreements in data extraction were resolved by discussion. We contacted 14 study authors for additional information but did not receive any data (Table S24, Data S1). For each study, we collected information on author details, year of publication, clinical setting, inclusion criteria, intervention group definition, comparator group definition, statistical methodology, number of patients transfused, number of units transfused, and blood management strategies implemented (management of anemia, bleeding, and coagulation). In addition, we collected information needed to assess the risk of bias. In terms of outcomes our primary outcome of interest was short-term mortality, defined as in-hospital, or where lacking, within 30-days. Therefore, we collected information on the number of deaths in each group and the time-period for mortality. Our pre-defined secondary outcomes included one-year mortality, hospital and ICU length of stay, infection, ventilator time, readmissions, stroke, acute myocardial infarction or other cardiac ischemia, renal complications, re-operation for bleeding, thromboembolism, acute respiratory distress, dementia, and disseminated intravascular coagulation (DIC). Renal outcomes were defined as the highest degree of kidney injury reported, irrespective of the measurement used. More detailed information on the other variables collected and their definitions are available from Table S8, Data S1. In accordance with the Cochrane Handbook, we assessed the risk of bias of individual studies in duplicate using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool.12 Studies with critical risk of bias were excluded from our systematic review, leaving only non-critical studies for analysis. Where more than one study of low to moderate risk of bias presented the results of an outcome of interest, and we judged these studies to be homogenous, we pooled these measures in meta-analyses.10 Dichotomous outcomes were reported as odds ratios (95% confidence intervals), with continuous outcomes reported as mean differences (95% confidence intervals). We examined heterogeneity among pooled studies using the I2 statistic and the Chi2 test, and as a rough guide considered Chi2 test p-value above .10 and an I2 statistic under 30% to suggest heterogeneity may not be important. All pooled data were analyzed using a random-effects model. We included studies that applied matching techniques to their study design as well as studies adjusting for confounders using multivariable regression techniques. To ensure results from non-randomized studies adjusted for confounders, we only collected numerators and denominators for dichotomous outcomes, or means and standard errors for continuous outcomes, from studies using matching techniques in their design. Where studies presented unadjusted and adjusted intervention effects from univariable and multivariable regression analyses we extracted the adjusted effect estimate and calculated its standard error for inclusion in our meta-analyses. Statistical analyses were performed using Review Manager 5.4.1 (RevMan, The Cochrane Collaboration, 2020).13 We planned to present results comparing non-transfusable to transfusable patients, therefore, any studies presenting estimates and 95% confidence intervals comparing transfusable to non-transfusable were inversed. To assess potential publication bias we presented a funnel plot for the primary outcome of short-term mortality. Deviations from the study protocol included adding hospital costs as an outcome measure and presenting a subgroup analysis of mortality in patients with severe anemia or hemorrhagic shock. Figure 1 summarizes the number of studies identified, screened for eligibility, and included in our systematic review. After duplicates were removed, our literature search returned 2848 article titles and abstracts, of which 2501 were excluded. Following this, 347 full-text articles were retrieved and assessed for eligibility and 306 excluded for not meeting our inclusion criteria. More details on exclusion reason are available from Table S9, Data S1. This left 41 studies published in 42 reports meeting the criteria for inclusion in our review.14-55 Study characteristics are presented in Table 1. Our literature search did not identify any randomized controlled trials meeting the eligibility criteria. Of the 41 included studies, all were retrospective cohort studies by design, and seven were abstracts.16, 22, 23, 34, 39, 45, 46 In the majority of studies, the non-transfusable cohort referred to those declining transfusions for personal or religious reasons.14, 16-54 We identified one study where patients did not receive an option for transfusion, potentially due to limited resources.15 We did not identify any studies that investigated patients who were non-transfusable due to rare blood types, or because of combat or disaster settings. We contacted 14 study authors for additional information but did not receive any data (Table S24, Data S1). We collected information on the individual PBM strategies applied to manage anemia, bleeding, and coagulopathy (Table S5 to S7, Data S1). Of the 41 studies included, 26 described the application of strategies to manage anemia,14, 18, 19, 21, 24-28, 30, 32-39, 43-45, 47, 49, 50, 53, 54 with a median of two strategies applied per study; 23 studies described the application of strategies to minimize bleeding,14, 17-20, 24-30, 33, 37, 38, 40, 43, 44, 47-49, 52, 54 with a median of two strategies per study; 15 studies described applying strategies for coagulopathy,14, 18, 22, 26, 30, 33, 36-38, 43, 44, 48, 49, 52, 54 with a median of one strategy per study (Table S18, Data S1). The number of patients in the non-transfusable cohort ranged from four to 322, and from 14 to 136,326 in the transfusable cohort. The most common clinical setting studied was cardiac surgery (n = 16),14, 18, 22, 25, 29, 34, 37, 38, 42-45, 48-50, 52 followed by orthopedic surgery (n = 8)17, 20, 27, 28, 33, 40, 53, 54 and urology (n = 4).16, 26, 31, 35 Other disciplines included in our systematic review were obstetrics and gynecology, hematology, critical care, internal medicine, cardiology, and trauma. Non-transfusable patients had more comorbidities, and were more likely to be female. Twelve out of 15 studies provided sufficient information on baseline hemoglobin and showed lower hemoglobin levels for non-transfusable patients at baseline.14, 16, 23, 24, 26, 28, 32, 35, 44, 45, 53, 54 We assessed the risk of bias within studies using the ROBINS-I tool,12 and present results in Table 1. Using the seven domains of the ROBINS-I tool, no studies were judged the low risk of bias, 11 studies were of moderate risk of bias,18, 24, 25, 29, 33, 38, 42, 47, 48, 51, 52 and 30 were serious risk of bias.14-17, 19-23, 26-28, 30-32, 34-37, 39-41, 43-46, 49, 50, 53, 54 Five of the 11 moderate risk of bias studies reported the nadir hemoglobin levels in non-transfusable and transfusable groups.24, 29, 33, 47, 52 Of these the mean nadir hemoglobin levels ranged from 53 to 102 g/L in the non-transfusable group and from 64 to 102 g/L in the transfusable group. Data on short-term mortality were provided in 35 of the 41 studies included in our review.,14, 15, 17-34, 37-42, 44, 46-53 with 32 reporting in-hospital mortality, and three 30-day mortality. Of these, 12 reported zero deaths in both groups,17, 19, 20, 25-28, 30, 33, 40, 49, 53 and the remaining 23 reported no significant differences between groups.14, 15, 18, 21-24, 29, 31, 32, 34, 37-39, 41, 42, 44, 46-48, 50-52 Eleven moderate risk of bias studies were included in the meta-analysis of short-term mortality (Figure 2).18, 24, 25, 29, 33, 38, 42, 47, 48, 51, 52 The odds ratio for mortality was 0.87 (95% confidence interval 0.61 to 1.25; p = .45; I2 = 0%) when comparing non-transfusable patients to transfusable patients. Four studies reported one-year mortality outcomes.16, 31, 34, 42 One study, of moderate risk of bias, reported significantly lower one-year mortality in non-transfusable patients when compared to transfusable patients (odds ratio = 0.43, 95% confidence interval, 0.23 to 0.79; p = .007).42 Three studies of serious risk of bias16, 31, 34 reported no statistically significant differences in one-year mortality. The funnel plot for short-term mortality indicates that the odds ratio is symmetrically distributed, suggesting publication bias is not likely (Figure 3). In addition, we assessed the direction of residual bias of studies which pointed to the assumption that the review is biased towards the transfused group (Table S17, Data S1). Table 2 presents random-effects meta-analyses of secondary outcomes in non-transfusable patients when compared to transfusable patients. Eighteen studies presented data on infections.14, 15, 19, 21-28, 37, 38, 41, 42, 45, 47, 54 Of these, two studies reported significantly fewer infections in non-transfusable patients,15, 42 with the remaining 16 reporting no statistically significant differences between groups.14, 19, 21-28, 37, 38, 41, 45, 47, 54 Five studies of moderate risk of bias were included in the meta-analysis for infection.24, 25, 38, 42, 47 The odds ratio for infection was 0.59 (95% confidence interval 0.34 to 1.03; p = .07; I2 = 23%) times lower in non-transfusable patients when compared to transfusable patients (Figure S20, Data S1). Odds ratio (M-H, Random, 95% CI) 0.59 [0.34, 1.03] p = .07; I2 = 23% Odds ratio (M-H, Random, 95% CI) 0.79 [0.38, 1.66] p = .54; I2 = 0% Odds ratio (M-H, Random, 95% CI) 0.55 [0.30, 1.01] p = .05; I2 = 28% Odds ratio (M-H, Random, 95% CI) 0.74 [0.51, 1.06] p = .10; I2 = 0% Odds ratio (M-H, Random, 95% CI) 0.71 [0.41, 1.23] p = .22; I2 = 0% Odds Ratio (M-H, Random, 95% CI) 0.57 [0.32, 1.01] p = .06; I2 = 0% Mean difference (IV, Random, 95% CI) 0.24 [−0.86, 1.33] p = .67; I2 = 0% Mean difference (IV, Random, 95% CI) −0.16 [−0.28, −0.04] p = .01; I2 = 0% Odds Ratio (M-H, Random, 95% CI) 1.16 [0.70, 1.93] p = .56; I2 = 0% Fifteen studies reported data on stroke outcomes,14, 18, 22, 23, 25, 29, 34, 37, 38, 42-44, 49, 50, 52 with three reporting zero stroke events in both groups.37, 38, 49 Of the remaining 12 studies, reported statistically significant differences between groups.14, 18, 22, 23, 25, 29, 34, 42-44, 50, 52 moderate risk of bias studies reported stroke 25, 29, 38, 42, 52 the odds ratio for stroke was 0.79 (95% confidence interval to p = .54; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Data on acute myocardial infarction were available from 16 18, 23, 24, 26, 29, 37, 38, 42, 44, 47, 49, 50, 52, 54 Two studies reported significantly lower acute myocardial infarction events in non-transfusable 47 The remaining 14 reported no statistically significant differences between groups.14, 18, 23, 24, 26, 29, 37, 38, 44, 49, 50, 52, 54 studies of moderate risk of bias were included in the meta-analysis for acute myocardial 24, 29, 38, 42, 47, 52 The pooled odds for acute myocardial infarction was 0.55 (95% confidence interval p = .05; I2 = times lower in non-transfusable patients when compared to transfusable patients (Figure Data S1). studies reported 18, 30, 37, 42, 49, 54 with reporting statistically significant differences between groups Two studies of moderate risk of bias were included in the meta-analysis for 42 The pooled odds ratio for was 0.74 (95% confidence interval, to p = .10; I2 = 0%) times lower in the non-transfusable patients when compared to the transfusable patients (Figure Data S1). Data were available on renal from 29, 35, 37, 38, 42, 44, 50, 52 with all studies reporting no statistically significant differences between studies of moderate risk of bias were included in the meta-analysis for renal 24, 25, 29, 38, 42, 52 The pooled odds ratio for renal was 0.71 (95% confidence interval to p = .22; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure S24, Data S1). Eleven studies presented the number of between study 18, 19, 34, 37, 38, 42, 49, 50, 52, 54 with one study reporting zero events in both of the studies included reported statistically significant differences in between The pooled odds for was 0.57 (95% confidence interval, to p = .06; I2 = 0%) times lower in non-transfusable patients when compared to transfusable patients. This was from the four studies of moderate risk of bias (Figure Data 38, 42, 52 studies reported length of hospital outcomes as means or 21, 30, 33, 35, 38, 39, 41, 45, 49, 50, 54 Of these data were available for mean and standard length of hospital from 38, 41, 45, 54 Two studies of serious risk of bias reported mean length of in non-transfusable 54 with the remaining reporting no statistically significant 38, 45, 46 Three studies of moderate risk of bias were included in the 25, The pooled mean difference for length of was 0.24 lower (95% confidence interval, to p = .67; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Four studies reported mean care 25, 38, In the pooled analysis the mean difference in care was (95% confidence interval, to p = .01; I2 = 0%) lower in non-transfusable patients when compared to transfusable patients. These results were from three studies of moderate risk of bias (Figure Data 25, We were unable to results for events and as both these outcomes were only by one study of moderate risk of study reported statistically significant differences between There was no low or moderate risk of bias studies identified for bleeding, or outcomes. Five studies of serious risk of bias collected bleeding 30, 32, 41, 46 with one reporting significantly more bleeding events in non-transfusable patients when compared to transfusable Two studies of serious risk of bias reported 54 with reporting statistically significant differences between One study of serious risk of bias reported as an and reported study found statistically significant differences between We did not any studies reporting on acute respiratory or Two studies of moderate risk of bias reported hospital We were unable to the results of these studies as one reported median the other The study reporting found costs were significantly lower among non-transfusable the study reporting means found no significant differences between Four studies reporting short-term mortality were in patients with severe anemia or hemorrhagic 21, 29, 47 with reporting statistically significant differences between Two moderate risk of bias studies were included in the 47 The odds ratio for mortality was 1.16 (95% confidence interval to p = .56; I2 = 0%) when comparing non-transfusable patients to transfusable patients (Figure Data S1). Our systematic review included 41 studies, with 11 studies of moderate risk of bias pooled in our analysis. In the meta-analysis of short-term mortality non-transfusable patients were not more likely to have increased mortality when compared to transfusable patients. This the in our subgroup analysis of patients with severe anemia or hemorrhagic shock. considered non-transfusable were more likely to have a in the care There were no statistically significant differences between non-transfusable and transfusable patients in terms of other pre-defined morbidity outcomes, non-transfusable patients to have fewer acute myocardial and and data on hospital costs suggest similar or even lower hospital To our this is the first systematic review and meta-analysis comparing outcomes in non-transfusable and transfusable patients. The of our review, not our literature search by or study design, is a We applied the Cochrane methodology, registered our protocol prior to commencing our review, and performed study data and data in Our study has a number of For as there were no randomized controlled trials identified, our meta-analyses pooled the results of studies. It is possible there is residual that contribute to the results observed. To minimize any potential bias, we only included studies for confounders in their study and we did not studies of serious or critical risk of bias. In addition, we assessed the direction of residual bias of studies, which pointed to the assumption that the review is biased towards the transfused group. the of studies are well these data can be in a number of settings, where randomized trials cannot be performed due to a our meta-analysis of studies necessary data to a research question for which randomized is not available. potential of our meta-analysis is the of blood the non-transfusable patients did not receive any allogeneic blood the transfusable patients, when transfused, This is likely to between clinical settings, and therefore any this In addition, seven of the 11 studies judged the moderate risk of bias therefore included in our were in the cardiac surgery setting, with the other four studies in critical care, and trauma. This may the generalizability of our to other patient However, while the majority of studies were in the cardiac surgery setting, of participants pooled were from other settings, with the study the most included patients from a of surgical and In addition, the of morbidity outcomes is a as it is likely to in and in from study to study and is therefore more in when compared to mortality and length of outcomes. To there are two of studies transfusion in adult hospitalized studies comparing transfused with patients as well as randomized controlled trials comparing liberal and restrictive transfusion Systematic reviews and meta-analyses of studies comparing transfused patients to patients transfusion is associated with increased mortality and of randomized trials comparing restrictive and liberal hemoglobin thresholds no differences in mortality between in some lower mortality is reported in patients to restrictive thresholds. For meta-analyses from 53 randomized controlled trials and found of meta-analyses as to moderate reported no statistically significant difference in mortality, while reported lower mortality with restrictive transfusion Our review a third of study to the literature on this comparing different bundles of care, namely the treatment non-transfusable and transfusable patients in results between these three of studies For not statistically significant we found a fewer infection events among non-transfusable patients. This is with a systematic review and meta-analysis of randomized controlled trials which reported that restrictive transfusion thresholds in a of severe There are three patient groups identified as patients who a red cell and have the and blood is patients declining to and patients in where blood is not available combat settings, due to or We compared patients that may have have a transfusion as part of their usual care, to similar patients who were able to receive transfusions but may or may not have been Our also included patients not at risk of receiving a transfusion who still a bundle of care to their own blood anemia, bleeding, and to similar patients who may not have had their blood to the Our review patients, clinicians, and to make a the of transfusion and The results of our systematic review and meta-analysis the that comparing outcomes in non-transfusable and transfusable patients. The results may that studies of low to moderate risk of bias indicate patients unable to receive allogeneic blood transfusions have similar clinical outcomes, and in some may have outcomes than patients able to receive transfusions. The results of our meta-analysis may also provide to more aspects of PBM to transfusable patients. the results from studies of moderate risk of bias indicate that no difference in mortality or morbidity between non-transfusable and transfusable patients. However, patients considered non-transfusable were treated at similar or hospital We and the of the for their in relevant All authors have the form at and no from any for the no with any that have an interest in the work in the no other or that to have the the study searched for with other independently screened found articles for eligibility, data data of the article the study independently screened found articles for eligibility, data data the publication public publication of the and and the statistical and at the of and the and the work and detail to the All authors the data for the All authors were involved in the All authors the to be Data S1. The is not for the or of any information by the than be to the author for the

Background:Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease).Methods:We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers.Results:Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24–7.34) but associations mostly showed increased risk.Conclusion:Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders.

Despite local therapies, commonly transurethral resection (TUR) followed by adjuvant treatments, non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence and progression. Intravesical Bacillus Calmette-Guérin (BCG) has been shown to reduce recurrence and progression in people with NMIBC following TUR, however many people do not respond to treatment, have recurrence shortly after, or cannot tolerate standard-dose therapy. The potential for synergistic antitumour activity of interferon (IFN)-alpha (α) and BCG provides some rationale for combination therapy for people who do not tolerate or respond to standard-dose BCG therapy. To assess the effects of intravesically administered BCG plus IFN-α compared with BCG alone for treating non-muscle-invasive bladder cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2016), MEDLINE (OvidSP) (1946 to 2016), Embase (OvidSP) (1974 to 2016), ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) as well as reference lists of retrieved articles and handsearched abstract proceedings of relevant conferences for the past three years. We applied no language restrictions. The date of last search of all databases was 25 August 2016. We included randomised controlled trials (RCTs) and pseudo-randomised trials assessing intravesically administered BCG plus IFN-α versus BCG alone in adults of either gender with histologically confirmed Ta and T1 superficial bladder cancer, with or without carcinoma in situ, treated with TUR. Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of included studies. We used Review Manager 5 for data synthesis and employed the random-effects model for meta-analyses. For prespecified outcomes, where we were unable to derive time-to-event information (e.g. time-to-recurrence), we assessed dichotomous outcomes (e.g. recurrence) instead. We assessed the quality of the evidence for the main comparisons using the GRADE approach. We included five RCTs involving a total of 1231 participants with NMIBC in this review. Due to poor reporting, the risk of bias in the included studies was often unclear. We assessed the studies under two main comparisons: intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs), and intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT). Intravesical BCG plus IFN-α versus intravesical BCG alone (four RCTs): We observed no clear difference between BCG plus IFN-α and BCG alone for recurrence (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.44 to 1.32; 4 RCTs; 925 participants; very low-quality evidence) or progression (average RR 0.26, 95% CI 0.04 to 1.87; 2 RCTs; 219 participants; low-quality evidence). The included RCTs did not report on the other primary outcome of this review, discontinuation of therapy due to adverse events. Regarding secondary outcomes, we observed no clear difference for disease-specific mortality (RR 0.38, 95% CI 0.05 to 3.05; 1 RCT; 99 participants; very low-quality evidence). Two RCTs reporting contradictory findings for adverse events could not be pooled due to variation in definitions. There were no data from the included RCTs on time-to-death or disease-specific quality of life. Intravesical BCG alternating with IFN-α versus intravesical BCG alone (one RCT): We observed shorter time-to-recurrence for participants in the BCG alternating with IFN-α group compared with the BCG alone group (hazard ratio (HR) 2.86, 95% CI 1.98 to 4.13; 1 RCT; 205 participants; low-quality evidence), but no clear differences in time-to-progression (HR 2.39, 95% CI 0.92 to 6.21; 1 RCT; 205 participants; low-quality evidence) and discontinuation of therapy due to adverse events (RR 2.97, 95% CI 0.31 to 28.09; 1 RCT; 205 participants; low-quality evidence). Regarding secondary outcomes, there were no clear differences between the BCG alternating with IFN-α and BCG alone groups for disease-specific mortality (HR 2.74, 95% CI 0.73 to 10.28; 1 RCT; 205 participants; low-quality evidence), time-to-death (overall survival) (HR 1.00, 95% CI 0.68 to 1.47; 1 RCT; 205 participants; low-quality evidence), or systemic or local adverse events (RR 1.65, 95% CI 0.41 to 6.73; 1 RCT; 205 participants; low-quality evidence). There were no data on disease-specific quality of life. We found low- to very low-quality evidence suggesting no clear differences in recurrence or progression with BCG plus IFN-α compared with BCG alone for people with NMIBC; there was no information to determine the effect on discontinuation of therapy due to adverse events. Low-quality evidence suggests BCG alternating with IFN-α compared with BCG alone may increase time-to-recurrence, however low-quality evidence also suggests no clear differences for time-to-progression or discontinuation of therapy due to adverse events.Additional high-quality, adequately powered trials using standardised instillation regimens and doses of both BCG and IFN-α, reporting outcomes in subgroups stratified by patient and tumour characteristics, and on long-term outcomes related not only to recurrence but also to progression, discontinuation due to adverse events, and mortality may help to clarify the ideal treatment strategy and provide a more definitive result.