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Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Pain is a multidimensional experience, potentially rendering unidimensional pain scales inappropriate for assessment. Prior research highlighted their inadequacy as reliable indicators of analgesic requirement. This systematic review aimed to compare multidimensional with unidimensional pain scales in assessing analgesic requirements in the emergency department (ED). Embase, Medline, CINAHL, and PubMed Central were searched to identify ED studies utilizing both unidimensional and multidimensional pain scales. Primary outcome was desire for analgesia. Secondary outcomes were amount of administered analgesia and patient satisfaction. Two independent reviewers screened, assessed quality, and extracted data of eligible studies. We assessed risk of bias with the ROBINS-I tool and provide a descriptive summary. Out of 845 publications, none met primary outcome criteria. Three studies analyzed secondary outcomes. One study compared the multidimensional Defense and Veterans Pain Rating Scale (DVPRS) to the unidimensional Numerical Rating Scale (NRS) for opioid administration. DVPRS identified more patients with moderate instead of severe pain compared to the NRS. Therefore, the DVPRS might lead to a potential reduction in opioid administration for individuals who do not require it. Two studies assessing patient satisfaction favored the short forms (SF) of the Brief Pain Inventory (BPI) and McGill Pain Questionnaire (MPQ) over the Visual Analogue Scale (VAS) and the NRS. Limited heterogenous literature suggests that in the ED, a multidimensional pain scale (DVPRS), may better discriminate moderate and severe pain compared to a unidimensional pain scale (NRS). This potentially impacts analgesia, particularly when analgesic interventions rely on pain scores. Patients might prefer multidimensional pain scales (BPI-SF, MPQ-SF) over NRS or VAS for assessing their pain experience., (© 2024. The Author(s).)

Background: Patients with heart failure with preserved ejection fraction (HFpEF) commonly experience exercise intolerance, resulting in reduced cardiorespiratory fitness. This is characterised by a decreased maximal oxygen uptake (V̇O 2peak ), which is determined by the product of cardiac output (CO) and arteriovenous oxygen difference (a-vDO 2 ). While exercise training has been shown to improve V̇O 2peak in HFpEF patients, the effects on CO remain unclear. The aim of this study is to systematically review and analyse the current evidence on the effects of supervised exercise training on CO in patients with HFpEF., Methods: We will systematically search for literature describing the effects of supervised exercise training on CO in patients with HFpEF. All eligible studies published before 30 June 2023 in the following electronic databases will be included: MEDLINE (Ovid), Embase (Ovid), SPORTDiscus (EBSCOhost), and CENTRAL (Cochrane Library). Effect sizes will be extracted for CO before and after a supervised exercise training intervention at rest and maximal exercise. Mass of heterogeneity (I 2 ) will be calculated, and either fixed-effect models or random-effect models will be used for meta-analysis. To detect a potential publication bias, funnel plot analyses will be performed., Discussion: While several studies have reported a positive effect of supervised exercise training on cardiorespiratory fitness, attempts to assess the underlying determinants of V̇O 2peak , CO, and a-vDO 2 are much scarcer, especially in patients with HFpEF. From a physiological perspective, measuring CO before and after supervised exercise training seems to be a reasonable way to accurately operationalise a potential improvement in cardiac function., Systematic Review Registration: PROSPERO CRD42022361485., (© 2024. The Author(s).)

Background: Patients with advanced vulvoperineal cancer require a multidisciplinary treatment approach to ensure oncological safety, timely recovery, and the highest possible quality of life (QoL). Reconstructions in this region often lead to complications, affecting approximately 30% of patients. Flap design has evolved towards perforator-based approaches to reduce functional deficits and (donor site) complications, since they allow for the preservation of relevant anatomical structures. Next to their greater surgical challenge in elevation, their superiority over non-perforator-based approaches is still debated., Methods: To compare outcomes between perforator and non-perforator flaps in female vulvoperineal reconstruction, we conducted a systematic review of English-language studies published after 1980, including randomized controlled trials, cohort studies, and case series. Data on demographics and surgical outcomes were extracted and classified using the Clavien-Dindo classification. We used a random-effects meta-analysis to derive a pooled estimate of complication frequency (%) in patients who received at least one perforator flap and in patients who received non-perforator flaps., Results: Among 2576 screened studies, 49 met our inclusion criteria, encompassing 1840 patients. The overall short-term surgical complication rate was comparable in patients receiving a perforator ( n = 276) or a non-perforator flap ( n = 1564) reconstruction ( p * > 0.05). There was a tendency towards fewer complications when using perforator flaps. The assessment of patients' QoL was scarce., Conclusions: Vulvoperineal reconstruction using perforator flaps shows promising results compared with non-perforator flaps. There is a need for the assessment of its long-term outcomes and for a systematic evaluation of patient QoL to further demonstrate its benefit for affected patients.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no specific support for the submitted work. CA-H received payments to his institution for a citation searching workshop by the University of Applied Sciences Northwestern Switzerland. JH received consulting fees from Medical University Brandenburg and payments for lecturing from the University of Applied Sciences Northwestern Switzerland, Catholic University of Applied Sciences, and Netzwerk Fachbibliotheken Gesundheit. From the TARCiS study group: JS received support from Alfred P Sloan Foundation; was funded by the US National Institutes of Health, National Science Foundation, US Office of Research Integrity, United States Institute of Museum and Library Services, and University of Illinois Urbana-Champaign; received book royalties from Morgan and Claypool; received consulting fees or honorariums from the European Commission, Jump ARCHES, NSF, and the Medical Library Association; received travel support by UIUC; contributes to the CREC (Communication of Retractions, Removals, and Expressions of Concern) Working Group; has non-financial associations with Crossref, COPE (Committee on Publication Ethics), the International Association of Scientific, Technical and Medical Publishers, the National Information Standards Organisation, and the Center for Scientific Integrity (parent organisation of Retraction Watch); and declares the National Information Standards Organisation as a subawardee on her Alfred P Sloan Foundation grant G-2022-19409. JG received payments for lecturing by York Health Economics Consortium. MJS received consulting fees at the Canadian Agency for Drugs and Technologies in Health and National Academy of Medicine (formerly Institute of Medicine) and for lecturing and support for attending a meeting at Institute for Quality and Efficiency in Health Care; and has a leadership role as secretary of the Ottawa Valley Health Library Association. AW received payments to her institution for a citation analysis workshop run via York Health Economics Consortium. SK declares non-financial interests as a member of the UK EQUATOR Centre and a coauthor of the PRISMA-S reporting guideline and was funded by Cancer Research UK (grant C49297/A27294); the current work was unrelated to this funding. PL is an employee of the National Institute for Health and Care Excellence. MR received payments by the Medical Library Association and declares non-financial interests as a member of the PhD programme affiliated with BMJ Publishing Group. ABo is a co-convenor of the Cochrane Qualitative and Implementation Methods Group and has authored methodological guidance on literature searching. All the other authors have no competing interests to disclose.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future., Competing Interests: Declaration of Competing Interest Philipp Anders is supported by the “Freiwillige Akademische Gesellschaft Basel” and “OPOS zugunsten von Wahrnehmungsbehinderten” foundations. Ursula Schmidt-Erfurth receives grant support from Genentech, Kodiak, Novartis, RetInSight and Roche and is a consultant for Apellis. Hendrick Scholl is a member of the Scientific Advisory Board of: Astellas, Boehringer Ingelheim, Gyroscope/Novartis, Janssen, Okuvision, and Third Rock Ventures. He is a consultant of Gerson Lehrman Group, Guidepoint Global, and Tenpoint Therapeutics. He is a member of a Data Monitoring and Safety Board/Committee for Belite Bio, ReNeuron Group Plc/Ora Inc., Roche, and member of a Steering Committee for Novo Nordisk. He is a co-director of the Institute of Molecular and Clinical Ophthalmology Basel (IOB) which receives funding from the University of Basel, the University Hospital Basel, Novartis, and the government of Basel-Stadt. Daniel Rueckert is a co-founder and shareholder of IXICO Plc. Sobha Sivaprasad has received funding/fees from Bayer, Novartis, AbbVie, Roche, Boehringer Ingelheim, Optos, EyeBiotech, Biogen, and Apellis. She is a member of a Data Monitoring and Safety Board/Committee for Bayer and a member of a Steering Committee for Novo Nordisk. Andrew Lotery is a consultant for Gyroscope/Novartis, Eyebio, Complement Therapeutics, Allergan, Apellis and Tarsus Pharmaceuticals. No other disclosures were reported. No conflicts related to this project., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis., Methods: We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses., Results: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively)., Conclusions: Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients., Prospero Registration: CRD42021272995., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The presence of polyethylene terephthalate (PET) oligomers in food contact materials (FCMs) is well-documented. Consumers are exposed through their migration into foods and beverages; however, there is no specific guidance for their safety evaluation., Objectives: This systematic evidence map (SEM) aims to identify and organize existing knowledge and associated gaps in hazard and exposure information on 34 PET oligomers to support regulatory decision-making., Methods: The methodology for this SEM was recently registered. A systematic search in bibliographic and gray literature sources was conducted and studies evaluated for inclusion according to the Populations, Exposures, Comparators, Outcomes, and Study type (PECOS) framework. Inclusion criteria were designed to record hazard and exposure information for all 34 PET oligomers and coded into the following evidence streams: human, animal, organism (non-animal), ex vivo, in vitro, in silico, migration, hydrolysis, and absorption, distribution, metabolism, excretion/toxicokinetics/pharmacokinetics (ADME/TK/PK) studies. Relevant information was extracted from eligible studies and synthesized according to the protocol., Results: Literature searches yielded 7445 unique records, of which 96 were included. Data comprised migration (560 entries), ADME/TK/PK-related (253 entries), health/bioactivity (98 entries) and very few hydrolysis studies (7 entries). Cyclic oligomers were studied more frequently than linear PET oligomers. In vitro results indicated that hydrolysis of cyclic oligomers generated a mixture of linear oligomers, but not monomers, potentially allowing their absorption in the gastrointestinal tract. Cyclic dimers, linear trimers and the respective smaller oligomers exhibit physico-chemical properties making oral absorption more likely. Information on health/bioactivity effects of oligomers was almost non-existent, except for limited data on mutagenicity., Conclusions: This SEM revealed substantial deficiencies in the available evidence on ADME/TK/PK, hydrolysis, and health/bioactivity effects of PET oligomers, currently preventing appropriate risk assessment. It is essential to develop more systematic and tiered approaches to address the identified research needs and assess the risks of PET oligomers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alex Odermatt reports financial support was provided by Federal Food Safety and Veterinary Office FSVO. Alex Odermatt reports administrative support was provided by Swiss Centre for Applied Human Toxicology (SCAHT). This involves handling of reporting to the FSVO and the transfer of funds from the FSVO. Martin Wilks reports a relationship with SCAHT that includes: director. Nicolas Roth reports a relationship with SCHAT that includes: employment. Jane Muncke and Birgit Geueke report a relationship with Food Packaging Forum that includes: employment. Jane Muncke and Birgit Geueke were not restricted in any way by the FPF in planning and conducting this work. Beat J. Brueschweiler reports a relationship with Swiss Federal Food Safety and Veterinary Office (FSVO) that includes: employment. Beat J. Brueschweiler acted in a personal expert capacity and not as a sponsor representative. Benoit Schilter reports a relationship with Nestlé R&D Centre that includes: previous employment. Benoit Schilter was not restricted in any way by Nestlé R&D Centre in planning and conduction this work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Citation tracking (CT) collects references with citation relationships to pertinent references that are already known. This scoping review maps the benefit of and the tools and terminology used for CT in health-related systematic literature searching. We included methodological studies on evidence retrieval by CT in health-related literature searching without restrictions on study design, language, or publication date. We searched MEDLINE/Ovid, Web of Science Core Collection, CINAHL/EBSCOhost, LLISFT/EBSCOhost, LISTA/EBSCOhost, conducted web searching via Google Scholar, backward/forward CT of included studies and pertinent reviews, and contacting of experts. Two reviewers independently assessed eligibility. Data extraction and analysis were performed by one reviewer and checked by another. We screened 11,861 references and included 47 studies published between 1985 and 2021. Most studies (96%) assessed the benefit of CT either as supplementary or primary/stand-alone search method. Added value of CT for evidence retrieval was found by 96% of them. Science Citation Index and Social Sciences Citation Index were the most common citation indexes used. Application of multiple citation indexes in parallel, co-citing or co-cited references, CT iterations, or software tools was rare. CT terminology was heterogeneous and frequently ambiguous. The use of CT showed an added value in most of the identified studies; however, the benefit of CT in health-related systematic literature searching likely depends on multiple factors that could not be assessed with certainty. Application, terminology, and reporting are heterogeneous. Based on our results, we plan a Delphi study to develop recommendations for the use and reporting of CT., (© 2023 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

This work aims to assess the performance of two post-arrest (out-of-hospital cardiac arrest, OHCA, and cardiac arrest hospital prognosis, CAHP) and one pre-arrest (good outcome following attempted resuscitation, GO-FAR) prediction model for the prognostication of neurological outcome after cardiac arrest in a systematic review and meta-analysis. A systematic search was conducted in Embase, Medline, and Web of Science Core Collection from November 2006 to December 2021, and by forward citation tracking of key score publications. The search identified 1'021 records, of which 25 studies with a total of 124'168 patients were included in the review. A random-effects meta-analysis of C-statistics and overall calibration (total observed vs. expected [O:E] ratio) was conducted. Discriminatory performance was good for the OHCA (summary C-statistic: 0.83 [95% CI 0.81-0.85], 16 cohorts) and CAHP score (summary C-statistic: 0.84 [95% CI 0.82-0.87], 14 cohorts) and acceptable for the GO-FAR score (summary C-statistic: 0.78 [95% CI 0.72-0.84], five cohorts). Overall calibration was good for the OHCA (total O:E ratio: 0.78 [95% CI 0.67-0.92], nine cohorts) and the CAHP score (total O:E ratio: 0.78 [95% CI 0.72-0.84], nine cohorts) with an overestimation of poor outcome. Overall calibration of the GO-FAR score was poor with an underestimation of good outcome (total O:E ratio: 1.62 [95% CI 1.28-2.04], five cohorts). Two post-arrest scores showed good prognostic accuracy for predicting neurological outcome after cardiac arrest and may support early discussions about goals-of-care and therapeutic planning on the intensive care unit. A pre-arrest score showed acceptable prognostic accuracy and may support code status discussions., (© 2022. The Author(s).)

Objectives: The main aim was a systematic evaluation of the current evidence on outcomes for patients undergoing right ventricular assist device (RVAD) implantation following left ventricular assist device (LVAD) implantation., Methods: This systematic review was registered on PROSPERO (CRD42019130131). Reports evaluating in-hospital as well as follow-up outcome in LVAD and LVAD/RVAD implantation were identified through Ovid Medline, Web of Science and EMBASE. The primary endpoint was mortality at the hospital stay and at follow-up. Pooled incidence of defined endpoints was calculated by using random effects models., Results: A total of 35 retrospective studies that included 3260 patients were analyzed. 30 days mortality was in favour of isolated LVAD implantation 6.74% (1.98-11.5%) versus 31.9% (19.78-44.02%) p = 0.001 in LVAD with temporary need for RVAD. During the hospital stay the incidence of major bleeding was 18.7% (18.2-19.4%) versus 40.0% (36.3-48.8%) and stroke rate was 5.6% (5.4-5.8%) versus 20.9% (16.8-28.3%) and was in favour of isolated LVAD implantation. Mortality reported at short-term as well at long-term was 19.66% (CI 15.73-23.59%) and 33.90% (CI 8.84-59.96%) in LVAD respectively versus 45.35% (CI 35.31-55.4%) p ⩽ 0.001 and 48.23% (CI 16.01-80.45%) p = 0.686 in LVAD/RVAD group respectively., Conclusion: Implantation of a temporary RVAD is allied with a worse outcome during the primary hospitalization and at follow-up. Compared to isolated LVAD support, biventricular mechanical circulatory support leads to an elevated mortality and higher incidence of adverse events such as bleeding and stroke.

Background: The identification of factors that specify prognostic models for postoperative results should be based on the best scientific evidence and expert assessment. We aimed to identify, map, and evaluate potential prognostic factors for the improvement of shoulder function in patients undergoing arthroscopic rotator cuff repair., Methods: Longitudinal primary studies of arthroscopic rotator cuff repair reporting any multivariable factor analyses for shoulder function improvement with an endpoint assessment of at least 6 months were included. We systematically searched EMBASE, Medline, and Scopus for articles published between January 2014 and June 2021. The risk of bias of included studies and the quality of evidence were assessed using the Quality in Prognosis Studies tool and an adapted Grading of Recommendations, Assessment, Development, and Evaluations framework., Results: Overall, 24 studies including 73 outcome analyses were included. We classified younger age and smaller tear size as probably prognostic for a greater improvement in objective outcomes. Shorter symptom duration, absence of a worker compensation claim, low preoperative level of functional status, and high preoperative pain level were classified as probably prognostic for greater improvement in patient-reported outcome measures. The quality of the synthesized evidence was low. Twenty-one studies had an overall high risk of bias., Conclusion: Six potential prognostic factors for shoulder function after arthroscopic rotator cuff repair were identified. Along with ongoing expert opinion assessments, they will feed into a prognostic model-building process., (© 2022 The Author(s).)

Background: Polyethylene terephthalate (PET) oligomers are ubiquitous in PET used in food contact applications. Consumer exposure by migration of PET oligomers into food and beverages is documented. However, no specific risk assessment framework or guidance for the safety evaluating of PET oligomers exist to date., Aim: The aim of this systematic evidence map (SEM) is to identify and organize existing knowledge clusters and associated gaps in hazard and exposure information of PET oligomers. Research needs will be identified as an input for chemical risk assessment, and to support future toxicity testing strategies of PET oligomers and regulatory decision-making., Search Strategy and Eligibility Criteria: Multiple bibliographic databases (incl. Embase, Medline, Scopus, and Web of Science Core Collection), chemistry databases (SciFinder-n, Reaxys), and gray literature sources will be searched, and the search results will be supplemented by backward and forward citation tracking on eligible records. The search will be based on a single-concept PET oligomer-focused strategy to ensure sensitive and unbiased coverage of all evidence related to hazard and exposure in a data-poor environment. A scoping exercise conducted during planning identified 34 relevant PET oligomers. Eligible work of any study type must include primary research data on at least one relevant PET oligomer with regard to exposure, health, or toxicological outcomes., Study Selection: For indexed scientific literature, title and abstract screening will be performed by one reviewer. Selected studies will be screened in full-text by two independent reviewers. Gray literature will be screened by two independent reviewers for inclusion and exclusion., Study Quality Assessment: Risk of bias analysis will not be conducted as part of this SEM., Data Extraction and Coding: Will be performed by one reviewer and peer-checked by a second reviewer for indexed scientific literature or by two independent reviewers for gray literature., Synthesis and Visualization: The extracted and coded information will be synthesized in different formats, including narrative synthesis, tables, and heat maps., Systematic Map Protocol Registry and Registration Number: Zenodo: https://doi.org/10.5281/zenodo.6224302., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context: Overtraining syndrome (OTS) is a condition characterized by a long-term performance decrement, which occurs after a persisting imbalance between training-related and nontraining-related load and recovery. Because of the lack of a gold standard diagnostic test, OTS remains a diagnosis of exclusion., Objective: To systematically review and map biomarkers and tools reported in the literature as potentially diagnostic for OTS., Data Sources: PubMed, Web of Science, and SPORTDiscus were searched from database inception to February 4, 2021, and results screened for eligibility. Backward and forward citation tracking on eligible records were used to complement results of database searching., Study Selection: Studies including athletes with a likely OTS diagnosis, as defined by the European College of Sport Science and the American College of Sports Medicine, and reporting at least 1 biomarker or tool potentially diagnostic for OTS were deemed eligible., Study Design: Scoping review following the guidelines of the Joanna Briggs Institute and PRISMA Extension for Scoping Reviews (PRISMA-ScR)., Level of Evidence: Level 4., Data Extraction: Athletes' population, criteria used to diagnose OTS, potentially diagnostic biomarkers and tools, as well as miscellaneous study characteristics were extracted., Results: The search yielded 5561 results, of which 39 met the eligibility criteria. Three diagnostic scores, namely the EROS-CLINICAL, EROS-SIMPLIFIED, and EROS-COMPLETE scores (EROS = Endocrine and Metabolic Responses on Overtraining Syndrome study), were identified. Additionally, basal hormone, neurotransmitter and other metabolite levels, hormonal responses to stimuli, psychological questionnaires, exercise tests, heart rate variability, electroencephalography, immunological and redox parameters, muscle structure, and body composition were reported as potentially diagnostic for OTS., Conclusion: Specific hormones, neurotransmitters, and metabolites, as well as psychological, electrocardiographic, electroencephalographic, and immunological patterns were identified as potentially diagnostic for OTS, reflecting its multisystemic nature. As exemplified by the EROS scores, combinations of these variables may be required to diagnose OTS. These scores must now be validated in larger samples and within female athletes.

Importance: Data on long-term survival beyond 12 months after out-of-hospital cardiac arrest (OHCA) of a presumed cardiac cause are scarce., Objective: To investigate the long-term survival of adult patients after surviving the initial hospital stay for an OHCA., Data Sources: A systematic search of the EMBASE and MEDLINE databases was performed from database inception to March 25, 2021., Study Selection: Clinical studies reporting long-term survival after OHCA were selected based on predefined inclusion and exclusion criteria according to a preregistered study protocol., Data Extraction and Synthesis: Patient data were reconstructed from Kaplan-Meier curves using an iterative algorithm and then pooled to generate survival curves. As a separate analysis, an aggregate data meta-analysis was performed., Main Outcomes and Measures: The primary outcome was long-term survival (>12 months) after OHCA for patients surviving to hospital discharge or 30 days after OHCA., Results: The search identified 15 347 reports, of which 21 studies (11 800 patients) were included in the Kaplan-Meier-based meta-analysis and 33 studies (16 933 patients) in an aggregate data meta-analysis. In the Kaplan-Meier-based analysis, the median survival time for patients surviving to hospital discharge was 5.0 years (IQR, 2.3-7.9 years). The estimated survival rates were 82.8% (95% CI, 81.9%-83.7%) at 3 years, 77.0% (95% CI, 75.9%-78.0%) at 5 years, 63.9% (95% CI, 62.3%-65.4%) at 10 years, and 57.5% (95% CI, 54.8%-60.1%) at 15 years. Compared with patients with a nonshockable initial rhythm, patients with a shockable rhythm had a lower risk of long-term mortality (hazard ratio, 0.30; 95% CI, 0.23-0.39; P < .001). Different analyses, including an aggregate data meta-analysis, confirmed these results., Conclusions and Relevance: In this comprehensive systematic review and meta-analysis, long-term survival after 10 years in patients surviving the initial hospital stay after OHCA was between 62% and 64%. Additional research is needed to understand and improve the long-term survival in this vulnerable patient population.

Background: Increasing evidence suggests improved time metrics leading to better clinical outcomes when stroke patients with suspected large vessel occlusion (LVO) are transferred directly to the angiography suite (DTAS) compared with cross-sectional imaging followed by transfer to the angiography suite. We performed a systematic review and meta-analysis on the efficacy and safety of DTAS approaches., Methods: We searched Embase, Medline, Scopus, and clinicaltrials.gov for studies comparing outcomes of DTAS and conventional triage. Eligible studies were assessed for risk of bias. We performed a random-effects meta-analysis on the differences of median door-to-groin and door-to-reperfusion times between intervention and control group. Secondary outcomes included good outcome at 90 days (modified Rankin Scale ⩽ 2) rate of symptomatic intracranial hemorrhage (sICH) and mortality within 90 days., Results: Eight studies (one randomized, one cluster-randomized trial and six observational studies) with 1938 patients were included. Door-to-groin and door-to-reperfusion times in the intervention group were on median 29.0 min [95% confidence interval (CI): 14.3-43.6; p  < 0.001] and 32.1 min (95% CI: 15.1-49.1; p  < 0.001) shorter compared with controls. Prespecified subgroup analyses for transfer ( n  = 1753) and mothership patients ( n  = 185) showed similar reductions of the door-to-groin and door-to-reperfusion times in response to the intervention. The odds of good outcome did not differ significantly between both groups but were numerically higher in the intervention group (odds ratio: 1.38, 95% CI: 0.97-1.95; p  = 0.07). There was no significant difference for mortality and sICH between the groups., Conclusion: DTAS approaches for the triage of suspected LVO patients led to a significant reduction in door-to-groin and door-to-reperfusion times but an effect on functional outcome was not detected. The subgroup analysis showed similar results for transfer and mothership patients. Registration: This study was registered in PROSPERO (CRD42020213621)., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Background: Post-operative shoulder stiffness (POSS) is one of the most frequent complications after arthroscopic rotator cuff repair (ARCR). Factors specifying clinical prediction models for the occurrence of POSS should rely on the literature and expert assessment. Our objective was to map prognostic factors for the occurrence of POSS in patients after an ARCR., Methods: Longitudinal studies of ARCR reporting prognostic factors for the occurrence of POSS with an endpoint of at least 6 months were included. We systematically searched Embase, Medline, and Scopus for articles published between January 1, 2014 and February 12, 2020 and screened cited and citing literature of eligible records and identified reviews. The risk of bias of included studies and the quality of evidence were assessed using the Quality in Prognosis Studies tool and an adapted Grading of Recommendations, Assessment, Development and Evaluations framework. A database was implemented to report the results of individual studies. The review was registered on PROSPERO (CRD42020199257)., Results: Seven cohort studies including 23 257 patients were included after screening 5013 records. POSS prevalence ranged from 0.51 to 8.75% with an endpoint ranging from 6 to 24 months. Due to scarcity of data, no meta-analysis could be performed. Overall risk of bias and quality of evidence was deemed high and low or very low, respectively. Twenty-two potential prognostic factors were identified. Increased age and male sex emerged as protective factors against POSS. Additional factors were reported but do require further analyses to determine their prognostic value., Discussion: Available evidence pointed to male sex and increased age as probable protective factors against POSS after ARCR. To establish a reliable pre-specified set of factors for clinical prediction models, our review results require complementation with an expert's opinion., (© 2022. The Author(s).)

Background: Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants' perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants' feedback on their views and experiences., Methods: We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019., Results: Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives., Conclusions: To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants' views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants., (© 2021. The Author(s).)

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The aims of this study were to assess and quantify hip abductor muscle strength deficits after total hip arthroplasty (THA) and to determine associations with external factors., Methods: Studies reporting on hip abductor muscle strength before and/or after THA performed for osteoarthritis or atraumatic osteonecrosis of the hip were considered for inclusion. Data sources were Embase, Medline, and the Cochrane Central Register of Controlled Trials. Muscle strength on the affected side was compared with the healthy contralateral side or with control subjects. Study quality was assessed using a modified Newcastle-Ottawa Scale., Results: Nineteen studies reporting on 875 subjects met the inclusion criteria. Patients scheduled for THA had a mean strength deficit of 18.6% (95% confidence interval (CI) [-33.9, -3.2%]) compared with control subjects. Abductor muscle strength then increased by 20.2% (CI [5.6, 34.8%]) at 4-6 months, 29.6% (CI [4.7, 54.4%]) at 9-12 months, and 49.8% (CI [-31.0, 130.6%]) at 18-24 months postoperatively compared with preoperative values. For unilateral THA, the mean torque ratio was 86.3% (CI [75.4, 97.2%]) and 93.4% (CI [75.1, 111.6%]) before and >24 months after THA, respectively. Study quality was low to moderate., Conclusion: Hip abductor muscle strength deficits may gradually improve during 24 months after THA possibly without complete recovery. Cautious interpretation of these findings is warranted because high-quality evidence is largely missing., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The production of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are tightly linked. The generation of ROS can be both the cause and a consequence of ER stress pathways, and an increasing number of human diseases are characterized by tissue atrophy in response to ER stress and oxidative injury. For the assessment of modulators of ER luminal ROS generation and for mechanistic studies, methods to monitor changes in ER reduction-oxidation (redox) states in a time-resolved and organelle-specific manner are needed. This has been greatly facilitated by the development of genetically encoded fluorescent probes, which can be targeted to different subcellular locations by specific amino acid extensions. One of these probes is the yellow fluorescent protein-based redox biosensor, HyPer. Here, we provide a protocol for the time-resolved monitoring of the oxidizing milieu in the ER of adherent mammalian cells using the ratiometric sensor, HyPerER, which is specifically targeted to the ER lumen., Competing Interests: Competing interestsThe authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

Objectives: Osgood-Schlatter disease (OSD) is a sport- and growth-associated knee pathology with locally painful alterations around the tibial tuberosity apophysis. Up to 10% of adolescents are affected by OSD. Treatment is predominantly conservative. The aims of this systematic review are to comprehensively identify conservative treatment options for OSD, compare their effectiveness in selected outcomes, and describe potential research gaps., Methods: A systematic literature search was conducted using CENTRAL, CINAHL, EMBASE, MEDLINE, and PEDro databases. In addition, ongoing and unpublished clinical studies, dissertations, and other grey literature on OSD were searched. We also systematically retrieved review articles for extraction of treatment recommendations., Results: Of 767 identified studies, thirteen were included, comprising only two randomised controlled trials (RCTs). The included studies were published from 1948 to 2019 and included 747 patients with 937 affected knees. Study quality was poor to moderate. In addition to the studies, 15 review articles were included, among which the most prevalent treatment recommendations were compiled., Conclusion: Certain therapeutic approaches, such as stretching, have apparent efficacy, but no RCT comparing specific exercises with sham or usual-care treatment exists. Carefully controlled studies on well-described treatment approaches are needed to establish which conservative treatment options are most effective for patients with OSD., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria., Materials and Methods: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733)., Results: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors., Conclusions: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results and/or cancer predisposition cascade genetic testing for HBOC and LS. We conducted a systematic review and meta-analysis of randomized trials that assessed intervention efficacy for these two outcomes. Additional outcomes were also recorded and synthesized when possible. Fourteen articles met the inclusion criteria and were included in the narrative synthesis and 13 in the meta-analysis. Lack of participant blinding was the most common risk of bias. Interventions targeted HBOC ( n = 5); both HBOC and LS ( n = 4); LS ( n = 3); or ovarian cancer ( n = 2). All protocols ( n = 14) included a psychoeducational and/or counseling component. Additional components were decision aids ( n = 4), building communication skills ( n = 4), or motivational interviewing ( n = 1). The overall effect size for family communication was small ( g = 0.085) and not significant ( p = 0.344), while for cascade testing, it was small ( g = 0.169) but significant ( p = 0.014). Interventions show promise for improving cancer predisposition cascade genetic testing for HBOC and LS. Future studies should employ family-based approaches and include racially diverse samples.

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Methods: Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Hirt J et al.)

Background: Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. Objective: We intend to develop recommendations for the use of citation tracking in health-related systematic literature searching. Our study will be guided by the following research questions: What are the benefits of citation tracking for health-related systematic literature searching? Which perspectives and experiences do experts in the field of literature retrieval methods have with regard to citation tracking in health-related systematic literature searching? Methods: Our study will have two parts: a scoping review and an expert survey. The scoping review aims at identifying methodological studies on benefits or problems of citation tracking in health-related systematic literature searching with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science Core Collection, two information science databases, and free web searching. Two reviewers will independently assess full texts of selected abstracts. We will conduct direct backward and forward citation tracking on included articles. The results of the scoping review will inform our expert survey through which we aim to learn about experts΄ perspectives and experiences. We will narratively synthesize the results and derive recommendations for performing health-related systematic reviews., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Hirt J et al.)

Background : Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Janiaud P et al.)

Introduction: Reduced hip abductor strength may indirectly lead to changes in knee kinematics and functional impairment and has been reported in patients with patellofemoral pain and knee osteoarthritis (OA). Limited information is available regarding hip abductor strength following total or unicompartmental knee arthroplasty (TKA/UKA). The aims of this systematic review are to synthesise the evidence of hip abductor muscle strength deficits in patients following TKA/UKA and to determine influencing factors for these deficits., Methods and Analysis: Embase, Medline, SportDiscus, the Web of Science Core Collection and Scopus will be searched for human-based clinical studies investigating hip abductor muscle strength after TKA/UKA for knee OA or avascular necrosis (AVN). Articles studying hip abductor strength after knee arthroplasty for post-traumatic OA will not be considered. No restriction on study design, prosthesis design, surgical approach, patient characteristics or severity of OA/AVN will be applied. We will search articles published between 1 January 1990 and the date of our last search. Only articles in English or German language will be considered for inclusion. Studies reporting manually measured muscle strength or measurements performed at hip abduction angles other than 0° will be excluded. References will be screened by two reviewers independently. Where necessary, a third author will make the final decision. The assessment of quality and risk of bias will be performed with the modified Newcastle-Ottawa scale. Data will be extracted and presented in a tabular form. Depending on availability, comparable subgroup and meta-analyses will be conducted. Patient characteristics such as age, sex and surgical approach or rehabilitation programme will be analysed, if sufficient data are available., Ethics and Dissemination: No ethics approval is required. The results will be published in a peer-reviewed journal and as conference presentation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Conservation of abductor muscle strength is directly associated with physical function after total hip replacement (THA). Although many studies have tried to explore and quantify a potential abductor muscle strength deficit after THA as well as identify possible causes and treatment options, this topic has not been addressed systematically., Methods and Analysis: Human-based studies reporting measurements of hip abductor strength will be included in this review. Studies reporting on hip abductor strength measured manually or isometric measurements at an abduction angle other than 0° will not be considered. No restriction will be placed on study design, publication date operative approach, prosthesis design, age and sex of the patients or severity of OA. Data sources will be Embase via embase.com, Medline ALL via Ovid and the Cochrane Central Register of Controlled Trials. The preliminary search was conducted on 5 May 2019. Data regarding absolute values or torque ratio of hip abductor torque between sides as well as patient demographic data, surgical approaches and rehabilitation protocols will be extracted. The assessment of quality and risk of bias will be performed with the modified Newcastle-Ottawa Scale. The screening, data extraction and quality assessment will be performed by two reviewers independently. Where necessary, a third review author will make a final judgement. Narrative synthesis as well as tabular presentation of the extracted data will be included. Whenever possible, metaregression and subgroup specific meta-analyses will be used to investigate the influence of time since THA and type of measurement (isokinetic or isometric) on the different outcomes. In case of sufficient information, these analyses will be extended to include characteristics such as age, sex, surgical approach or rehabilitation programme., Ethics and Dissemination: No ethics approval is required. The results will be disseminated through peer-reviewed publications and conference presentations., Prospero Registration Number: CRD42020153185., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The necessity of antibiotic prophylaxis for postoperative urinary tract infections (UTIs) after transurethral resection of bladder tumours is controversial. This potentially leads to the overuse of antibiotic prophylaxis and rising antimicrobial resistance rates. The objective of this systematic review and meta-analysis is to compare the impact of different antimicrobial prophylaxis schemes versus placebo on the prevention of postoperative UTI and asymptomatic bacteriuria., Methods: We designed and registered a study protocol for a systematic review and meta-analysis of randomized controlled trials and non-randomized (e.g. cohort, case-control) studies examining any form of antibiotic prophylaxis in patients with transurethral resection of bladder tumours. Literature searches will be conducted in several electronic databases (from inception onwards), including MEDLINE (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials (CENTRAL). Grey literature will be identified through searching conference abstracts. The primary outcome will be postoperative urinary tract infections. The secondary outcome will be asymptomatic bacteriuria. Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential conflicts will be resolved through discussion. The study methodological quality (or bias) will be appraised using appropriate tools (e.g. Risk of Bias 2.0 tool and Newcastle-Ottawa Scale). If feasible, we will conduct random-effects meta-analysis of outcome data. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g. study design, publication year, the setting of the study, and antibiotics regimen). We will also search, identify, and discuss potential risk factors for urinary tract infections following transurethral resection of bladder tumours. This may serve as basis for a scoping review., Discussion: In times of rising antimicrobial resistance rates, sound evidence on the necessity of antibiotic prophylaxis is essential for implementation into guideline recommendations and for decision-making in clinical practice., Systematic Review Registration: PROSPERO, CRD42019131733.

Background: The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca 2+ store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair. Although depletion of luminal Ca 2+ from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear., Results: We found that Ca 2+ mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca 2+ efflux. Inducible reduction of the ER lumen by GSH flux was independent of the Ca 2+ -binding chaperone calreticulin, which has previously been implicated in this process. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca 2+ mobilization. While the action of puromycin was ascribable to Ca 2+ leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear., Conclusions: Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca 2+ mobilization. We postulate the existence of a Ca 2+ - and cyclosporine A-sensitive GSH transporter in the ER membrane. These findings have important implications for ER redox homeostasis under normal physiology and ER stress.

Sedentary behavior contributes to increased atherosclerotic risk in adults. Whether or not this can be extended to pediatric populations is unclear. This systematic review assessed associations of sedentary behavior with large artery structure and function in pediatric populations. MEDLINE, EMBASE, CENTRAL, and Web of Science were searched from the earliest available date to 31st of December 2018. Analyses of associations of sedentary behavior with large artery structure or function in a pediatric (sub-)population were included, adhering to the PRISMA guidelines. The protocol was published in advance on PROSPERO (CRD42018112996). Study quality and quality of evidence were analyzed using NHLBI Study Quality assessment tools and GRADE. Six observational studies found no association of exposure and outcome variables, and one had contradicting results. One intervention found reduced flow-mediated dilation after 3 h of uninterrupted sitting. Exposure and outcome measures were highly heterogeneous. Study quality was low to moderate. Quality of evidence was very low or low in the observational studies and high in the intervention.Conclusion: In pediatric populations, current evidence is limited and of low quality about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of vascular dysfunction and atherosclerotic risk. Future studies should emphasize a careful choice of the adequate type and measurement site of a biomarker for large artery structure and function as well as conduct a detailed assessment of sedentary behavior patterns.Trial registration: PROSPERO Registration Number: CRD42018112996What is known: • An independent association of sedentary behavior and biomarkers of large artery structure and function has been demonstrated in adults. • In children, sedentary behavior is directly associated with classical cardiovascular risk factors like elevated blood glucose levels, insulin resistance, high blood pressure, obesity, and elevated blood lipids.What is new: • Currently, only few studies of low quality in children and adolescents provide limited evidence about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of atherosclerosis. • The type and measurement site of vascular biomarker need to be chosen carefully, and a detailed assessment of sedentary behavior patterns is important to minimize the methodological bias.

Objective: This scoping review aims at systematically identifying prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Appenzeller-Herzog C et al.)

Background & Aims: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD., Methods: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses., Results: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc., Conclusions: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In the mammalian endoplasmic reticulum, oxidoreductin-1α (Ero1α) generates protein disulfide bonds and transfers them specifically to canonical protein-disulfide isomerase (PDI) to sustain oxidative protein folding. This oxidative process is coupled to the reduction of O 2 to H 2 O 2 on the bound flavin adenine dinucleotide cofactor. Because excessive thiol oxidation and H 2 O 2 generation cause cell death, Ero1α activity must be properly regulated. In addition to the four catalytic cysteines (Cys 94 , Cys 99 , Cys 104 , and Cys 131 ) that are located in the flexible active site region, the Cys 208 -Cys 241 pair located at the base of another flexible loop is necessary for Ero1α regulation, although the mechanistic basis is not fully understood. The present study revealed that the Cys 208 -Cys 241 disulfide was reduced by PDI and other PDI family members during PDI oxidation. Differential scanning calorimetry and small angle X-ray scattering showed that mutation of Cys 208 and Cys 241 did not grossly affect the thermal stability or overall shape of Ero1α, suggesting that redox regulation of this cysteine pair serves a functional role. Moreover, the flexible loop flanked by Cys 208 and Cys 241 provides a platform for functional interaction with PDI, which in turn enhances the oxidative activity of Ero1α through reduction of the Cys 208 -Cys 241 disulfide. We propose a mechanism of dual Ero1α regulation by dynamic redox interactions between PDI and the two Ero1α flexible loops that harbor the regulatory cysteines., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Cellular metabolism provides various sources of hydrogen peroxide (H2O2) in different organelles and compartments. The suitability of H2O2 as an intracellular signaling molecule therefore also depends on its ability to pass cellular membranes. The propensity of the membranous boundary of the endoplasmic reticulum (ER) to let pass H2O2 has been discussed controversially. In this essay, we challenge the recent proposal that the ER membrane constitutes a simple barrier for H2O2 diffusion and support earlier data showing that (i) ample H2O2 permeability of the ER membrane is a prerequisite for signal transduction, (ii) aquaporin channels are crucially involved in the facilitation of H2O2 permeation, and (iii) a proper experimental framework not prone to artifacts is necessary to further unravel the role of H2O2 permeation in signal transduction and organelle biology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The endoplasmic reticulum (ER) is the main cellular Ca(2+)storage unit. Among other signalling outputs, the ER can release Ca(2+)ions, which can, for instance, communicate the status of ER protein folding to the cytosol and to other organelles, in particular the mitochondria. As a consequence, ER Ca(2+)flux can alter the apposition of the ER with mitochondria, influence mitochondrial ATP production or trigger apoptosis. All aspects of ER Ca(2+)flux have emerged as processes that are intimately controlled by intracellular redox conditions. In this review, we focus on ER-luminal redox-driven regulation of Ca(2+)flux. This involves the direct reduction of disulfides within ER Ca(2+)handling proteins themselves, but also the regulated interaction of ER chaperones and oxidoreductases such as calnexin or ERp57 with them. Well-characterized examples are the activating interactions of Ero1α with inositol 1,4,5-trisphosphate receptors (IP3Rs) or of selenoprotein N (SEPN1) with sarco/endoplasmic reticulum Ca(2+)transport ATPase 2 (SERCA2). The future discovery of novel ER-luminal modulators of Ca(2+)handling proteins is likely. Based on the currently available information, we describe how the variable ER redox conditions govern Ca(2+)flux from the ER., (© 2016 Authors; published by Portland Press Limited.)

Endoplasmic reticulum (ER) oxidoreductin 1α (Ero1α) is a disulfide producer in the ER of mammalian cells. Besides four catalytic cysteines (Cys(94), Cys(99), Cys(394), Cys(397)), Ero1α harbors four regulatory cysteines (Cys(104), Cys(131), Cys(208), Cys(241)). These cysteines mediate the formation of inhibitory intramolecular disulfide bonds, which adapt the activation state of the enzyme to the redox environment in the ER through feedback signaling. Accordingly, disulfide production by Ero1α is accelerated by reducing conditions, which minimize the formation of inhibitory disulfides, or by mutations of regulatory cysteines. Here we report that reductive stimulation enhances Ero1α activity more potently than the mutation of cysteines. Specifically, mutation of Cys(208)/Cys(241) does not mechanistically mimic reductive stimulation, as it lowers the turnover rate of Ero1α in presence of a reducing agent. The Cys(208)/Cys(241) pair therefore fulfills a function during catalysis that reaches beyond negative regulation. In agreement, we identify a reciprocal crosstalk between the stabilities of the Cys(208)-Cys(241) disulfide and the inhibitory disulfide bonds involving Cys(104) and Cys(131), which also controls the recruitment of the H2O2 scavenger GPx8 to Ero1α. Two possible mechanisms by which thiol-disulfide exchange at the Cys(208)/Cys(241) pair stimulates the catalytic turnover under reducing conditions are discussed., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)