Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis.

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.

Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

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.

SOD1 is a novel prognostic biomarker of acute kidney injury following cardiothoracic surgery.

BACKGROUND: Acute kidney injury (AKI) is a major burden among hospitalized and critical care patients. Among hospitalized patients that progress to severe AKI there is increased risk for morbidity, mortality, and the need for renal replacement therapy (RRT). As there are no specific treatments for AKI, the discovery of novel biomarkers that predict the progression of AKI may aid in timely implementation of supportive care to improve outcomes. METHODS: We collected urine from 204 patients that developed Stage 1 AKI by AKIN criteria within 72 h following cardiothoracic surgery. Urine samples were collected at the time of the initial diagnosis of AKI and stored at -80° C. Among the 204 patients, 25 progressed to a composite primary outcome of Stage 3 AKI, requirement of RRT, or 30-day mortality. The remaining 179 patients did not progress beyond Stage 2 AKI and were considered controls. Urinary concentrations of SOD1 and SOD1 activity were measured following collection of all samples. Samples were thawed and urinary superoxide dismutase 1 (SOD1) concentrations were measured by sandwich ELISA and urinary SOD1 activity was measured through a commercially available colorimetric assay. RESULTS: Urinary concentrations of SOD1 were significantly elevated (67.0 ± 10.1 VS 880.3 ± 228.8 ng/ml, p < 0.0001) in patients that progressed to severe AKI and were able to predict the progression to severe AKI (AUC - 0.85, p < 0.0001). Furthermore, total SOD activity also increased in the urine of patients that required RRT (77.6% VS 49.81% median inhibition, p < 0.01) and was able to predict the need for RRT (AUC: 0.83, p < 0.01). CONCLUSION: These findings show that urinary SOD1 concentrations and SOD activity are novel prognostic biomarkers for severe AKI following cardiothoracic surgery.

Coadministered pneumococcal conjugate vaccine decreases immune response to hepatitis A vaccine: a randomized controlled trial.

OBJECTIVES: We explored the influence of coadministration on safety and immunogenicity of the most common travellers' vaccine hepatitis A (HepA) and the pneumococcal conjugate vaccine (PCV) increasingly used both at home and before travel. METHODS: Volunteers aged ≥18 years (n = 305) were randomly assigned 1:1:1 into three groups receiving: 13-valent PCV (PCV13) + HepA, PCV13, or HepA. Anti-pneumococcal IgG concentrations, opsonophagocytic activity (OPA) titres, and total hepatitis A antibody (anti-HAV) concentrations were measured before and 28 ± 3 days after vaccination. Adverse events (AEs) were recorded over 4 weeks. RESULTS: After vaccination, the anti-HAV geometric mean concentration was significantly lower in the PCV13+HepA than the HepA group: 34.47 mIU/mL (95% CI: 26.42-44.97 mIU/mL) versus 72.94 mIU/mL (95% CI: 55.01-96.72 mIU/mL), p < 0.001. Anti-HAV ≥10 mIU/mL considered protective was reached by 71 of 85 (83.5%) in the PCV13+HepA group versus 76 of 79 (96.2%) in the HepA group, p 0.008. The increases in anti-pneumococcal IgG and OPA levels were comparable in the PCV13+HepA and PCV13 groups, apart from a bigger rise in the PCV13+HepA group for serotype 3 (one-way ANOVA: serotype 3 IgG p 0.010, OPA p 0.002). AEs proved more frequent among those receiving PCV13 than HepA, but simultaneous administration did not increase the rates: ≥one AE was reported by 45 of 56 (80.4%) PCV13, 43 of 54 (79.6%) PCV13+HepA, and 25 of 53 (47.2%) HepA recipients providing structured AE data. DISCUSSION: Coadministration of HepA and PCV13 did not cause safety concerns, nor did it impact the patients' response to PCV13, apart from serotype 3. However, coadministered PCV13 significantly impaired antibody responses to HepA.

Evaluating the food safety and risk assessment evidence-base of polyethylene terephthalate oligomers: A systematic evidence map.

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.

Citation tracking for systematic literature searching: A scoping review.

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.

Prognostic factors for improvement of shoulder function after arthroscopic rotator cuff repair: a systematic review.

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.

Discovery of seven novel putative antigens in membranous nephropathy and membranous lupus nephritis identified by mass spectrometry.

Multiple autoantigens have been identified in membranous nephropathy (MN) by tissue-based proteomics. However, antigenic targets of disease are unknown for over 10% of patients with MN and over half of those with membranous lupus nephritis (MLN). Here, we identified multiple new targets in PLA2R-/THSD7A-/EXT-/NELL1-quadruple negative MN biopsies through mass spectrometry of immune complexes recovered from biopsy tissue of patients with MN. Patients with MN negative for these four antigens were identified from Arkana Laboratories case archives. Protein G immunoprecipitation recovered immune complexes from frozen biopsy tissue from 142 quadruple-negative cases and 278 cases of known antigen type, followed by interrogation by mass spectrometry. Potential putative antigens were confirmed through paraffin immunofluorescence and co-localization with IgG within immune deposits. Consecutive series of 165 cases of PLA2R-negative MN and 142 MLN biopsies were screened to determine the frequency for each potential antigen. Seven putative antigens were discovered within immune complexes from biopsies of patients with MN including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN. Peptides from these proteins were not enriched in the 278 cases of known antigen type. Between three to 30 unique peptides were detected for each new target. Frequencies of each biomarker, determined by staining consecutive case series, ranged from under 1 to 4.9%. NPR3 and CD206 were only positive in index cases. All cases showed co-localization of IgG within the immune deposits. Thus, seven putative antigens were newly identified in MN and MLN. Due to the number of antigens identified, it is becoming impractical to type PLA2R-negative MN or MLN cases through immunostaining alone. A multiplex approach is needed for subtyping of these diseases.

Predicting neurological outcome in adult patients with cardiac arrest: systematic review and meta-analysis of prediction model performance.

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.

Evaluating the food safety and risk assessment evidence-base of polyethylene terephthalate oligomers: Protocol for a systematic evidence map.

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.

Long-term Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-analysis.

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.

Direct to angiography suite approaches for the triage of suspected acute stroke patients: a systematic review and meta-analysis.

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).

Preparing for patients with high-consequence infectious diseases: Example of a high-level isolation unit.

INTRODUCTION: Patients with high-consequence infectious diseases (HCID) are rare in Western Europe. However, high-level isolation units (HLIU) must always be prepared for patient admission. Case fatality rates of HCID can be reduced by providing optimal intensive care management. We here describe a single centre's preparation, its embedding in the national context and the challenges we faced during the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic. METHODS: Ten team leaders organize monthly whole day trainings for a team of doctors and nurses from the HLIU focusing on intensive care medicine. Impact and relevance of training are assessed by a questionnaire and a perception survey, respectively. Furthermore, yearly exercises with several partner institutions are performed to cover different real-life scenarios. Exercises are evaluated by internal and external observers. Both training sessions and exercises are accompanied by intense feedback. RESULTS: From May 2017 monthly training sessions were held with a two-month and a seven-month break due to the first and second wave of the SARS-CoV-2 pandemic, respectively. Agreement with the statements of the questionnaire was higher after training compared to before training indicating a positive effect of training sessions on competence. Participants rated joint trainings for nurses and doctors at regular intervals as important. Numerous issues with potential for improvement were identified during post processing of exercises. Action plans for their improvement were drafted and as of now mostly implemented. The network of the permanent working group of competence and treatment centres for HCID (Ständiger Arbeitskreis der Kompetenz- und Behandlungszentren für Krankheiten durch hochpathogene Erreger (STAKOB)) at the Robert Koch-Institute (RKI) was strengthened throughout the SARS-CoV-2 pandemic. DISCUSSION: Adequate preparation for the admission of patients with HCID is challenging. We show that joint regular trainings of doctors and nurses are appreciated and that training sessions may improve perceived skills. We also show that real-life scenario exercises may reveal additional deficits, which cannot be easily disclosed in training sessions. Although the SARS-CoV-2 pandemic interfered with our activities the enhanced cooperation among German HLIU during the pandemic ensured constant readiness for the admission of HCID patients to our or to collaborating HLIU. This is a single centre's experience, which may not be generalized to other centres. However, we believe that our work may address aspects that should be considered when preparing a unit for the admission of patients with HCID. These may then be adapted to the local situations.

Prognostic factors for the occurrence of post-operative shoulder stiffness after arthroscopic rotator cuff repair: a systematic review.

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.

The Metabolic Signature of Cardiorespiratory Fitness: A Systematic Review.

BACKGROUND: Cardiorespiratory fitness (CRF) is a potent health marker, the improvement of which is associated with a reduced incidence of non-communicable diseases and all-cause mortality. Identifying metabolic signatures associated with CRF could reveal how CRF fosters human health and lead to the development of novel health-monitoring strategies. OBJECTIVE: This article systematically reviewed reported associations between CRF and metabolites measured in human tissues and body fluids. METHODS: PubMed, EMBASE, and Web of Science were searched from database inception to 3 June, 2021. Metabolomics studies reporting metabolites associated with CRF, measured by means of cardiopulmonary exercise test, were deemed eligible. Backward and forward citation tracking on eligible records were used to complement the results of database searching. Risk of bias at the study level was assessed using QUADOMICS. RESULTS: Twenty-two studies were included and 667 metabolites, measured in plasma (n = 619), serum (n = 18), skeletal muscle (n = 16), urine (n = 11), or sweat (n = 3), were identified. Lipids were the metabolites most commonly positively (n = 174) and negatively (n = 274) associated with CRF. Specific circulating glycerophospholipids (n = 85) and cholesterol esters (n = 17) were positively associated with CRF, while circulating glycerolipids (n = 152), glycerophospholipids (n = 42), acylcarnitines (n = 14), and ceramides (n = 12) were negatively associated with CRF. Interestingly, muscle acylcarnitines were positively correlated with CRF (n = 15). CONCLUSIONS: Cardiorespiratory fitness was associated with circulating and muscle lipidome composition. Causality of the revealed associations at the molecular species level remains to be investigated further. Finally, included studies were heterogeneous in terms of participants' characteristics and analytical and statistical approaches. PROSPERO REGISTRATION NUMBER: CRD42020214375.

Outcome of right ventricular assist device implantation following left ventricular assist device implantation: Systematic review and meta-analysis.

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.

Diagnosing Overtraining Syndrome: A Scoping Review.

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.

Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews.

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.

Development of ACE2 autoantibodies after SARS-CoV-2 infection.

BACKGROUND: Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. METHODS AND FINDINGS: We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies. CONCLUSIONS: Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.