BackgroundSternotomy provides access to the mediastinum, heart and great vessels for congenital cardiac surgery in children. The contribution of this incision to the systemic inflammatory response during open-heart surgery, particularly in combination with the complement-mediated response to cardiopulmonary bypass (CPB), is unknown. This study aimed to characterize the inflammatory mediator profile of sternotomy and contrast that with CPB-associated inflammation.MethodsThis study is a post-hoc analysis of a single-arm prospective clinical study (NCT05154864) of 40 pediatric patients undergoing congenital cardiac surgery with CPB. Arterial blood samples were taken before and after sternotomy, but before CPB initiation (sternotomy phase), and after CPB exposure (CPB phase). Thirty-three inflammatory mediators from the cytokine, chemokine, complement, and adhesion molecule families were measured. The mediator changes were calculated for each phase and described using median fold changes. A principal component analysis with hierarchical clustering (PCA-HCPC) was conducted on mediator changes over the sternotomy phase.ResultsCompared to baseline, all 16 cytokines and chemokines assessed increased through the sternotomy phase, while complement and adhesion molecules were static or decreased. The most active mediators were IL-1β (3.3x median fold increase), CXCL2 (3.3x), IL-6 (2.6x), IL-10 (2.6x), GM-CSF (2.3x), IL-1α (2.2x) and IL-2 (1.7x). The PCA-HCPC showed three statistically significant clusters, cluster 1 grouped cytokines and chemokines with the sternotomy phase, while complement mediators and adhesion molecules were in separate clusters. In contrast to the CPB exposure, sternotomy showed a predominant contribution of TNF, IL-1α, IL-1β, IL-2, TRAIL, CCL3, CCL4, CXCL1, CXCL2 and GM-CSF to the systemic inflammatory response.ConclusionsSternotomy and related tissue trauma produce a distinct systemic inflammatory mediator profile, consisting of pro-inflammatory cytokines and chemokines but not complement. The mediators IL-6, CXCL8, IL-1Ra and IL-10 are sequentially induced by both sternotomy and CPB, representing sequential immunologic stimulation during the cardiac operation.

Background: Sanguineous preparation of the cardiopulmonary bypass (CPB) circuit with allogeneic blood products is known to contain substantial complement mediator burden. This study aims to assess the longitudinal immunologic impacts during pediatric CPB. Methods: In this post-hoc analysis of a prospective observational cohort study, 40 pediatric patients undergoing cardiac surgery with CPB were grouped by CPB prime type indicated by standard of care (sanguineous vs crystalloid). Arterial samples were collected before CPB, after CPB initiation, and at 30-min intervals until weaning or 180 min. Luminex® measured concentrations of 33 inflammatory mediators for time series and fold change comparison between groups. Results: The sanguineous prime group (n = 26) was younger (4.0 [0.2-6.0] versus 48.5 [39.0-69.5] months; P < .001) and smaller (4.9 [3.4-6.6] versus 17.2 [14.9-19.6] kg; P < .001) than the crystalloid prime group (n = 14). The sanguineous group had significantly more circulating complement mediators, including C3a, C3b, and C5a, and soluble adhesion molecules throughout the CPB time series (P < .05). TNF, IL-1α, and IL-1β were relatively static in both groups, although slightly more prominent in the crystalloid group (P < .05). IL-6, IL-10, and CXCL8 profiles were comparable between groups. Conclusions: Patients who receive sanguineous CPB prime have elevated complement and soluble cellular adhesion molecule burden throughout CPB, relative to a crystalloid prime. Therefore, these allogeneic preparations should be considered an immunogenic stimulus during pediatric CPB, and future innovation should focus on less inciting alternatives.

BACKGROUND:Pediatric cardiac surgery with cardiopulmonary bypass (CPB) is associated with systemic inflammation. This trial aimed to determine whether continuous high-exchange ultrafiltration during CPB has a clinical immunomodulatory effect. METHODS:This single-center, double-blind trial enrolled pediatric patients weighing <15 kg undergoing cardiac surgery who were randomly allocated to continuous high-exchange subzero-balance ultrafiltration (H-SBUF; 60 mL/kg per hour effluent extraction) or continuous low-exchange subzero-balance ultrafiltration (L-SBUF; 6 mL/kg per hour effluent extraction) administered during CPB. The primary outcome was peak postoperative vasoactive-ventilation-renal (VVR) score. Secondary outcomes included acute kidney injury, low cardiac output syndrome, health care utilization, and inflammatory mediator fold change throughout CPB (NCT04920643). RESULTS:A total of 104 patients were randomly allocated to H-SBUF (n = 52) or L-SBUF (n = 52). The primary outcome was similar between groups as the peak VVR score was 26.9 (2.1-77.9) in the H-SBUF group and 27.8 (0.8-76.7) in the L-SBUF group (P = .67). There were no operative deaths and no significant differences in acute kidney injury, low cardiac output syndrome, ventilation time, inotropic agent use time, intensive care unit stay, or hospital length of stay (P > .05). The H-SBUF group had a higher fold change for interleukin-1α, P-selectin, and vascular cell adhesion molecule 1 (P < .05), whereas 36 other mediators were not significantly different between groups (P > .05). CONCLUSIONS:In pediatric patients undergoing cardiac surgery with CPB, continuous high-exchange SBUF did not reduce peak VVR score compared with low-exchange SBUF. Furthermore, there were no differences in secondary clinical outcomes, and the immunologic profile was largely similar between groups.

Activation of the alternative complement pathway by artificial extracorporeal surfaces is relevant to several clinical applications such as cardiac surgery with cardiopulmonary bypass (CPB), thoracic organ transplantation and hemodialysis. In the pediatric cardiac surgery population, complement mediators have been associated with systemic inflammation, post-operative morbidity and delayed recovery. Small children require CPB circuit prepared with allogeneic blood products and these sanguineous primes have substantially higher concentrations of biologically active anaphylatoxins C3a and C5a relative to the patient’s baseline circulation. Sequential samples were collected during forty-five ex-vivo sanguineous prime preparations of CPB circuits coated with phosphorylcholine, as a biocompatibility technology, to characterize complement activation in this context. We observed and quantified evidence of alternative and terminal complement pathway activation indicated by dynamic concentration increases of C3a, C3b, C5a and terminal complement complex. Circuit exposure time was a predictor of only C3a concentration in multivariable generalized linear mixed-effects models. Despite modern biocompatibility technology, there is significant alternative complement activation during ex-vivo sanguineous CPB prime preparation. Patient exposure to this activated mediator burden during CPB could promote systemic endothelial inflammation with negative end-organ and post-operative clinical impacts. Further research is required to evaluate and inhibit complement responses to artificial surfaces broadly used for clinical care.

BackgroundCardiopulmonary bypass is associated with systemic inflammation during pediatric cardiac surgery and features elevated systemic concentrations of complement, cytokines and chemokines. The objective of this study is to quantify the immunologic efficacy of ultrafiltration (UF) used continuously throughout CPB.MethodsPediatric patients were enrolled in a single-arm prospective clinical study (NCT05154864) and received standard cardiac operations, CPB and subzero-balance ultrafiltration (SBUF) with an effluent extraction rate of 30 mL/kg/hr and conventional ultrafiltration (CUF). Paired arterial and UF effluent samples were taken at regular intervals during CPB and the concentration of 33 inflammatory mediators were measured. An exploratory counterfactual analysis assessed whether UF removed a significant amount of mediator mass using area under the curve (AUC), generalized linear mixed-effects models (GLMEM), and median fold change [95% CI] comparisons between observed data (UF) and reconstructed counterfactual data (no UF).ResultsForty consecutive eligible consenting patients participated; the majority were male (58%), age of 7.3 (1.7 - 39.0) months and weight of 6.7 (4.6 - 14.9) kg. All patients received UF therapy with effluent extraction of 155 (100 - 185) ml/kg during CPB. C3a, C5a, TNF, IL-1α, IL-1β, IL-1Ra, IL-2, IL-6, IL-10, CCL2, CCL3, CCL4, CXCL1, CXCL2, CXCL8, ET1, GM-CSF and TRAIL were detected in the UF effluent. In the counterfactual analysis, only C3a was significantly extracted by UF using AUC (p = 3.5 × 10-12), GLMEM (p = 2.3 × 10-87), and median fold change [95% CI] as C3a showed a decrease of -0.2 [-0.3 to 0] relative to CPB initiation, in the observed data, compared to the counterfactual with a median fold increase of 4.3 [3.1 - 5.3].ConclusionsUltrafiltration during pediatric CPB extracts cytokines and chemokines continuously throughout CPB with relatively low effectiveness. In an exploratory counterfactual analysis, C3a was the only inflammatory mediator meaningfully removed from the circulation by UF.

INTRODUCTION:A new training model known as "Competence by Design" (CBD) is centered on evaluating "entrustable professional activities" and "milestones" and it represents a paradigm change from time-based to outcome-based learning and evaluation. This study presents a qualitative quality assurance and improvement assessment of the current state of CBD in cardiac surgery training at a single center. METHODS:An initial questionnaire was distributed to three focus groups: educators, traditional-system trainees, and CBD trainees. Building on the questionnaire responses, in-depth interviews were conducted and qualitative thematic data analysis was performed to identify recurrent themes. RESULTS:Thirteen participants were interviewed (6 educators and 7 residents, n = 4 traditional-system trainees and n = 3 CBD trainees). Thematic analysis generated 16 themes, including six major themes. CBD (1) promotes a more standardized approach to surgical training, (2) allows for more objective assessment of residents' progress, (3) encourages a focused approach to specific skill development, (4) comes with increased administrative workloads, (5) allows for early recognition of struggling or failing residents with documentation, and (6) presents challenges in understanding and implementation for both residents and educators. CONCLUSIONS:To our knowledge, this is the first study to assess the benefits and pitfalls of CBD in a Canadian cardiac surgery training program with feedback from both educators and trainees. Our participants felt that CBD has value in providing more standardized training, more elaborate and well-documented assessments, more detailed and meaningful feedback, and outcome-based training focused on the acquisition of surgical skills despite increased administrative workloads. Our participants identified specific challenges involved in understanding and implementing the CBD model.

Introduction Surgical repair is the standard of care for most infants and children with congenital heart disease. Cardiopulmonary bypass (CPB) is required to facilitate these operations but elicits a systemic inflammatory response, leading to postoperative organ dysfunction, morbidity and prolonged recovery after the surgery. Subzero-balance ultrafiltration (SBUF) has been shown to extract proinflammatory cytokines continuously throughout the CPB exposure. We hypothesize that a high-exchange SBUF (H-SBUF) will have a clinically relevant anti-inflammatory effect compared with a low-exchange SBUF (L-SBUF). Methods and analysis The ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) trial is a randomised, double-blind, parallel-group randomised trial conducted in a single paediatric cardiac surgery centre. Ninety-six patients less than 15 kg undergoing cardiac surgery with CPB will be randomly assigned to H-SBUF during CPB or L-SBUF during CPB in a 1:1 ratio with stratification by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score 1 and STAT score 2-5. The primary outcome is peak postoperative vasoactive-ventilation-renal score. Time series and peak values of vasoactive-ventilation renal score, vasoactive-inotrope score, ventilation index and oxygenation index will be collected. Secondary clinical outcomes include acute kidney injury, ventilator-free days, inotrope-free days, low cardiac output syndrome, mechanical circulatory support, intensive care unit length of stay and operative mortality. Secondary biomarker data include cytokine, chemokine and complement factor concentrations at baseline before CPB, at the end of CPB exposure and 24 hours following CPB. Analyses will be conducted on an intention-to-treat principle. Ethics and dissemination The study has ethics approval (#1024932 dated August 31, 2021) and enrolment commenced in September 2021. The primary manuscript and any subsequent analyses will be submitted for peer-reviewed publication. Trial registration number NCT04920643.

BackgroundThe inflammatory response to cardiopulmonary bypass (CPB) in pediatric patients remains an unresolved challenge. Sanguineous CPB prime, composed of allogenic blood products, is one potentially important stimulus. This study aims to identify specific inflammatory mediators active in sanguineous CPB prime and their impact on the inflammatory response at CPB initiation.MethodsIn a post-hoc analysis of a prospective observational cohort study (NCT05154864), where pediatric patients undergoing cardiac surgery with CPB were enrolled after informed consent, patients were grouped by CPB prime type (sanguineous vs crystalloid). Arterial samples were collected post-sternotomy as a baseline and again at CPB initiation from all patients. In the sanguineous group, CPB prime samples were also collected after buffered ultrafiltration but before CPB initiation. Luminex® measured concentrations of 24 inflammatory mediators for comparison between groups. Statistical analyses were by Mann-Whitney test and Wilcoxon signed-rank test. Data are presented as median [IQR].ResultsForty consecutive pediatric patients participated. The sanguineous group (n = 26) was younger (4.0 [0.2 - 6.0] vs 48.5 [39.0 - 69.5] months; p = 2.6 × 10-7) and smaller (4.9 [34 - 6.6] vs 17.2 [14.9 - 19.6] kg; p = 2.6 × 10-7) than the crystalloid group (n = 14). Despite this, baseline concentrations of 20 complement and cytokine concentrations were comparable between groups (p > 0.05) while four showed differences between groups (p < 0.05). The sanguineous prime contained supraphysiologic concentrations of complement mediators: C2, C3, C3a, C3b, and C5a. Correspondingly, upon CPB initiation, patients receiving sanguineous prime exhibited a significantly larger burden of C2, C3, C3b, C5, and C5a (p < 0.001) relative to the crystalloid group. Cytokine and chemokine mediators were present at trace levels in the sanguineous prime.ConclusionsSanguineous prime contains activated complement that accelerates the inflammatory response at CPB initiation in neonates and infants. Immunomodulatory interventions targeting complement during CPB prime preparation could offer substantial benefits for these vulnerable patients.

Abstract Background Cardiopulmonary bypass (CPB) causes systemic inflammation during pediatric cardiac surgery, which can contribute to post-operative organ dysfunction and prolonged recovery. This study aims to identify key inflammatory mediators related to this clinically significant immunologic response. Methods Pediatric patients were enrolled in a single-arm prospective clinical study (NCT05154864) and received standard cardiac operation, CPB and subzero-balance ultrafiltration. Arterial samples were taken before CPB initiation and immediately after weaning, and concentrations of 33 inflammatory mediators were assayed. A principal component analysis with hierarchical clustering (PCA-HCPC) included inflammatory mediator concentrations measured at the end of CPB, validated peak post-operative clinical scores, ventilation time and intensive care length of stay. Mahalanobis distance assessed statistical differences between clusters. Spearman’s correlation described the linear relationship between mediator concentrations at the end of CPB and intensive care length of stay. Results are median (IQR). Results Forty consecutive patients were enrolled; the majority were male (58%), age of 7.3 (1.7–39.0) months and weight of 6.7 (4.6–14.9) kg. The PCA-HCPC revealed activated complement factors along with all peak clinical scores and prolonged intensive care requirements in the same cluster. Cytokine, chemokine, and leukocyte adhesion molecule concentrations were found in two other distinct clusters (Mahalanobis distance = 16.5; p = 0.004 and Mahalanobis distance = 17.4; p = 5.8 × 10–4). Mediator concentrations of C2 (Rho = 0.50; p = 0.001), C3 (Rho = 0.58; p = 1.1 × 10–4), C3b (Rho = 0.47; p = 0.002), C5 (Rho = 0.48; p = 0.002) and C5a (Rho = 0.63; 1.7 × 10–5) showed linear correlations with intensive care unit length of stay. Conclusions Activated complement factors, but not pro-inflammatory cytokines or chemokines, were most related to cardiopulmonary dysfunction and prolonged recovery in this novel analysis. Investigation of therapies that inhibit complement to dampen CPB-associated inflammation and enhance recovery after pediatric cardiac surgery is warranted. Trial Registration ClinicalTrials.gov, NCT05154864

Cardiopulmonary bypass (CPB) causes systemic inflammation, contributing to post-operative organ dysfunction and prolonged recovery after pediatric cardiac surgery. Various immunologic pathways are stimulated during cardiac surgery and CPB, however, it is unclear which mediators are relevant to clinical outcomes. Furthermore, there are no effective anti-inflammatory therapies for CPB-associated inflammation. This study aims to evaluate a novel form of ultrafiltration and identify key inflammatory mediators related to organ dysfunction following pediatric cardiac surgery.

Background Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators. Methods Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated. Results A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi 2 statistic = 18.8, Chi 2 with Yates’ correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = − 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF. Conclusions CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery. Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864 .

A rare case of unique and previously unreported variant of transposition of great arteries with bilateral coni, ventricular septal defect, and triple-chambered left ventricle which led to an unexpected and accelerated post-natal cardiac anatomical and physiologic deviation from prenatal and immediate postnatal diagnosis altering the surgical management and patient outcome.

Abstract High-flow nasal cannula (HFNC) therapy is commonly used in the pediatric intensive care unit (PICU) for postextubation respiratory support. This hypothesis-generating retrospective cohort study aimed to compare postextubation PICU length of stay in infants extubated to HFNC and low flow oxygen (LF) in PICU following cardiac surgery. Of 136 infants (newborn to 1 year) who were intubated and mechanically ventilated in PICU following cardiac surgery, 72 (53%) were extubated to HFNC and 64 (47%) to LF. Compared with patients extubated to LF, those extubated to HFNC had significantly longer durations of cardiopulmonary bypass (152 vs. 109 minutes; p  = 0.002), aortic cross-clamp (90 vs. 63 minutes; p  = 0.003), and invasive mechanical ventilation (3.2 vs. 1.6 days; p  < 0.001), although demographic and preoperative clinical variables were similar. No significant difference was observed in postextubation PICU length of stay between HFNC and LF groups in unadjusted analysis (3.3 vs. 2.6 days, respectively; p  = 0.19) and after controlling for potential confounding variables (F [1,125] = 0.17, p  = 0.68, R 2  = 0.16). Escalation of therapy was similar between HFNC and LF groups (8.3 vs. 14.1%; p  = 0.41). HFNC was effective as rescue therapy for six patients in the LF group requiring escalation of therapy. Need for reintubation was similar between HFNC and LF groups (8.3 vs. 4.7%; p  = 0.5). Although extubation to HFNC was associated with a trend toward longer postextubation PICU length of stay and was successfully used as rescue therapy for several infants extubated to LF, our results must be interpreted with caution given the limitations of our study.

Medical students' career choices are influenced by many factors. However, it is unclear how perceptions of cardi-ology and cardiac surgery affect students' career choices in either specialty. This study assessed impact of advice on specialty interest, sources of advice, and what factors were associated with interest in cardiology and/or cardiac sur-gery. Important sources of advice were peers, preceptors, lectures, and clinical experiences. Interest in minimally invasive/new technologies and procedure-based care were the most common persuading factors in cardiac surgery and cardiology. Medical educators should acknowledge the importance of early exposure in their field, involve-ment in lectures, and extracurricular events.

Case report of a unicorn: anomalous double ostium left main coronary artery with common intra-mural connection. Three-dimensional virtual endo-luminal angioscopy and catheter-based imaging confirmed the diagnosis, subsequently avoiding cardiac surgical intervention.

Due to resource restrictions related to the COVID-19 pandemic, many pediatric patients are facing substantial delays for surgery, potentially resulting in additional distress for caregivers. We aimed to assess the experiences and psychosocial distress of parents during COVID-19 as they relate to the pandemic, waiting for surgery, and the combined effects of both events. The was a cross-sectional qualitative study. Parents with children who faced treatment delays during the initial wave of the COVID-19 pandemic for elective, non-emergent procedures across a variety of surgical specialties were recruited. Semi-structured telephone interviews and thematic analysis were utilized. Thematic saturation was reached with eighteen participants. Four themes were identified: coping with COVID-19, distress levels, quality and nature of communication with the surgical team, and the experience of COVID-19 related hospital restrictions. Participants reported varying levels of distress due to the delay in surgery, such as the fear of developmental delay or disease progression for their child. They also indicated their own physical and mental health had been impacted by emotional distress related to both COVID-19 and delays in treatment. Most participants experienced the COVID-19-related hospital restrictions as distressing. This related predominantly to limiting in-hospital caregivers to only one caregiver. Participants were found to have substantial levels of psychosocial distress. Targeted social and emotional support may be helpful in reducing parental distress as the pandemic timeframe continues. Within the limits of individual health systems, reducing restrictions to the number of allowed care givers may help allay distress felt by parents.

The use of cardiopulmonary bypass (CPB) can be associated with significant hemodilution, coagulopathy and a systemic inflammatory response for infants and children undergoing cardiac surgery. Intra-operative ultrafiltration has been used for decades to ameliorate these harmful effects. The novel combination of a continuous and non-continuous form of ultrafiltration, Subzero Balance Simple Modified Ultrafiltration (SBUF-SMUF) here described, seeks to enhance recovery from pediatric cardiac surgery and CPB.

Background Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory syndrome that adversely impacts cardiopulmonary function and can contribute to prolonged postoperative recovery. Intra-operative ultrafiltration during CPB is a strategy developed by pediatric cardiac specialists, aiming to dampen the inflammatory syndrome by removing circulating cytokines and improving coagulation profiles during the cardiac operation. Although ultrafiltration is commonly used in the pediatric population, it is not routinely used in the adult population. This study aims to evaluate if randomized evidence supports the use of continuous intra-operative ultrafiltration to enhance recovery for adults undergoing cardiac surgery with CPB. Methods This systematic review and meta-analysis will include randomized controlled trials (RCT) that feature continuous forms of ultrafiltration during adult cardiac surgery with CPB, specifically assessing for benefit in mortality rates, invasive ventilation time and intensive care unit length of stay (ICU LOS). Relevant RCTs will be retrieved from databases, including MEDLINE, Embase, CENTRAL and Scopus, by a pre-defined search strategy. Search results will be screened for inclusion and exclusion criteria by two independent persons with consensus. Selected RCTs will have study demographics and outcome data extracted by two independent persons and transferred into RevMan. Risk of bias will be independently assessed by the Revised Cochrane Risk-of-Bias (RoB2) tool and studies rated as low-, some-, or high- risk of bias. Meta-analyses will compare the intervention of continuous ultrafiltration against comparators in terms of mortality, ventilation time, ICU LOS, and renal failure. Heterogeneity will be measured by the χ 2 test and described by the I 2 statistic. A sensitivity analysis will be completed by excluding included studies judged to have a high risk of bias. Summary of findings and certainty of the evidence, determined by the GRADE approach, will display the analysis findings. Discussion The findings of this systematic review and meta-analysis will summarize the evidence to date of continuous forms of ultrafiltration in adult cardiac surgery with CPB, to both inform adult cardiac specialists about this technique and identify critical questions for future research in this subject area. Systematic review registration This systematic review and meta-analysis is registered in PROSPERO CRD42020219309 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020219309 ).