Organ-on-a-chip for studying immune cell adhesion to liver sinusoidal endothelial cells: the potential for testing immunotherapies and cell therapy trafficking.

Immunotherapy has changed the landscape of treatment options for patients with hepatocellular cancer. Checkpoint inhibitors are now standard of care for patients with advanced tumours, yet the majority remain resistant to this therapy and urgent approaches are needed to boost the efficacy of these agents. Targeting the liver endothelial cells, as the orchestrators of immune cell recruitment, within the tumour microenvironment of this highly vascular cancer could potentially boost immune cell infiltration. We demonstrate the successful culture of primary human liver endothelial cells in organ-on-a-chip technology followed by perfusion of peripheral blood mononuclear cells. We confirm, with confocal and multiphoton imaging, the capture and adhesion of immune cells in response to pro-inflammatory cytokines in this model. This multicellular platform sets the foundation for testing the efficacy of new therapies in promoting leukocyte infiltration across liver endothelium as well as a model for testing cell therapy, such as chimeric antigen receptor (CAR)-T cell, capture and migration across human liver endothelium.

Second annual report from the ISSPP PIPAC database.

Objectives: To monitor the results of PIPAC directed therapy based on data from the International Society for the Study of the Pleura and Peritoneum (ISSPP) PIPAC database. Methods: Analysis of data from patients entered between June 15th, 2020, and February 28th, 2023. Results: Twelve centers reported 2,456 PIPAC procedures in 809 patients (median 2, range 1-18) with peritoneal metastasis (PM) from different primary tumors. Approximately 90 % had systemic chemotherapy prior to PIPAC. Twenty-eight percent were treated in prospective protocols. Overall non-access rate was 3.5 %. Concomitant surgical procedures were performed during PIPAC in 1.6 % of the patients. Median length of stay was 2 days. A total of 95 surgical complications were recorded, but only 22 % of these were graded ≥3b. Seventeen-hundred-and-three adverse events were noted, and 8 % were classified ≥3. The rate of complete or major histological response (peritoneal regression grade score, PRGS≤2) increased between the first and the third PIPAC in the group of patients who were evaluated by PRGS, and a PRGS ≤2 or a reduction of the mean PRGS of at least 1 between first and third PIPAC were observed in 80 %. Disease progression (50 %) or technical issues (19 %) were the most important reasons for stopping PIPAC treatment. Median overall survival from first PIPAC directed treatment varied from 10.7 months (CI 8.7-12.5) in gastric cancer to 27.1 months (16.4-50.5) in mesothelioma. Conclusions: The ISSPP PIPAC database provides substantial real-world data supporting the use of PIPAC directed therapy in patients with PM from different primary tumors.

The use of a porcine model to teach advanced abdominal wall dissection techniques.

BACKGROUND: In the era of minimally invasive surgery, it is clear that a robust simulation model is required for the training of surgeons in advanced abdominal wall reconstruction. The purpose of this experimentation was to evaluate whether a porcine model could be used to teach advanced minimally invasive abdominal wall dissection techniques to novice surgeons. Secondary objectives included: time to completion, identification of various anatomical landmarks, to note the difference in porcine and human models and finally, the ability to dock a Da Vinci Xi robotic platform on the porcine model. METHODOLOGY: Two post-fellowship surgeons were given the task of performing an extended total extraperitoneal dissection (ETEP) on one female Landrace pig under the supervision of a surgeon experienced in robotic-assisted ventral hernia repair. This included insertion of ports, developing a retro-rectus plane, crossover from left to right rectus, bilateral transverse abdominus release, and sub-diaphragmatic dissection. A 5-mm vessel sealer was used to facilitate the dissection. The steps of the surgery were given to the trainees, and an experienced hernia surgeon guided the steps of dissection. The emphasis of the tasks was to develop the planes of extraperitoneal dissection to demonstrate that the porcine model could be considered for a viable and realistic model for training. RESULTS: The candidates were able to successfully complete the task and dock a Da Vinci Xi with the porcine model providing a realistic platform for training. CONCLUSION: The porcine model can be a considerable tool in the education of surgeons embarking on learning the art of minimally invasive abdominal wall reconstruction techniques. The advantage of live tissue dissection, similarity in anatomy and the relatively inexpensive availability of porcine models, makes it an unparalleled form of simulation-based training. We believe that this will have transitional capabilities to robotic ETEP education for complex hernia repair.

Opioid prescribing, pain, and hospital stay of general surgery patients with oxycodone allergies in South Australia.

BACKGROUND: The frequency of oxycodone adverse reactions, subsequent opioid prescription, effect on pain and patient care in general surgery patients are not well known. This study aimed to determine prevalence of documented oxycodone allergy and intolerances (independent variables) in a general surgical cohort, and association with prescribing other analgesics (particularly opioids), subjective pain scores, and length of hospital stay (dependent variables). METHODS: This retrospective cohort study included general surgery patients from two South Australian hospitals between April 2020 and March 2022. Multivariable logistic regression evaluated associations between previous oxycodone allergies and intolerances, prescription records, subjective pain scores, and length of hospital stay. RESULTS: Of 12 846 patients, 216 (1.7%) had oxycodone allergies, and 84 (0.7%) oxycodone intolerances. The 216 oxycodone allergy patients had lower odds of receiving oxycodone (OR 0.17, P < 0.001), higher odds of tramadol (OR 3.01, P < 0.001) and tapentadol (OR 2.87, P = 0.001), but 91 (42.3%) still received oxycodone and 19 (8.8%) morphine. The 84 with oxycodone intolerance patients had lower odds of receiving oxycodone (OR 0.23, P < 0.001), higher odds of fentanyl (OR 3.6, P < 0.001) and tramadol (OR 3.35, P < 0.001), but 42 (50%) still received oxycodone. Patients with oxycodone allergies and intolerances had higher odds of elevated subjective pain (OR 1.60, P = 0.013; OR 2.36, P = 0.002, respectively) and longer length of stay (OR 1.36, P = 0.038; OR 2.24, P = 0.002, respectively) than patients without these. CONCLUSIONS: General surgery patients with oxycodone allergies and intolerances are at greater risk of worse postoperative pain and longer length of stay, compared to patients without. Many still receive oxycodone, and other opioids that could cause cross-reactivity.

Surgery's Rosetta Stone: Natural language processing to predict discharge and readmission after general surgery.

BACKGROUND: This study aimed to examine the accuracy with which multiple natural language processing artificial intelligence models could predict discharge and readmissions after general surgery. METHODS: Natural language processing models were derived and validated to predict discharge within the next 48 hours and 7 days and readmission within 30 days (based on daily ward round notes and discharge summaries, respectively) for general surgery inpatients at 2 South Australian hospitals. Natural language processing models included logistic regression, artificial neural networks, and Bidirectional Encoder Representations from Transformers. RESULTS: For discharge prediction analyses, 14,690 admissions were included. For readmission prediction analyses, 12,457 patients were included. For prediction of discharge within 48 hours, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.86 and 0.86 for Bidirectional Encoder Representations from Transformers, 0.82 and 0.81 for logistic regression, and 0.82 and 0.81 for artificial neural networks. For prediction of discharge within 7 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.82 and 0.81 for Bidirectional Encoder Representations from Transformers, 0.75 and 0.72 for logistic regression, and 0.68 and 0.67 for artificial neural networks. For readmission prediction within 30 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.55 and 0.59 for Bidirectional Encoder Representations from Transformers and 0.77 and 0.62 for logistic regression. CONCLUSION: Modern natural language processing models, particularly Bidirectional Encoder Representations from Transformers, can effectively and accurately identify general surgery patients who will be discharged in the next 48 hours. However, these approaches are less capable of identifying general surgery patients who will be discharged within the next 7 days or who will experience readmission within 30 days of discharge.

Sociocultural and Demographic Factors Predict Readmissions for General Surgery Patients.

INTRODUCTION: Readmission is a poor outcome for both patients and healthcare systems. The association of certain sociocultural and demographic characteristics with likelihood of readmission is uncertain in general surgical patients. METHOD: A multi-centre retrospective cohort study of consecutive unique individuals who survived to discharge during general surgical admissions was conducted. Sociocultural and demographic variables were evaluated alongside clinical parameters (considered both as raw values and their proportion of change in the 1-2 days prior to admission) for their association with 7 and 30 days readmission using logistic regression. RESULTS: There were 12,701 individuals included, with 304 (2.4%) individuals readmitted within 7 days, and 921 (7.3%) readmitted within 30 days. When incorporating absolute values of clinical parameters in the model, age was the only variable significantly associated with 7-day readmission, and primary language and presence of religion were the only variables significantly associated with 30-day readmission. When incorporating change in clinical parameters between the 1-2 days prior to discharge, primary language and religion were predictive of 30-day readmission. When controlling for changes in clinical parameters, only higher comorbidity burden (represented by higher Charlson comorbidity index score) was associated with increased likelihood of 30-day readmission. CONCLUSIONS: Sociocultural and demographic patient factors such as primary language, presence of religion, age, and comorbidity burden predict the likelihood of 7 and 30-day hospital readmission after general surgery. These findings support early implementation a postoperative care model that integrates all biopsychosocial domains across multiple disciplines of healthcare.

Vital signs and medical emergency response (MER) activation predict in-hospital mortality in general surgery patients: a study of 15 969 admissions.

BACKGROUND: The applicability of the vital signs prompting medical emergency response (MER) activation has not previously been examined specifically in a large general surgical cohort. This study aimed to characterize the distribution, and predictive performance, of four vital signs selected based on Australian guidelines (oxygen saturation, respiratory rate, systolic blood pressure and heart rate); with those of the MER activation criteria. METHODS: A retrospective cohort study was conducted including patients admitted under general surgical services of two hospitals in South Australia over 2 years. Likelihood ratios for patients meeting MER activation criteria, or a vital sign in the most extreme 1% for general surgery inpatients (<0.5th percentile or > 99.5th percentile), were calculated to predict in-hospital mortality. RESULTS: 15 969 inpatient admissions were included comprising 2 254 617 total vital sign observations. The 0.5th and 99.5th centile for heart rate was 48 and 133, systolic blood pressure 85 and 184, respiratory rate 10 and 31, and oxygen saturations 89% and 100%, respectively. MER activation criteria with the highest positive likelihood ratio for in-hospital mortality were heart rate ≤ 39 (37.65, 95% CI 27.71-49.51), respiratory rate ≥ 31 (15.79, 95% CI 12.82-19.07), and respiratory rate ≤ 7 (10.53, 95% CI 6.79-14.84). These MER activation criteria likelihood ratios were similar to those derived when applying a threshold of the most extreme 1% of vital signs. CONCLUSIONS: This study demonstrated that vital signs within Australian guidelines, and escalation to MER activation, appropriately predict in-hospital mortality in a large cohort of patients admitted to general surgical services in South Australia.

The Adelaide Score: An artificial intelligence measure of readiness for discharge after general surgery.

BACKGROUND: This study aimed to examine the performance of machine learning algorithms for the prediction of discharge within 12 and 24 h to produce a measure of readiness for discharge after general surgery. METHODS: Consecutive general surgery patients at two tertiary hospitals, over a 2-year period, were included. Observation and laboratory parameter data were stratified into training, testing and validation datasets. Random forest, XGBoost and logistic regression models were evaluated. Each ward round note time was taken as a different event. Primary outcome was classification accuracy of the algorithmic model able to predict discharge within the next 12 h on the validation data set. RESULTS: 42 572 ward round note timings were included from 8826 general surgery patients. Discharge occurred within 12 h for 8800 times (20.7%), and within 24 h for 9885 (23.2%). For predicting discharge within 12 h, model classification accuracies for derivation and validation data sets were: 0.84 and 0.85 random forest, 0.84 and 0.83 XGBoost, 0.80 and 0.81 logistic regression. For predicting discharge within 24 h, model classification accuracies for derivation and validation data sets were: 0.83 and 0.84 random forest, 0.82 and 0.81 XGBoost, 0.78 and 0.79 logistic regression. Algorithms generated a continuous number between 0 and 1 (or 0 and 100), representing readiness for discharge after general surgery. CONCLUSIONS: A derived artificial intelligence measure (the Adelaide Score) successfully predicts discharge within the next 12 and 24 h in general surgery patients. This may be useful for both treating teams and allied health staff within surgical systems.

Depression after stoma surgery: a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors. METHODS: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model. REGISTRATION: PROSPERO, CRD42021262345. RESULTS: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2-58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia-Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not. CONCLUSIONS: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period.

Metformin ameliorates ROS-p53-collagen axis of fibrosis and dyslipidemia in type 2 diabetes mellitus-induced left ventricular injury.

BACKGROUND: The link between oxidative stress (ROS), apoptosis (p53) and fibrosis (collagen) in type 2 diabetes mellitus (T2DM)-induced cardiac injury in the presence and absence of the antidiabetic drug, metformin has not been investigated before. MATERIAL AND METHODS: T2DM was induced in rats by a combination of high carbohydrate and fat diets (HCFD) and streptozotocin (50 mg/kg) injection. The protection group started metformin (200 mg/kg) treatment 14 days prior to the induction of diabetes and continued on metformin and HCFD until being sacrificed at week 12. RESULTS: Diabetes significantly induced blood levels of ROS and left ventricular p53 and collagen expression that was inhibited by metformin. Metformin also significantly reduced glycated haemoglobin and dyslipidemia induced by diabetes. In addition, a significant correlation between ROS-p53-collagen axis and glycaemia and hyperlipidaemia was observed. CONCLUSIONS: These findings show that metformin provides substantial protection against diabetic cardiomyopathy-induced ROS-p53 mediated fibrosis and dyslipidemia.

Patient-Reported Bowel, Urinary, and Sexual Outcomes After Laparoscopic-Assisted Resection or Open Resection for Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized Clinical Trial (ALaCart).

OBJECTIVE: The aim of this study was to compare patient-reported urinary, bowel, and sexual functioning of ALaCaRT Trial participants randomized to open or laparoscopic surgery for rectal cancer. SUMMARY BACKGROUND DATA: The primary endpoint, noninferiority of laparoscopic surgical resection adequacy, was not established. METHODS: Participants completed QLQ-CR29 at baseline, 3, and 12 months post-surgery. Additionally, women completed Rosen's Female Sexual Functioning Index (FSFI). Men completed the International Index of Erectile Function (IIEF) and QLQ-PR25. We compared the proportions of participants in each group who experienced moderate/severe symptoms/dysfunction at each time-point and compared mean difference scores from baseline to 12 months between groups. All analyses were intention-to-treat. Sexual functioning analyses included only the participants who expressed sexual interest at baseline. RESULTS: Baseline PRO compliance of 475 randomized participants was 88%. At 12 months, a lower proportion of open surgery participants experienced moderate-severe fecal incontinence and sore skin, compared to Laparoscopic participants, and a lower proportion of men randomized to open surgery experienced moderate-severe urinary symptoms. There were no differences at 3 months for bowel or urinary symptoms. Sexual functioning among sexually interested participants was similar between groups at 3 and 12 months; however, a lower proportion of women reported moderate to severe sexual dissatisfaction at 3 months in the open as compared to the laparoscopic group, (Rebecca.mercieca@sydney.edu.au., 95% CI 0.03-0.39). DISCUSSION: Despite the slightly lower proportions of open surgery participants self-reporting moderate-severe symptoms for 3 of 16 urinary/bowel domains, and lack of differences in sexual domains, it remains difficult to recommend one surgical approach over another for rectal resection.

Assessing the impact of the 2018 National Health and Medical Research Council polyp surveillance guidelines on compliance with surveillance intervals at two public hospitals.

BACKGROUND: Several studies have highlighted poor compliance with surveillance colonoscopy guidelines. The National Health and Medical Research Council (NHMRC) guidelines were revised in 2018 and were more complex than the previous iteration (2011). The aim of this study was to determine the impact of 2018 NHMRC polyp surveillance guidelines on compliance with colonoscopy surveillance intervals. METHODS: A multicentre retrospective clinical audit was conducted between January 2020 and February 2021. Patients awaiting a colonoscopy for polyp surveillance at two public tertiary care hospitals in South Australia were included. Compliance rates of recommended polyp surveillance colonoscopy intervals after implementation of 2018 NHMRC guidelines were compared with 2011 NHMRC guidelines. The projected impact on colonoscopy bookings of the change in guideline intervals was modelled to 5 and 10 years, factoring in differences in compliance. RESULTS: Of 3996 patients awaiting colonoscopy services at two public hospitals in South Australia, 1984 patients (60% male, median age 61 years) were waitlisted for polyp surveillance. Overall compliance with surveillance guidelines was >60%. Implementation of the 2018 NHMRC guidelines significantly reduced compliance from 65.8% (2011 guidelines) to 50.8% (2018) (χ2 <0.001, OR 0.5). Modelling projections to 5 and 10 years demonstrated that application of the 2018 guidelines significantly increases the projected number of colonoscopy bookings per year. CONCLUSION: The revised 2018 NHMRC guidelines have resulted in significantly poorer compliance post-implementation, possibly due to their increased complexity. This has potential to increase the surveillance colonoscopy waiting list burden.

Metformin Is Associated with the Inhibition of Renal Artery AT1R/ET-1/iNOS Axis in a Rat Model of Diabetic Nephropathy with Suppression of Inflammation and Oxidative Stress and Kidney Injury.

Diabetes is the most common cause of end-stage renal disease, also called kidney failure. The link between the renal artery receptor angiotensin II type I (AT1R) and endothelin-1 (ET-1), involved in vasoconstriction, oxidative stress, inflammation and kidney fibrosis (collagen) in diabetes-induced nephropathy with and without metformin incorporation has not been previously studied. Diabetes (type 2) was induced in rats and another group started metformin (200 mg/kg) treatment 2 weeks prior to the induction of diabetes and continued on metformin until being culled at week 12. Diabetes significantly (p < 0.0001) modulated renal artery tissue levels of AT1R, ET-1, inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and the advanced glycation end products that were protected by metformin. In addition, diabetes-induced inflammation, oxidative stress, hypertension, ketonuria, mesangial matrix expansion, and kidney collagen were significantly reduced by metformin. A significant correlation between the AT1R/ET-1/iNOS axis, inflammation, fibrosis and glycemia was observed. Thus, diabetes is associated with the augmentation of the renal artery AT1R/ET-1/iNOS axis as well as renal injury and hypertension while being protected by metformin.

Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin-Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis.

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit­desmin and sarcomere­and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.

Software Analysis of Colonoscopy Videos Enhances Teaching and Quality Metrics.

Purpose Machine learning algorithms were hypothesized as being able to predict the quality of colonoscopy luminal images. This is to enhance training and quality indicators in endoscopy. Methods A separate study involving a randomized controlled trial of capped vs. un-capped colonoscopies provided the colonoscopy videos for this study. Videos were analyzed with an algorithm devised by the Australian Institute for Machine Learning. The image analysis validated focus measure, steerable filters-based metrics (SFIL), was used to assess luminal visualization quality and was compared with two independent clinician assessments (C1 and C2). Goodman and Kruskal's gamma (G) measure was used to assess rank correlation data using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY). Results A total of 500 random colonoscopy video clips were extracted and analyzed, 88 being excluded. SFIL scores matched with C1 in 45% and C2 in 42% of cases, respectively. There was a significant correlation between SFIL and C1 (G = 0.644, p < 0.005) and SFIL and C2 (G = 0.734, p < 0.005). Conclusion This study demonstrates that machine learning algorithms can recognize the quality of luminal visualization during colonoscopy. We intend to apply this in the future to enhance colonoscopy training and as a metric for quality assessment.

Gastrointestinal recovery after surgery: protocol for a systematic review.

INTRODUCTION: Gastrointestinal recovery after surgery is of worldwide significance. Postoperative gastrointestinal dysfunction is multifaceted and known to represent a major source of postoperative morbidity, however, its significance to postoperative care across all surgical procedures is unknown. The complexity of postoperative gastrointestinal recovery is poorly defined within gastrointestinal surgery, and even less so outside this field. To inform the clinical care of surgical patients worldwide, this systematic review and meta-analysis will aim to characterise the duration of postoperative gastrointestinal recovery that can be expected across all surgical procedures and determine the associations between factors that may affect this. METHODS AND ANALYSIS: MEDLINE, Embase, Cochrane Library and CINAHL will be searched for studies reporting the time to first postoperative passage of stool after any surgical procedure. We will screen records, extract data and assess risk of bias in duplicate. Forest plots will be constructed for time to postoperative gastrointestinal recovery, as assessed by various outcome measures. Because of potential heterogeneity, a random-effects model will be used throughout the meta-analysis. Funnel plots will be used to test for publication bias. Meta-regressions will be undertaken where the outcome is the mean time to first postoperative passage of stool, with potential predictors and confounders being patient characteristics, postoperative outcomes and surgical factors. ETHICS AND DISSEMINATION: This study will not involve human or animal subjects and, thus, does not require ethics approval. The outcomes will be disseminated via publication in peer-reviewed scientific journal(s) and presentations at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42021256210.