Efficiency of polymyxin B treatment against nosocomial infection: a systematic review and meta-analysis.

Background: Some cohort studies have explored the effects and safety of polymyxin B (PMB) in comparison to other antibiotics for the treatment of nosocomial infections, yielding inconsistent results. This systematic review aims to explore the effectiveness and safety of PMB and compared it with other antibiotics. Methods: A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science, searching specific terms to identify quantitative cohort studies or RCTs that compared the effects of PMB with other antibiotics in terms of their efficacy and safety. The Newcastle-Ottawa Scale (NOS) was conducted to evaluate the risk of bias of observational studies. Odds ratios with 95% confidence intervals were used for outcome assessment. We evaluated heterogeneity using the I 2 test. Results: A total of 22 observational trials were included in the analysis. The PMB group had a higher mortality rate compared to the control group (odds ratio: 1.84, 95% CI: 1.36-2.50, p<0.00001, I 2 = 73%). while, the ceftazidime-avibactam group demonstrated a distinct advantage with lower mortality rates, despite still exhibiting high heterogeneity (odds ratio 2.73, 95% confidence interval 1.59-4.69; p = 0.0003; I 2 = 53%). Additionally, the PMB group had a lower nephrotoxicity rate compared to the colistin group but exhibited high heterogeneity in the results (odds ratio 0.58, 95% CI 0.36-0.93; p = 0.02; I 2 = 73%). Conclusion: In patients with nosocomial infections, PMB is not superior to other antibiotics in terms of mortality, specifically when compared to ceftazidime-avibactam. However, PMB demonstrated an advantage in terms of nephrotoxicity compared to colistin.

Association between pretreatment lymphocyte count and efficacy of immune-enhancing therapy in acute necrotising pancreatitis: a post-hoc analysis of the multicentre, randomised, placebo-controlled TRACE trial.

Background: Immune-enhancing thymosin alpha 1 (Tα1) therapy may reduce infected pancreatic necrosis (IPN) in acute necrotising pancreatitis (ANP). However, the efficacy might be impacted by lymphocyte count due to the pharmacological action of Tα1. In this post-hoc analysis, we tested the hypothesis that pre-treatment absolute lymphocyte count (ALC) determines whether patients with ANP benefit from Tα1 therapy. Methods: A post-hoc analysis of data from a multicentre, double-blind, randomised, placebo-controlled trial testing the efficacy of Tα1 therapy in patients with predicted severe ANP was performed. Patients from 16 hospitals of China were randomised to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the frst 7 days and 1.6 mg once a day for the following 7 days or a matching placebo during the same period. Patients who discontinued the Tα1 regimen prematurely were excluded. Three subgroup analyses were conducted using the baseline ALC (at randomisation), and the group allocation was maintained as intention-to-treat. The primary outcome was the incidence of IPN 90 days after randomisation. The fitted logistic regression model was applied to identify the range of baseline ALC where Tα1 therapy could exert a maximum effect. The original trial is registered with ClinicalTrials.gov, NCT02473406. Findings: Between March 18, 2017, and December 10, 2020, a total of 508 patients were randomised in the original trial, and 502 were involved in this analysis, with 248 in the Tα1 group and 254 in the placebo group. Across the three subgroups, there was a uniform trend toward more significant treatment effects in patients with higher baseline ALC. Within the subgroup of patients with baseline ALC≥0.8 × 10ˆ9/L (n = 290), the Tα1 therapy significantly reduced the risk of IPN (covariate adjusted risk difference, -0.12; 95% CI, -0.21,-0.02; p = 0.015). Patients with baseline ALC between 0.79 and 2.00 × 10ˆ9/L benefited most from the Tα1 therapy in reducing IPN (n = 263). Interpretation: This post-hoc analysis found that the efficacy of immune-enhancing Tα1 therapy on the incidence of IPN may be associated with pretreatment lymphocyte count in patients with acute necrotising pancreatitis. Funding: National Natural Science Foundation of China.

Evidence-based guideline for the prevention and management of perioperative infection.

BACKGROUND: We have updated the guideline for preventing and managing perioperative infection in China, given the global issues with antimicrobial resistance and the need to optimize antimicrobial usage and improve hospital infection control levels. METHODS: We conducted a comprehensive evaluation of the evidence for prevention and management of perioperative infection, based on the concepts of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The strength of recommendations was graded and voted using the Delphi method and the nominal group technique. Revisions were made to the guidelines in response to feedback from the experts. RESULTS: There were 17 questions prepared, for which 37 recommendations were made. According to the GRADE system, we evaluated the body of evidence for each clinical question. Based on the meta-analysis results, recommendations were graded using the Delphi method to generate useful information. CONCLUSIONS: This guideline provides evidence to perioperative antimicrobial prophylaxis that increased the rational use of prophylactic antimicrobial use, with substantial improvement in the risk-benefit trade-off.

Impactful publications of critical care medicine research in China: A bibliometric analysis.

Background: Although publications have been increasing rapidly, the research quality has yet to improve in the field of critical care medicine (CCM) in China. This study aimed at investigating the current status of and the influential factors for impactful publications in CCM research by Chinese authors. Methods: Publications by authors with the affiliation of critical care medicine department or intensive care unit (CCM/ICU) in Chinese as well as American hospitals from 2001 to 2020 were retrieved from the Web of Science Core Collection (WoSCC) database for this bibliometric analysis. Moreover, statistical analyses to test factors affecting impactful publications by Chinese authors were performed. Results: Of 13,487 articles retrieved by this search strategy, 6,622 were published by Chinese authors as first or corresponding authors. The annual publications by Chinese authors have been rapidly increasing from 2001 to 2020, and so did the citations to these articles. However, the proportion in the world of publications by Chinese authors was much less than that by American authors each year [M (IQR): 1.85 (9.592) vs. 27.77 (7.3), p < 0.001]. In addition, impactful articles were significantly less published by Chinese than by American authors, including articles either in journals with a high impact factor (p < 0.001) or in the top 10 journals in the field of CCM (5.4 vs 13.4%, p < 0.001), and articles with high citation frequency as well (p < 0.001). Moreover, the percentage of impactful publications by Chinese authors was likely associated with academic background and regions of the author's affiliations, funds support, public health events of COVID-19, and collaboration between authors. Conclusion: Our results demonstrated that CCM research in China grew rapidly in the recent 20 years. However, the impactful publications remained limited, largely owing to the shortage of comprehensive research training, inactive collaboration, and underfunded CCM research.

Factors Associated With Deep Sedation Practice in Mechanically Ventilated Patients: A Post hoc Analysis of a Cross-Sectional Survey Combined With a Questionnaire for Physicians on Sedation Practices.

Purpose: The study aimed to explore factors associated with deep sedation practice in intensive care units (ICUs). Materials and Methods: A post hoc analysis was conducted for a cross-sectional survey on sedation practices in mechanically ventilated (MV) patients, combined with a questionnaire for physicians regarding their preferences for light sedation (P-pls Score) in 92 Chinese ICUs. Results: There were 457 and 127 eligible MV patients in the light and deep sedation groups respectively. A multivariable logistic regression analysis demonstrated that the control mode of mechanical ventilation, plasma lactate level, and the Sequential Organ Failure Assessment (SOFA) score were independent risk factors for deep sedation practice (p <0.01). Notably, the adjusted odds ratio (95% CI) of the average P-pls score in the ICU ≤ 2 for deep sedation practice was 1.861 (1.163, 2.978, p = 0.01). In addition, the areas under curves of receiver operating characteristics (AUC-ROC) of the model to predict the probability of deep sedation practice were 0.753 (0.699, 0.806) and 0.772 (0.64, 0.905) in the training set and the validation set, respectively. The 28-day mortality was increased in patients with exposure to deep sedation practice but not significantly. Conclusion: Both factors related to stressful stimuli and the ICU physicians' perception of patient tolerability in mechanical ventilation were likely associated with deep sedation practice in MV patients.

Overexpression of interleukin-10 in engineered macrophages protects endothelial cells against LPS-induced injury in vitro.

Endothelial dysfunction is a primary pathophysiological change in sepsis. Macrophages are known to interact with vascular endothelial cells during the development of sepsis. Recently, drug delivery based on engineered macrophages was reported as an alternative approach for the management of diseases. Interleukin-10 (IL10) is a well-known anti-inflammatory cytokine, which reduces inflammation and inhibits dysfunction of endothelial cells caused by sepsis. It is currently poorly understood whether genetically modified macrophages with overexpression of IL10 are able to restore endothelial integrity and function at the cellular level. In this study, we used lentiviral vectors to construct RAW264.7 macrophages engineered to overexpress IL10 (IL10-eM) and investigated the effects of the IL10-eM supernatant on LPS-induced endothelial dysfunction using a noncontact coculture system. We found that cotreatment with IL10-eM supernatant significantly attenuates the effects of LPS-induced dysfunction of endothelial cells, including endothelial inflammatory response, endothelial permeability, and apoptosis. In addition, we discovered that LPS-induced downregulation of VE-cadherin and high production of reactive oxygen species were significantly attenuated upon IL10-eM exposure. Furthermore, upregulation of IL6, TNFα, and Bax was decreased after treatment of cells with IL10-eM supernatant. These results demonstrated that supernatant from engineered macrophages genetically modified with IL10 can effectively protect endothelial cells against LPS-induced dysfunction in vitro, suggesting that exosomes from such engineered macrophages may have therapeutic effects against sepsis.

Tools Are Needed to Promote Sedation Practices for Mechanically Ventilated Patients.

Suboptimal sedation practices continue to be frequent, although the updated guidelines for management of pain, agitation, and delirium in mechanically ventilated (MV) patients have been published for several years. Causes of low adherence to the recommended minimal sedation protocol are multifactorial. However, the barriers to translation of these protocols into standard care for MV patients have yet to be analyzed. In our view, it is necessary to develop fresh insights into the interaction between the patients' responses to nociceptive stimuli and individualized regulation of patients' tolerance when using analgesics and sedatives. By better understanding this interaction, development of novel tools to assess patient pain tolerance and to define and predict oversedation or delirium may promote better sedation practices in the future.

Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Risk Potential for Organ Dysfunction Associated With Sodium Bicarbonate Therapy in Critically Ill Patients With Hemodynamic Worsening.

Background: The role of sodium bicarbonate therapy (SBT) remains controversial. This study aimed to investigate whether hemodynamic status before SBT contributed to the heterogeneous outcomes associated with SBT in acute critically ill patients. Methods: We obtained data from patients with metabolic acidosis from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score matching (PSM) was applied to match the SBT group with the control group. Logistic regression and Cox regression were used to analyze a composite of newly "developed or exacerbated organ dysfunction" (d/eOD) within 7 days of ICU admission and 28-day mortality associated with SBT for metabolic acidosis. Results: A total of 1,765 patients with metabolic acidosis were enrolled, and 332 pairs obtained by PSM were applied to the final analyses in the study. An increased incidence of newly d/eOD was observed in the SB group compared with the control group (54.8 vs. 44.6%, p < 0.01). Multivariable logistic regression indicated that the adjusted OR of SBT for this composite outcome was no longer significant [OR (95% CI): 1.39 (0.9, 1.85); p = 0.164]. This effect of SBT did not change with the quintiles stratified by pH. Interestingly, SBT was associated with an increased risk of the composite of newly d/eOD in the subgroup of patients with worsening hemodynamics before SBT [adjusted OR (95% CI): 3.6 (1.84, 7.22), p < 0.001]. Moreover, the risk potential for this composite of outcomes was significantly increased in patients characterized by both worsening [adjusted OR (95% CI): 2.91 (1.54, 5.47), p < 0.001] and unchanged hemodynamics [adjusted OR (95% CI): 1.94 (1.01, 3.72), p = 0.046] compared to patients with improved hemodynamics before SBT. Our study failed to demonstrate an association between SBT and 28-day mortality in acute critically ill patients with metabolic acidosis. Conclusions: Our findings did not demonstrate an association between SBT and outcomes in critically ill patients with metabolic acidosis. However, patients with either worsening or unchanged hemodynamic status in initial resuscitation had a significantly higher risk potential of newly d/eOD subsequent to SBT.

[Interpretation of Guidelines for controlling confounding factors and reporting results in causal inference studies].

Causal inference research is a causal test designed to assess the impact of exposures on outcomes.Both experimental and observational studies can be used to examine causal associations between exposure factors and outcomes. Experimental studies are sometimes limited by factors such as ethics or experimental conditions. Observational studies account for a large proportion in clinical studies, but the effectiveness and research value of observational studies will be affected if the design of observational studies is not rigorous and the confounding factors are not well controlled.The Guidelines for controlling confounding factors and reporting results in causal inference studie formulated by a special group of 47 editors from 35 journals from all over the world provide good guidance to researchers. This article interprets the guidelines and hopes to provide help for clinical researchers.

Derivation and Validation of an Ensemble Model for the Prediction of Agitation in Mechanically Ventilated Patients Maintained Under Light Sedation.

OBJECTIVES: Light sedation is recommended over deep sedation for invasive mechanical ventilation to improve clinical outcome but may increase the risk of agitation. This study aimed to develop and prospectively validate an ensemble machine learning model for the prediction of agitation on a daily basis. DESIGN: Variables collected in the early morning were used to develop an ensemble model by aggregating four machine learning algorithms including support vector machines, C5.0, adaptive boosting with classification trees, and extreme gradient boosting with classification trees, to predict the occurrence of agitation in the subsequent 24 hours. SETTING: The training dataset was prospectively collected in 95 ICUs from 80 Chinese hospitals on May 11, 2016, and the validation dataset was collected in 20 out of these 95 ICUs on December 16, 2019. PATIENTS: Invasive mechanical ventilation patients who were maintained under light sedation for 24 hours prior to the study day and who were to be maintained at the same sedation level for the next 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 578 invasive mechanical ventilation patients from 95 ICUs in 80 Chinese hospitals, including 459 in the training dataset and 119 in the validation dataset, were enrolled. Agitation was observed in 36% (270/578) of the invasive mechanical ventilation patients. The stepwise regression model showed that higher body temperature (odds ratio for 1°C increase: 5.29; 95% CI, 3.70-7.84; p < 0.001), greater minute ventilation (odds ratio for 1 L/min increase: 1.15; 95% CI, 1.02-1.30; p = 0.019), higher Richmond Agitation-Sedation Scale (odds ratio for 1-point increase: 2.43; 95% CI, 1.92-3.16; p < 0.001), and days on invasive mechanical ventilation (odds ratio for 1-d increase: 0.95; 95% CI, 0.93-0.98; p = 0.001) were independently associated with agitation in the subsequent 24 hours. In the validation dataset, the ensemble model showed good discrimination (area under the receiver operating characteristic curve, 0.918; 95% CI, 0.866-0.969) and calibration (Hosmer-Lemeshow test p = 0.459) in predicting the occurrence of agitation within 24 hours. CONCLUSIONS: This study developed an ensemble model for the prediction of agitation in invasive mechanical ventilation patients under light sedation. The model showed good calibration and discrimination in an independent dataset.

Dexmedetomidine for the prevention of postoperative delirium in patients after intracranial operation for brain tumours (DEPOD study): a study protocol and statistical plan for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium (POD) is prevalent in patients after major surgery and is associated with adverse outcomes. Several studies have reported that dexmedetomidine, a highly selective α2-adrenergic receptor agonist, can decrease the incidence of POD. However, neurosurgical patients are usually excluded from previous studies. The present study was designed to investigate the impact of prophylactic use of low-dose dexmedetomidine on the incidence of POD in patients after intracranial operation. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blinded and placebo-controlled trial. Seven hundred intensive care unit admitted patients after elective intracranial operation for brain tumours under general anaesthesia are randomly assigned to the dexmedetomidine group or the placebo group with a 1:1 ratio. For patients in the dexmedetomidine group, a continuous infusion of dexmedetomidine will be started at a rate of 0.1 µg/kg/hour immediately after enrolment on the day of operation and continued until 08:00 on postoperative day 1. For patients in the placebo group, normal saline will be administered at the same rate as in the dexmedetomidine group. The patients will be followed up for 28 days after enrolment. The primary endpoint is the incidence of POD, which is assessed two times per day using the Confusion Assessment Method for the intensive care unit (ICU), during the first 5 postoperative days. The secondary endpoints include the incidence of dexmedetomidine-related adverse events and non-delirium complications, the length of stay in the ICU and hospital and all-cause 28-day mortality after the operation. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (No KY2019-091-02) and registered at ClinicalTrials.gov. The results of the trial will be presented at national and international conferences relevant to subject fields and submitted to international peer-reviewed journals. TRIAL REGISTRATION NUMBER: Trial registration number: NCT04399343; Pre-results.

Impact of Shenfu injection on a composite of organ dysfunction development in critically ill patients with coronavirus disease 2019 (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). TRIAL DESIGN: This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. PARTICIPANTS: The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7th version) issued by National Health Commission of the People's Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. INTERVENTION AND COMPARATOR: The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7th version so far). MAIN OUTCOMES: The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI RANDOMISATION: The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. BLINDING (MASKING): The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study is expected to recruit 300 patients with COVID-19, (150 in each group). TRIAL STATUS: Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

[Strategies for infection control in managing critically ill patients with suspected coronavirus disease 2019 in non-designated hospital].

The management of healthcare services for the suspected cases in non-designated hospitalsis a serious concern in controlling coronavirus disease 2019 (COVID-19) epidemic. Owing to the complexity of care providers, large requirement of medical supplies as well as the possible needs off frequent transfers, the major difficulty is preventing the coronavirus from spreading while caring the suspected critical cases before the 2019 novel coronavirus ribonucleic acid test results are reported. For the purpose of enhancing the prevention of the propagation of COVID-19, this article puts emphasis on the following aspects in non-designated hospital Peking University Third Hospital: preparatory procedures of receiving critical suspected patients, the management of medical personnel during the waiting session of RNA test results, the delivering procedures of testing samples, the management of referred medical wastes, daily operations including the cleaning and sanitizing of caring units and the management of related patients after the testing session.

Different depths of sedation versus risk of delirium in adult mechanically ventilated patients: A systematic review and meta-analysis.

BACKGROUND: Delirium is multifactorial. This study aimed at determining the association between different depths of sedation and the risk of delirium in adult mechanically ventilated patients. METHODS: A systematic literature retrieval was conducted in databases including Cochrane Central Register of Controlled Trials, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature for publications available till December 2019 without limitation in study type, and followed by a secondary retrieval for related literature. STATA15.1 and WinBugs 14.3 were used in statistical analyses for different sedation depths as the intervention. The main endpoint was delirium occurrence. Secondary endpoints were agitation-related adverse events and mortality. RESULTS: We included 18 studies comprising 8001 mechanically ventilated patients. Different sedation depths were not associated with the occurrence of delirium (OR = 1.00, 95%CI: 0.64-1.58, P = 0.993). Among the 18 enrolled studies, this finding was not confounded by the dosage of benzodiazepines (OR = 0.96, 95%CI: 0.79-1.17, P = 0.717) in eight randomized controlled trials(RCTs) or the patients' disease severity(OR 0.95, 95%CI: 0.79-1.13, P = 0.548) in 10 RCTs. However, contrasting results were found in non-RCTs. The deeper sedation group had a significantly increased risk for death(OR = 1.82, 95% CI: 1.23-2.69, P = 0.003), whereas lighter sedation seemed a potential risk for agitation-related adverse events (OR = 0.61, 95%CI: 0.45-0.84, P = 0.002). CONCLUSIONS: It is inconclusive whether significantly different sedation depths would change the risk of delirium in adult mechanically ventilated patients. TRIAL REGISTRATION NUMBER: The study was registered in PROSPERO(http://www.crd.york.ac.uk/PROSPERO/) under registration number CRD42019145276.