Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review

<div><p>The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I² 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.</p></div

Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta- analyses prior to initiating a first-in-human trial

Abstract Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies

PRISMA flow diagram.

<p>PRISMA flow diagram.</p

Subgroup analyses of mesenchymal stem cellson the odds of mortality in preclinical models of acute lung injury.

<p><b>Fig 3A</b>: Forest plot of mesenchymal stem cells on the odds of mortality at a priori determined time points. <b>Fig 3B</b>: Forest plot of mesenchymal stem cells on the odds of mortality according to animal species, gender and experimental model of acute lung injury. <b>Fig 3C</b>: Forest plot of mesenchymal stem cells on the odds of mortality according to MSC origin, source, preparation, and route of administration, as well as comparator control groups. Subgroup analyses conducted to examine the robustness of the treatment effect according to the clinical relevance of the ALI model (timing of MSC administration in relation to ALI induction and resuscitation of the animals) (<b>Fig 3D</b>) indicated a reduction in the odds of death regardless of the timing of administration of the cells, although the protective effect of MSCs appeared less the longer the delay in treatment initiation. There were no significant differences in the treatment effect of MSCs with more clinically relevant animal models (e.g. use of antibiotics, resuscitation fluid, or the combination of resuscitation fluid and antibiotics). Analyses conducted according to selective outcome reporting and incomplete outcome reporting did not reveal substantial differences in the estimate of effect (<b>Fig 3E</b>). <b>Fig 3D</b>: Forest plot of mesenchymal stem cells on the odds of mortality according to timing of MSC administration and method of resuscitation. <b>Fig 3E</b>: Forest plot of mesenchymal stem cells on the odds of mortality according to domains of the Cochrane Risk of Bias.</p

Funnel plot of standard error by log odds ratio for overall mortality indicates the possibility of publication bias.

<p>Funnel plot of standard error by log odds ratio for overall mortality indicates the possibility of publication bias.</p

Forest plot of mesenchymal stem cellson the odds of mortality in preclinical models of acute lung injury.

<p>Letters indicate two separate mortality experiments within one publication.</p

Effect of BMI on safety of bariatric surgery during the COVID-19 pandemic, procedure choice, and safety protocols - An analysis from the GENEVA Study

Background: It has been suggested that patients with a Body Mass Index (BMI) of &gt; 60 kg/m2 should be offered expedited Bariatric Surgery (BS) during the Coronavirus Disease-2019 (COVID-19) pandemic. The main objective of this study was to assess the safety of this approach. Methods: We conducted a global study of patients who underwent BS between 1/05/2020 and 31/10/2020. Patients were divided into three groups according to their preoperative BMI -Group I (BMI &lt; 50 kg/m2), Group II (BMI 50-60 kg/m2), and Group III (BMI &gt; 60 kg/m2). The effect of preoperative BMI on 30-day morbidity and mortality, procedure choice, COVID-19 specific safety protocols, and comorbidities was assessed. Results: This study included 7084 patients (5197;73.4 % females). The mean preoperative weight and BMI were 119.49 &amp; PLUSMN; 24.4 Kgs and 43.03 &amp; PLUSMN; 6.9 Kg/m2, respectively. Group I included 6024 (85 %) patients, whereas Groups II and III included 905 (13 %) and 155 (2 %) patients, respectively.The 30-day mortality rate was higher in Group III (p = 0.001). The complication rate and COVID-19 infection were not different. Comorbidities were significantly more likely in Group III (p = &lt; 0.001). A significantly higher proportion of patients in group III received Sleeve Gastrectomy or One Anastomosis Gastric Bypass compared to other groups. Patients with a BMI of &gt; 70 kg/m2 had a 30-day mortality of 7.7 % (2/26). None of these patients underwent a Roux-en-Y Gastric Bypass. Conclusion: The 30-day mortality rate was significantly higher in patients with BMI &gt; 60 kg/m2. There was, however, no significant difference in complications rates in different BMI groups, probably due to differences in procedure selection

30-Day Morbidity and Mortality of Bariatric Surgery During the COVID-19 Pandemic: a Multinational Cohort Study of 7704 Patients from 42 Countries.

BACKGROUND There are data on the safety of cancer surgery and the efficacy of preventive strategies on the prevention of postoperative symptomatic COVID-19 in these patients. But there is little such data for any elective surgery. The main objectives of this study were to examine the safety of bariatric surgery (BS) during the coronavirus disease 2019 (COVID-19) pandemic and to determine the efficacy of perioperative COVID-19 protective strategies on postoperative symptomatic COVID-19 rates. METHODS We conducted an international cohort study to determine all-cause and COVID-19-specific 30-day morbidity and mortality of BS performed between 01/05/2020 and 31/10/2020. RESULTS Four hundred ninety-nine surgeons from 185 centres in 42 countries provided data on 7704 patients. Elective primary BS (n = 7084) was associated with a 30-day morbidity of 6.76% (n = 479) and a 30-day mortality of 0.14% (n = 10). Emergency BS, revisional BS, insulin-treated type 2 diabetes, and untreated obstructive sleep apnoea were associated with increased complications on multivariable analysis. Forty-three patients developed symptomatic COVID-19 postoperatively, with a higher risk in non-whites. Preoperative self-isolation, preoperative testing for SARS-CoV-2, and surgery in institutions not concurrently treating COVID-19 patients did not reduce the incidence of postoperative COVID-19. Postoperative symptomatic COVID-19 was more likely if the surgery was performed during a COVID-19 peak in that country. CONCLUSIONS BS can be performed safely during the COVID-19 pandemic with appropriate perioperative protocols. There was no relationship between preoperative testing for COVID-19 and self-isolation with symptomatic postoperative COVID-19. The risk of postoperative COVID-19 risk was greater in non-whites or if BS was performed during a local peak