Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Producción CientíficaBackground: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Development of Semi-Static Steam Process for the Production of Sludge-Based Adsorbents

In this study, a specially developed unique process was used to prepare sludge-based activated adsorbents (SBAs) from municipal sewage sludge collected from a wastewater treatment plant in Sharjah. A reaction chamber is designed to allow the carbonization and activation of sewage sludge in a saturated steam environment generated inside the chamber (semi-static). The semi-static steam process is carried out in the absence of any external gas flow into the reaction chamber. The activated sample is subjected to acid treatment. Other SBA samples are also prepared at the same temperatures using a conventional method in the presence of external flow of nitrogen gas. The surface chemistry for the SBA samples is characterized using Boehm titrations, pH measurement, ash content and scanning electron microscope integrated with energy-dispersive spectroscopy (EDAX). The semi-static steam method results in the formation of an SBA sample with acidic surface and higher carbon content as compared with the samples prepared by the conventional method. The metal contents of the SBAs are significantly different and depend on the methods of preparation. Nitrogen sorption isotherms are measured and used for the analysis of structure and porosity. The BET surface area for the SBA sample produced in the proposed method is calculated to be 838 m 2 /g. The SBA samples are then compared for adsorption efficiency of lead ions from aqueous solution, which is observed to be dependent on the microporosity and surface basicity

Lingering SARS-CoV-2 in Gastric and Gallbladder Tissues of Patients with Previous COVID-19 Infection Undergoing Bariatric Surgery

Background Lingering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gut tissue might be a source of infection during bariatric surgery. This study aimed to confirm the presence of SARS-CoV-2 nucleocapsid in gastric and gallbladder tissues removed during bariatric surgery in individuals previously infected with coronavirus disease 2019 (COVID-19) who had negative polymerase chain reaction results prior to the surgery.Methods Gastric and gallbladder specimens from 80 patients who underwent bariatric surgery between November 2021 and May 2022 and had a history of COVID-19 infection with gastrointestinal symptoms were examined for the presence of lingering SARS-CoV-2 nucleocapsid proteins using immunohistochemistry.Results Gastric specimens from 26 (32.5%) patients and 4 (100%) cholecystectomy specimens showed positive cytoplasmic staining for the anti-SARS-CoV-2 nucleocapsid protein in surface mucosal epithelial cells. The mean age was 37.8 +/- 10.3 years. The average body mass index was 44.2 +/- 7.0 kg/m(2); most of the patients were females (71.3%). The positive staining group was significantly younger than the negative staining group (p = 0.007). The full-dose vaccination rate was 58.8%, with a median of 91 days after the last vaccine dose. A positive serological anti-spike IgG response was observed in 99% of the patients. The median time between initial COVID-19 infection and surgery was 274 and 380 days in the positive and negative staining groups, respectively (p = 0.371).Conclusion Gastric and gallbladder tissues can retain SARS-CoV-2 particles for a long time after COVID-19 infection, handling stomach specimens from patients during an operation must be done with care, as we usually do, but now with the knowledge that in 1/3 of patients they can be present. Performing LSG on post-COVID patients did not seem to increase perioperative morbidity.Anesthesiolog

Impact of bariatric surgery on the effectiveness of serological response after COVID-19 vaccination

Purpose The primary objective of the current study is to determine whether bariatric surgery reversed the negative impact of obesity on the serological response after the COVID-19 vaccination. This objective is achieved in two steps: (a) quantifying the negative impact of obesity on the serological response after COVID-19 vaccination if it is present, and (b) testing whether bariatric surgery reversed this impact. The secondary objective was to monitor the occurrence of adverse events. Methods This is a prospective cohort study between May 2021 and August 2021 on the strength of serological response after COVID-19 vaccination. Patients were classified into three groups. Group A (controls with normal or overweight), Group B (bariatric patients pre-operative), and Group C (bariatric patients post-operative). Quantitative antibodies against SARS-CoV-2 RBD with a strong neutralizing capacity were quantified from sera after at least 2 weeks post-vaccination. Results Of the 276 participants, Group A had n = 73, Group B had n = 126, and Group C had n = 77 patients. Overall, a strongly positive vaccine serological response was observed among 86% in group A, 63% in Group B, and 88% in Group C. Group C showed 5.33 times [95% CI 2.15 to 13.18] higher immune response than group B. Mild to moderate adverse events occurred in 30.1% [95% CI 24.7 to 35.9] of the study samples. Adverse events with the whole virus, mRNA, and vector vaccines occurred in 25%, 28%, and 37%, respectively. Conclusion Vaccinating and bariatric surgery are safe and effective treatments in the serological response in patients who suffer from obesity