Transfusion Related Acute Lung Injury (TRALI) Caused by Red Blood Cell Transfusion Involving Residual Plasma Anti-HLA Antibodies: A report on two Cases and General Considerations

TRALI is considered a serious hazard among immune complications of blood transfusion and its occurrence is admitted to be globally underestimated. Each type of blood product is likely to cause TRALI. We report here on two consecutive observations of TRALI caused by red blood cell concentrates, in which anti-HLA class I and class II antibodies resulting from post-gravitational allo-immunization were evidenced in donors. HLA class I and II antigenic community between recipients and donors' husbands were found and strong reacting IgG antibodies directed at several of those common antigens were detected in the donors' serum. Both donors had more than 3 pregnancies, raising the issue of blood donor selection or of plasma reduction for cellular products

Extracellular Vesicle Characteristics in β-thalassemia as Potential Biomarkers for Spleen Functional Status and Ineffective Erythropoiesis

β-thalassemia major (β-TM) is a therapeutically challenging chronic disease in which ineffective erythropoiesis is a main pathophysiological factor. Extracellular vesicles (EVs) are membrane-enclosed vesicles released by cells into biological fluids; they are involved in intercellular communication and in multiple physiological and pathological processes. The chaperone heat-shock protein 70 (HSP70), which is released from cells via EVs, aggravates ineffective erythropoiesis in β-TM. We propose that β-TM EVs may show specific signatures, reflecting disease mechanisms, stages and severity. Our study aims were to define EV profiles in β-TM patients, investigate the influence of hypersplenism and splenectomy on EV features, and explore the association of circulating EVs with ineffective erythropoiesis and iron-overload parameters. We characterized circulating EVs in 35 transfusion-dependent β-thalassemia patients and 35 controls using several techniques. Nanoparticle-tracking analysis revealed increased EV concentration in patients vs. controls (P = 0.0036), with smaller EV counts and sizes in patients with hypersplenism. Flow cytometry analysis showed lower levels of RBC and monocyte EVs in patients vs. controls. RBC-EV levels correlated with patient hematocrit, reflecting degree of anemia. The procoagulant potential of the EVs evaluated by flow cytometry revealed lower levels of endothelial protein C receptor-labeled EVs in patients vs. controls, and increased tissue factor-to-tissue factor pathway inhibitor-labeled EV ratio in splenectomized patients, suggesting a hypercoagulable state. Protein content, evaluated in EV pellets, showed increased levels of HSP70 in patients (P = 0.0018), inversely correlated with transfusion requirement and hemoglobin levels, and positively correlated with reticulocyte, erythropoietin and lactate dehydrogenase levels. This first description of EVs in patients with hypersplenism reveals the spleen’s importance in EV physiology and clearance. Circulating EV-HSP70 levels were associated with markers of ineffective erythropoiesis, hemolysis and hematological disease severity. EV analysis in β-TM—reflecting spleen status, hypercoagulability state and ineffective erythropoiesis—may serve as a biomarker of disease dynamics, supporting both anticipation of the risk of complications and optimizing treatment

Development of the SPUR tool : a profiling instrument for patient treatment behavior

International audienceBackground: Long-term treatment adherence is a worldwide concern, with nonadherence resulting from a complex interplay of behaviors and health beliefs. Determining an individual’s risk of nonadherence and identifying the drivers of that risk are crucial for the development of successful interventions for improving adherence. Here, we describe the development of a new tool assessing a comprehensive set of characteristics predictive of patients’ treatment adherence based on the Social, Psychological, Usage and Rational (SPUR) adherence framework. Concepts from existing self-reporting tools of adherence-related behaviors were identified following a targeted MEDLINE literature review and a subset of these concepts were then selected for inclusion in the new tool. SPUR tool items, simultaneously generated in US English and in French, were tested iteratively through two rounds of cognitive interviews with US and French patients taking long-term treatments for chronic diseases. The pilot SPUR tool, resulting from the qualitative analysis of patients’ responses, was then adapted to other cultural settings (China and the UK) and subjected to further rounds of cognitive testing. Results: The literature review identified 27 relevant instruments, from which 49 concepts were included in the SPUR tool (Social: 6, Psychological: 13, Usage: 11, Rational: 19). Feedback from US and French patients suffering from diabetes, multiple sclerosis, or breast cancer (n = 14 for the first round; n = 16 for the second round) indicated that the SPUR tool was well accepted and consistently understood. Minor modifications were implemented, resulting in the retention of 45 items (Social: 5, Psychological: 14, Usage: 10, Rational: 16). Results from the cognitive interviews conducted in China (15 patients per round suffering from diabetes, breast cancer or chronic obstructive pulmonary disease) and the UK (15 patients suffering from diabetes) confirmed the validity of the tool content, with no notable differences being identified across countries or chronic conditions. Conclusion Our qualitative analyses indicated that the pilot SPUR tool is a promising model that may help clinicians and health systems to predict patient treatment behavior. Further steps using quantitative methods are needed to confirm its predictive validity and other psychometric properties

Endoscopic internal drainage for the management of leak, fistula, and collection after sleeve gastrectomy: our experience in 617 consecutive patients

Background: Endoscopy plays a pivotal role in the management of adverse events (AE) following bariatric surgery. Leaks, fistulae, and post-operative collection after sleeve gastrectomy (SG) may occur in up to 10% of cases. Objectives: To evaluate the efficacy and safety of endoscopic internal drainage (EID) for the management of leak, fistula, and collection following SG. Setting: Retrospective, observational, single center study on patients referred from several bariatric surgery departments to an endoscopic referral center. Methods: EID was used as first-line treatment for the management of leaks, fistulae, and collections. Leaks and fistulae were treated with double pigtail stent (DPS) deployment in order to guarantee internal drainage and second intention cavity obliteration. Collections were treated with endoscropic ultrasound (EUS)–guided deployment of DPS or lumen apposing metal stents. Results: A total of 617 patients (83.3% female; mean age, 43.1 yr) were enrolled in the study for leak (n = 300, 48.6%), fistula (n = 285, 46.2%), and collection (n = 32, 5.2%). Median follow-up was 19.5 months. Overall clinical success was 84.7% whereas 15.3% of cases required revisional surgery after EID failure. Clinical success according to type of AE was 89.5%, 78.5%, and 90% for leak, fistula, and collection, respectively. A total of 10 of 547 (1.8%) presented a recurrence during follow-up. A total of 28 (4.5%) AE related to the endoscopic treatment occurred. At univariate logistic regression predictors of failure were: fistula (OR 2.012), combined endoscopic approach (OR 2.319), need for emergency surgery (OR 1.755), and previous endoscopic treatment (OR 4.818). Conclusion: Early EID for the management of leak, fistula, and post-operative collection after SG seems a safe and effective first-line approach with good long-term results

Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model

Thirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown in transfected HeLa cells that readthrough of nonsense mutations in the MECP2 gene can be achieved by treatment with gentamicin and geneticin. This study was performed to test if readthrough can also be achieved in cells endogenously expressing mutant MeCP2 and to evaluate potentially more effective readthrough compounds. A mouse model was generated carrying the R168X mutation in the MECP2 gene. Transfected HeLa cells expressing mutated MeCP2 fusion proteins and mouse ear fibroblasts isolated from the new mouse model were treated with gentamicin and the novel aminoglycosides NB30, NB54, and NB84. The localization of the readthrough product was tested by immunofluorescence. Readthrough of the R168X mutation in mouse ear fibroblasts using gentamicin was detected but at lower level than in HeLa cells. As expected, the readthrough product, full-length Mecp2 protein, was located in the nucleus. NB54 and NB84 induced readthrough more effectively than gentamicin, while NB30 was less effective. Readthrough of nonsense mutations can be achieved not only in transfected HeLa cells but also in fibroblasts of the newly generated Mecp2R168X mouse model. NB54 and NB84 were more effective than gentamicin and are therefore promising candidates for readthrough therapy in Rett syndrome patients

Nonaminoglycoside compounds induce readthrough of nonsense mutations

Large numbers of genetic disorders are caused by nonsense mutations for which compound-induced readthrough of premature termination codons (PTCs) might be exploited as a potential treatment strategy. We have successfully developed a sensitive and quantitative high-throughput screening (HTS) assay, protein transcription/translation (PTT)–enzyme-linked immunosorbent assay (ELISA), for identifying novel PTC-readthrough compounds using ataxia-telangiectasia (A-T) as a genetic disease model. This HTS PTT-ELISA assay is based on a coupled PTT that uses plasmid templates containing prototypic A-T mutated (ATM) mutations for HTS. The assay is luciferase independent. We screened ∼34,000 compounds and identified 12 low-molecular-mass nonaminoglycosides with potential PTC-readthrough activity. From these, two leading compounds consistently induced functional ATM protein in ATM-deficient cells containing disease-causing nonsense mutations, as demonstrated by direct measurement of ATM protein, restored ATM kinase activity, and colony survival assays for cellular radiosensitivity. The two compounds also demonstrated readthrough activity in mdx mouse myotube cells carrying a nonsense mutation and induced significant amounts of dystrophin protein

How effective are incident reporting systems for improving patient safety? A systematic literature review

Context: Incident reporting systems (IRSs) are used to gather information on patient safety incidents. However, and despite the financial burden they imply, little is known about their effectiveness. This paper reviews systematically the effectiveness of IRSs as a method of improving patient safety through organizational learning. Method: This systematic literature review identified two groups of studies: a) studies comparing the effectiveness of IRSs relative to other methods of error reporting and b) studies examining the effectiveness of IRSs on settings, structures and outcomes in respect of improvements to patient safety. We used thematic analysis to compare the effectiveness of IRSs with other methods and to synthesize what was effective, where and why. Then, to assess the evidence concerning the ability of IRSs to facilitate organizational learning, we analyzed studies using the concepts of single loop and double loop learning. Findings: In total, 43 studies were identified. Eight studies compared IRSs with other methods, while 35 explored the effectiveness of IRSs on settings, structures and outcomes. We did not find strong evidence that IRSs perform better than other methods. We found some evidence of single loop learning, that is, changes to clinical settings or processes as a consequence of learning from IRSs, but little evidence either of improvements to outcomes or of changes to latent managerial factors involved in error production. In addition, there was insubstantial evidence of IRSs enabling double loop learning that is, cultural change or change of mindset. Conclusions: The results indicate IRSs could be more effective if there were explicit criteria for what counts as an incident; they are owned and led by clinical teams rather than centralized hospital departments; and embedded within organizations as part of wider safety programs

Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia

Data availability: Research data are not shared.Supplementary Information oi available online at: https://www.nature.com/articles/s41598-021-98012-w#Sec14 .Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.Grants from MSD-Avenir and APHP funded the SURVIBIO study; Alexandre Nuzzo received Ph.D. Grants from “Fondation de l'Avenir” and the French Gastroenterology Society (SNFGE)