Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

Lung Transplantation for Primary Ciliary Dyskinesia and Kartagener Syndrome: A Multicenter Study.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener's syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27-3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14-1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Occurrence, Distribution, and Management of Aphid-Transmitted Viruses in Cucurbits in Spain.

The effectiveness of pest and disease management in crops relies on knowledge about their presence and distribution in crop-producing areas. Aphids and whiteflies are among the main threats to vegetable crops since these hemipterans feed on plants, causing severe damage, and are also able to transmit a large number of devastating plant viral diseases. In particular, the widespread occurrence of aphid-transmitted viruses in cucurbit crops, along with the lack of effective control measures, makes surveillance programs and virus epidemiology necessary for providing sound advice and further integration into the management strategies that can ensure sustainable food production. This review describes the current presence and distribution of aphid-transmitted viruses in cucurbits in Spain, providing valuable epidemiological information, including symptom expressions of virus-infected plants for further surveillance and viral detection. We also provide an overview of the current measures for virus infection prevention and control strategies in cucurbits and indicate the need for further research and innovative strategies against aphid pests and their associated viral diseases.

Remote control of transgene expression using noninvasive near-infrared irradiation.

This study investigated whether noninvasive near-infrared (NIR) energy could be transduced into heat in deep-seated organs in which adenovirus type-5 vectors tend to accumulate, thereby activating heat shock protein (HSP) promoter-mediated transgene expression, without local administration of photothermal agents. NIR irradiation of the subdiaphragmatic and left dorsocranial part of the abdominal cavity of adult immunocompetent C3H/HeNRj mice with an 808-nm laser effectively increased the temperature of the irradiated regions of the liver and spleen, respectively, resulting in the accumulation of the heat-inducible HSP70 protein. Spatial control of transgene expression was achieved in the NIR-irradiated regions of the mice administered an adenoviral vector carrying a firefly luciferase (fLuc) coding sequence controlled by a human HSP70B promoter, as assessed by bioluminescence and immunohistochemistry analyses. Levels of reporter gene expression were modulated by controlling NIR power density. Spatial control of transgene expression through NIR-focused activation of the HSP70B promoter, as well as temporal regulation by administering rapamycin was achieved in the spleens of mice inoculated with an adenoviral vector encoding a rapamycin-dependent transactivator driven by the HSP70B promoter and an adenoviral vector carrying a fLuc coding sequence controlled by the rapamycin-activated transactivator. Mice that were administered rapamycin and exposed to NIR light expressed fLuc activity in the splenic region, whereas no activity was detected in mice that were only administered rapamycin or vehicle or only NIR-irradiated. Thus, in the absence of any exogenously supplied photothermal material, remote control of heat-induced transgene expression can be achieved in the liver and spleen by means of noninvasive NIR irradiation.

Conocimiento de los estudiantes de medicina sobre los cuidados paliativos / Medical students’ knowledge of palliative care

Introducción: La historia de los cuidados paliativos es extensa, pues se remonta a los hospicios medievales de la Europa antigua, para posteriormente centrarse en su desarrollo como lugares de acompañamiento para los enfermos en la etapa final de la vida; son considerados como un derecho y parte fundamental de la salud al estar entrelazados con los conceptos de dignidad humana, los principios de autonomía humana y de calidad de vida. Objetivo: Se buscó la realización de un estudio relativo al conocimiento de la disciplina de Cuidados Paliativos por parte de los estudiantes de la carrera de médico cirujano y partero de la Facultad de Medicina de la Universidad Autónoma de Nuevo León, además de la percepción hacia esta disciplina. Metodología: Estudio del tipo transversal y descriptivo, utilizando un cuestionario a partir del Palliative Care Knowledge Test (Prueba de Conocimiento de Cuidados Paliativos, PCKT) distribuido por medios electrónicos, requiriendo del consentimiento informado de los estudiantes para ser incluidos; aquellos que cumplieron con los criterios de inclusión fueron divididos en 3 grupos. Resultados: Se incluyeron 201 estudiantes; 115 se encontraban en el grupo de 10.o > semestre, 26 en el grupo de 1-5.o y el resto en el de 6-9.o; 84 habían recibido alguna formación en cuidados paliativos como materia optativa al no encontrarse dentro del marco curricular. Los temas de farmacología fueron los más desconocidos para los estudiantes de los 3 grupos, además de existir inexperiencia sobre cuándo debe iniciarse este tipo de cuidados. Conclusión: Se encontró la necesidad de incluir los cuidados paliativos dentro de las materias de tipo curricular para la adquisición de competencias de la disciplina como las relativas a dar malas noticias y cuidados al final de la vida, con el objetivo de establecer mejores áreas de preparación para los futuros profesionales médicos. (AU)

Introduction: The history of palliative care is extensive, dating back to the medieval hospices of ancient Europe, to later focus on its development as a place of accompaniment for the sick at the end of life; it is considered a right and a fundamental part of health as it is intertwined with the concepts of human dignity, the principles of human autonomy and quality of life. Objective: The aim was to carry out a study on the knowledge of the discipline of Palliative Care by students of the “médico cirujano y partero” career of the Medicine Faculty from the Universidad Autónoma de Nuevo León, in addition to the perception towards this discipline. Methodology: Cross-sectional and descriptive study, using a questionnaire based on the Palliative Care Knowledge Test (PCKT) distributed electronically, requiring the informed consent of the students to be included; those meeting the inclusion criteria were divided into 3 groups. Results: A total of 201 students were included; 115 were in the 10th > semester group, 26 in the 1st-5th group and the rest in 6th-9th; 84 had received some training in palliative care as an elective subject as it was not within the curricular framework. Pharmacology topics were the most unfamiliar to the students in the 3 groups, in addition to inexperience about when this type of care should be initiated. Conclusion: It was found necessary to include palliative care within the curricular subjects for the acquisition of competencies of the discipline such as those related to giving bad news and end-of-life care; with the aim of establishing better areas of preparation for future medical professionals. (AU)

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial metabolic reprogramming.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs' intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (Δ Ψm ), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics. Author Summary: Pneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.

Lung transplant waitlist outcomes among ABO blood groups vary based on disease severity.

BACKGROUND: Blood group O candidates have lower lung transplantation rates despite having the most common blood group. We postulated that waitlist outcomes among these candidates and those with other blood types vary with disease severity and lung allocation score (LAS). METHODS: We performed a retrospective cohort study of 32,772 waitlist candidates using the United Network of Organ Sharing registry from May 2005 to 2020. After identifying an interaction between blood group and LAS, we evaluated the association between blood group and waitlist outcomes within LAS quartiles using unadjusted and adjusted competing risk models. RESULTS: In the lowest LAS quartile, blood group O had a 20% reduced transplantation rate (SHR: 0.80, 95%CI: 0.75-0.85) and higher waitlist death/removal (1.33, 95%CI: 1.15-1.55) compared with group A. Blood group AB had a 52% higher transplantation rate (SHR: 1.52, 95%CI: 1.34-1.73) in the lowest LAS quartile compared with group A. In the highest LAS quartile, there was no difference in transplantation rates between groups O and A. In contrast, group B had a 19% reduced transplantation rate (SHR, 0.81 95%CI: 0.73-0.89) and AB had a 28% reduced transplantation rate (SHR: 0.72, 95%CI: 0.61-0.86) in the highest LAS quartile. Additionally, groups B and AB had increased risk of waitlist death/removal in the highest LAS quartile compared with A (SHR: 1.27, 95%CI: 1.08-1.48; SHR: 1.31, 95%CI: 1.00-1.72). CONCLUSIONS: Waitlist outcomes among ABO blood groups vary depending on illness severity, which is represented by LAS. Blood group O has lower transplantation rates at low LAS while groups B and AB have lower transplantation rates at high LAS.

Outcomes of Heller Myotomy for Esophageal Achalasia: Lessons From a 48-Year Prospective Experience With 4 Different Techniques.

OBJECTIVE: To provide information on long-term outcomes of Heller myotomy for esophageal achalasia with or without an antireflux fundoplication. BACKGROUND: Since the adoption of the Heller myotomy, surgeons have modified the original technique in order to balance the cure of dysphagia and the consequent cardial incontinence. METHODS: Totally, 470 patients underwent primary Heller myotomy between 1955 and 2020. A long abdominal myotomy (AM) was performed in 83 patients, the Ellis limited transthoracic myotomy (TM) in 30, the laparotomic Heller-Dor (L-HD) in 202, the videolaparoscopic Heller-Dor (VL-HD) in 155. The HD was performed under intraoperative manometric assessment. Starting on 1973 these patients underwent a prospective follow-up program of timed lifelong clinical, radiological, endoscopic evaluations. RESULTS: Median follow-up time was 23.06 years [interquantile range (IQR): 15.04-32.06] for AM, 29.22 years (IQR: 13.46-40.17) for TM, 14.85 years (IQR: 11.05-21.56) for L-HD and 7.51 years (IQR: 3.25-9.60) for VL-HD. In AM, relapse of dysphagia occurred in 25/71 (35.21%), in TM in 11/30 (36.66%), in LH-D in 10/201 (4.97%), in VL-HD in 3/155 (1.93%). Erosive-ulcerative esophagitis was diagnosed for AM in 28.16%, for TM in 30%, for L-HD in 8.45%, for VL-HD in 2.58%. Overall, the outcome was satisfactory in 52.11% for AM, 41.9% for TM, 89.05% for L-HD, 96.12% for VL-HD. CONCLUSIONS: The Dor fundoplication drastically reduces postmyotomy gastroesophageal reflux. The Heller-Dor operation is a competitive option for the cure of esophageal achalasia if this operation is performed according to the rules of surgical physiology learned by means of intraoperative manometry.

Reconsidered surgical aortic valve replacement after declined transcatheter valve implantation.

BACKGROUND: Outcomes for high surgical risk patients who declined transcatheter aortic valve implantation (TAVI) and then reconsidered for conventional aortic valve replacement (rSAVR) for severe calcific aortic stenosis are not well known. METHODS: This single-centre, case-control study (rSAVR vs Conservative group) retrospectively analysed patients for rSAVR (2009-2019). Multivariable logistic regression was used to identify independent predictors of composite of neurological sequelae/renal failure/deep sternal wound infection/re-exploration and death. Survival was compared using Kaplan-Meier curves and log-rank test. A Cox proportional hazards model was used to determine predictors of survival. RESULTS: TAVI was denied in 519/1095 patients, 114(10.4%) had rSAVR (cases) and 405 (37%) were managed conservatively (controls). Mean age for rSAVR was 80 years (IQR: 73.5-85 years). The commonest reason for declining TAVI was prohibitive high risk due to multiple comorbidities. Among rSAVR, hospital mortality was 2.2% and stroke was 4.4%. Median follow-up was conservative; 14.4 months versus rSAVR; 34.8 months. Five-year survival was conservative; 12.6% versus rSAVR; and 59.5% (overall conservative; 38.0% vs. rSAVR; 60.5%, p < 0.001). rSAVR was protective (hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.26, 0.51, p < 0.001) and high comorbidities had high hazard (HR: 1.57, 95% CI: 1.19, 2.07, p = 0.001). rSAVR had fewer hospital readmission episodes (Conservative; 13.6/patient-year vs. rSAVR; 6.9/patient-year, p = 0.002). CONCLUSIONS: rSAVR may be considered in high surgical risk elderly patients who have been declined TAVI in centres with low operative mortality. rSAVR may be superior to conservative management in carefully selected patients.

Isogenic GAA-KO Murine Muscle Cell Lines Mimicking Severe Pompe Mutations as Preclinical Models for the Screening of Potential Gene Therapy Strategies.

Pompe disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation.

Survival After Lung Transplantation for Chronic Hypersensitivity Pneumonitis: Results From a Large International Cohort Study.

Repeated exposure to antigens via inhalation is the primary cause of hypersensitivity pneumonitis, a form of interstitial pneumonia. The chronic form of hypersensitivity pneumonitis leads to progressive loss of respiratory function; lung transplantation is the only therapeutic option for chronically ill patients. The ESTS Lung Transplantation Working Group conducted a retrospective multicentred cohort study to increase the body of knowledge available on this rare indication for lung transplantation. Data were collected for every patient who underwent lung transplant for hypersensitivity pneumonitis in participating centres between December 1996 and October 2019. Primary outcome was overall survival; secondary outcome was freedom from chronic lung allograft dysfunction. A total of 114 patients were enrolled from 9 centres. Almost 90% of patients were diagnosed with hypersensitivity pneumonitis before transplantation, yet the antigen responsible for the infection was identified in only 25% of cases. Eighty per cent of the recipients received induction therapy. Survival at 1, 3, and 5 years was 85%, 75%, and 70%, respectively. 85% of the patients who survived 90 days after transplantation were free from chronic lung allograft dysfunction after 3 years. The given study presents a large cohort of HP patients who underwent lung transplants. Overall survival rate is higher in transplanted hypersensitivity pneumonitis patients than in those suffering from any other interstitial lung diseases. Hypersensitivity pneumonitis patients are good candidates for lung transplantation.

Scrotal arteriovenous malformation: Case report.

Scrotal arteriovenous malformations (AVM) are extremely rare, making them difficult and complex to diagnose, and a therapeutic challenge; few cases of this type have been reported in the literature. This article reports the case of a male patient, 12 years old, with congenital AVM and background of treatment with sclerotherapy and embolization: it was decided to perform a surgical resection, which was successful. Angiography is obligatory in arteriolar cases, and it was backed up with surgical AVM treatment, taking into account the great importance of pre-surgical embolization.

Risk Factors and Outcomes for Gastroparesis After Lung Transplantation.

BACKGROUND: Gastroparesis is common after lung transplantation and is associated with worse transplant outcomes, including the development of chronic lung allograft dysfunction (CLAD). This study sought to identify the prevalence, risk factors, and outcomes associated with a new diagnosis of gastroparesis after lung transplantation. METHODS: This was a single-center retrospective study of patients who underwent lung transplantation in 2008-2018. The primary outcome was a new diagnosis of gastroparesis within 3 years of transplant. Secondary outcomes included a new diagnosis of gastroesophageal reflux and the association between gastroparesis and both post-transplant survival and CLAD-free survival. Multivariable logistic regression was used to compare diagnosis of gastroparesis and gastroesophageal reflux, while multivariable Cox proportional hazards models were used to analyze gastroparesis and post-transplant outcomes. RESULTS: Of 616 patients with no prior history of gastroparesis, 107 (17.4%) were diagnosed with delayed gastric emptying within 3 years of transplant. On multivariable logistic regression, black race (OR 2.16, 95% CI 1.18-3.98, p = 0.013) was significantly associated with a new diagnosis of gastroparesis. Age, sex, history of diabetes, connective tissue disease, type of transplant, diagnosis group, renal function, and body mass index were not predictive of gastroparesis post-transplant. Gastroparesis was significantly associated with CLAD (HR 1.76, 95% CI 1.20-2.59, p = 0.004), but not with overall mortality (HR 1.16, p = 0.43). CONCLUSION: While gastroparesis is common after lung transplantation, it remains difficult to predict which patients will develop these complications post-transplant. Black patients were more likely to be diagnosed with gastroparesis after adjusting for relevant confounders. Gastroparesis is associated with increased risk of CLAD, and further studies are needed to assess whether early detection and treatment can reduce the incidence of CLAD.

Is It Safe to Let Trainees Operate on High Risk Cardiac Surgery Cases?

Increasing complexity in cardiac operations has raised the discussion on trainee autonomy and the number of cases required to achieve competency. This study compares outcomes among cases done by trainees vs consultants for high risk patients. 696 (trainee=158 vs consultant=438) major high risk cardiac operations (Euroscore >10) were reviewed at a single center. Observations were propensity matched to consultant or trainee based on several baseline characteristics. Euroscore was: Trainee; 12.3 ± 1.6 versus Consultant; 12.8 ± 2.2, p=.036. Multivariable analysis did not identify trainee as a risk factor for worse in-hospital mortality (OR; 0.95, CI; 0.4-2.2, p=.914) or composite outcome of length of stay >30 days, deep sternal infection, new hemodialysis, new stroke or transient ischemic attack, in-hospital death or reoperation (OR; 0.64, CI; 0.39-1.03, p=.069). NYHA class, diabetes and emergency/salvage surgery were predictors of worse composite outcome. After propensity matching (130 pairs), there was no difference in reoperation rates (3.1% versus 4.6%, p=.727), inhospital death (5.4% versus 7.7%, p=.607) or composite outcome (20.8% versus 29.2%, p=.152). There was no statistical difference in cross clamp times (Trainee; 74.0 ± 32.7 min vs Consultant; 82.6 ± 51.1, p=.229) and bypass times (Trainee; 116.3 ± 52.8 min versus Consultant 135.3 ± 72.6 min, p=.055). The length of stay was similar (18.2 ± 13.2 days versus 19.9 ± 15.6 days, p=.302). It is possible for trainees to perform high risk cardiac surgery without compromising the quality of patient care.

Identification of Lung Transplant Recipients With a Survival Benefit After Fundoplication.

BACKGROUND: Gastroesophageal reflux disease (GERD) and aspiration of enteric contents are associated with worse outcomes after lung transplantation. The purpose of this study was to elucidate populations of patients who benefit the most from fundoplication after lung transplantation. METHODS: Lung transplantations from 2001 to 2019 (n = 971) were retrospectively reviewed and stratified by fundoplication before (n = 128) or after (n = 24) chronic lung allograft dysfunction (CLAD) development vs patients who did not undergo fundoplication. Patients with a fundoplication before CLAD were propensity matched to patients without a fundoplication. The primary outcome of interest was posttransplant survival. Time-to-event rates were calculated using a multivariable Cox proportional hazards model and Kaplan-Meier functions. RESULTS: Fundoplication before CLAD improved posttransplant survival before and after propensity matching, and it remained a significant predictor after adjusting for baseline characteristics (hazard ratio [HR],0.57; 95 % confidence interval [CI], 0.4 to 0.8; P = .001). Transplant recipients with a restrictive disorder (HR, 0.46; 95 % CI, 0.3 to 0.73; P = .001), age younger than 65 years (HR, 0.48; 95 % CI, 0.32 to 0.71; P < ;0.001), and with both single (HR, 0.47; 95 % CI, 0.28 to 0.79; P = .005) and double (HR, 0.55; 95 % CI, 0.32 to 0.93; P = .027) lung transplants had a significant decrease in mortality after fundoplication. The effect was present after excluding early deaths and CLAD diagnoses. Gastroesophageal reflux disease diagnosed by pH, impedance, or esophagogastroduodenoscopy was not associated with worse outcomes. Among patients with CLAD, a fundoplication was an independent predictor of post-CLAD survival (HR, 0.27; 95 % CI; 0.12 to 0.61; P = .002). CONCLUSIONS: Fundoplication before or after CLAD development is an independent predictor of survival. Younger patients with restrictive disease, independent of the type of transplant, have a survival benefit. Gastroesophageal reflux disease diagnosed by conventional methods was not associated with worse survival.

Extracorporeal life support as a bridge to pulmonary retransplantation: prognostic factors for survival in a multicentre cohort analysis.

OBJECTIVES: Pulmonary retransplant (ReTx) is considered a controversial procedure. Despite literature reporting outcomes following ReTx, limited data exist in recipients bridged to their ReTx on extracorporeal life support (ECLS). The goal of this study was to investigate the outcomes of recipients bridged to a first-time ReTx by ECLS. METHODS: We performed a retrospective multicentre cohort analysis from 10 centres in Europe, Asia and North America. The primary outcome was overall survival. Risk factors were analysed using Cox regression models. RESULTS: ECLS as a bridge to a first-time ReTx was performed in 50 recipients (ECLS-ReTx). During the study period, 210 recipients underwent a first-time ReTx without bridging on ECLS (regular-ReTx) and 4959 recipients had a primary pulmonary transplant (index-Tx). The overall 1-year (55%) and 5-year (29%) survival was significantly worse for the ECLS-ReTx group.Compared to the index-Tx group, the mortality risk was significantly higher after ECLS-ReTx [hazard ratio 2.76 (95% confidence interval 1.94-3.91); P < 0.001] and regular-ReTx [hazard ratio 1.65 (95% confidence interval 1.36-2); P < 0.001].In multivariable analysis, recipient age ≥35 years, time interval <1 year from index-Tx, primary graft dysfunction as transplant indication, venoarterial-extracorporeal membrane oxygenation and Zurich donor score ≥4 points were significant risk factors for mortality in ECLS-ReTx recipients. CONCLUSIONS: Recipients for ECLS-ReTx should be carefully selected. Risk factors, such as recipient age, intertransplant interval, primary graft dysfunction as transplant indication and type of ECLS should be kept in mind before bridging these patients on ECLS to ReTx.

Aspiration of conjugated bile acids predicts adverse lung transplant outcomes and correlates with airway lipid and cytokine dysregulation.

INTRODUCTION: Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes. METHODS: Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections. RESULTS: Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p < 0.001 and 7.3; 2.4-22; p < 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines. CONCLUSIONS: Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes.

Verification of an agent-based disease model of human Mycobacterium tuberculosis infection.

Agent-based models (ABMs) are a powerful class of computational models widely used to simulate complex phenomena in many different application areas. However, one of the most critical aspects, poorly investigated in the literature, regards an important step of the model credibility assessment: solution verification. This study overcomes this limitation by proposing a general verification framework for ABMs that aims at evaluating the numerical errors associated with the model. A step-by-step procedure, which consists of two main verification studies (deterministic and stochastic model verification), is described in detail and applied to a specific mission critical scenario: the quantification of the numerical approximation error for UISS-TB, an ABM of the human immune system developed to predict the progression of pulmonary tuberculosis. Results provide indications on the possibility to use the proposed model verification workflow to systematically identify and quantify numerical approximation errors associated with UISS-TB and, in general, with any other ABMs.

Survival benefit from a second arterial conduit to the circumflex circulation persists in elderly after coronary artery bypass surgery.

BACKGROUND: This retrospective propensity matched study investigated the impact of age on the survival benefit from a second arterial conduit to the left-sided circulation. METHODS: Data for isolated coronary artery bypass surgery were collected from October 2004 to March 2014. All patients with an internal mammary artery graft to left anterior descending artery and additional arterial or venous graft to the circumflex circulation were included. Propensity matching was used to balance co-variates and generate odds of death for each observation. Odds ratios (venous vs. arterial) were charted against age. RESULTS: The in-hospital mortality rate was 1.12% (arterial) vs. 1.24% (venous) (p = 0.77). The overall 10-year survival was 74.6% (venous) vs. 82.6% (arterial) (p = 0.001). A total of 1226 patients were successfully matched to the venous or arterial (second conduit to circumflex territory after left internal mammary artery to left anterior descending artery) cohorts. Odds ratio for death (venous to arterial) showed a linear decremental overall survival benefit for the second arterial graft to circumflex circulation with increasing age. CONCLUSIONS: The survival benefit of a second arterial graft persists through all age groups with a gradual decline with increasing age over the decades. Elderly patients should not be denied a second arterial graft to the circumflex circulation based on age criterion alone.

Assessment of the Current Status of Potyviruses in Watermelon and Pumpkin Crops in Spain: Epidemiological Impact of Cultivated Plants and Mixed Infections.

Viral infections on cucurbit plants cause substantial quality and yield losses on their crops. The diseased plants can often be infected by multiple viruses, and their epidemiology may depend, in addition to the agro-ecological management practices, on the combination of these viral infections. Watermelon mosaic virus (WMV) is one of the most prevalent viruses in cucurbit crops, and Moroccan watermelon mosaic virus (MWMV) emerged as a related species that threatens these crops. The occurrence of WMV and MWMV was monitored in a total of 196 apical-leaf samples of watermelon and pumpkin plants that displayed mosaic symptoms. The samples were collected from 49 fields in three major cucurbit-producing areas in Spain (Castilla La-Mancha, Alicante, and Murcia) for three consecutive (2018-2020) seasons. A molecular hybridization dot-blot method revealed that WMV was mainly (53%) found in both cultivated plants, with an unadvertised occurrence of MWMV. To determine the extent of cultivated plant species and mixed infections on viral dynamics, two infectious cDNA clones were constructed from a WMV isolate (MeWM7), and an MWMV isolate (ZuM10). Based on the full-length genomes, both isolates were grouped phylogenetically with the Emergent and European clades, respectively. Five-cucurbit plant species were infected steadily with either WMV or MWMV cDNA clones, showing variations on symptom expressions. Furthermore, the viral load varied depending on the plant species and infection type. In single infections, the WMV isolate showed a higher viral load than the MWMV isolate in melon and pumpkin, and MWMV only showed higher viral load than the WMV isolate in zucchini plants. However, in mixed infections, the viral load of the WMV isolate was greater than MWMV isolate in melon, watermelon and zucchini, whereas MWMV isolate was markedly reduced in zucchini. These results suggest that the impaired distribution of MWMV in cucurbit crops may be due to the cultivated plant species, in addition to the high prevalence of WMV.