Percutaneous coronary intervention (PCI) for chronic total occlusions (CTO) is common despite the equivocal evidence regarding its benefits. This study aimed to evaluate the impact of pre-PCI viability or ischemia assessment on left ventricular (LV) function, ischemic burden, symptoms, and major adverse cardiovascular events in CTO patients. A systematic search of PubMed/MEDLINE, EMBASE, CENTRAL, Web of Science Core Collection, ClinicalTrials.eu, and ClinicalTrials.gov was conducted. Studies assessing viability and/or ischemia before PCI with follow-up data were included. Quality was assessed using Cochrane Risk of Bias 2.0 and ROBINS-I tools. Meta-analyses were conducted for quantitative outcomes and narrative synthesis for heterogeneous data. A total of 21 studies (3 randomized, 18 observational) were included; notably, among the randomized trials, only one required the presence of viability or ischemia as an inclusion criterion. Twenty-one studies were included in this review. Cardiac magnetic resonance was the most used imaging modality, followed by positron emission tomography. Successful PCI was associated with improved LV ejection fraction (MD: 3.97

BACKGROUND:Genetic predisposition plays a major role in the development of invasive pulmonary aspergillosis (IPA). The risk and course of IPA vary significantly among patients, yet continuously new genetic mechanisms that influence individual antifungal immune responses are being discovered. While genetic variability in interleukin (IL)-1 family cytokines is recognized as an important cause of disease susceptibility, it is unclear whether and how less-studied IL-1 family members, such as the IL-36 cytokine subfamily, are genetically regulated and influence the risk of infection. METHODS:We analyzed how genetic variants in the IL36 loci associate with the risk of IPA in 328 eligible recipients of allogeneic hematopoietic stem cell transplants and their corresponding donors. The functional consequences of relevant genetic variants were investigated using clinical samples and in vitro infection models. RESULTS:We report that recipient, but not donor, single-nucleotide polymorphisms (SNPs) rs895497 in IL36A and rs4849142 in IL36B increase the risk of IPA after transplantation. The strongest contribution of these SNPs to infection risk was observed in a combined analysis of transplant pairs. IL-36β was expressed in both human type II-like alveolar epithelial cells and macrophages following Aspergillus fumigatus infection. The risk genotype was associated with impaired production of IL-1β in bronchoalveolar lavage fluid samples from infected patients, as well as in fungal-stimulated macrophages. Moreover, macrophages harboring the risk genotype exhibited impaired fungicidal activity. CONCLUSIONS:Our findings suggest that genotype-specific mechanisms mediated by IL-36β act on the nonhematopoietic compartment, can impair antifungal immune responses in macrophages, and ultimately predispose to transplant recipient susceptibility to IPA.

INTRODUCTION AND OBJECTIVES:Chronic coronary total occlusion (CTO) optimal therapeutic management remains a topic of debate despite its association with adverse clinical outcomes. This study aimed to compare clinical outcomes of patients with CTOs treated with coronary artery bypass graft (CABG) versus medical therapy (MT), assessing the effect of CTO revascularization in patients with multivessel disease undergoing CABG. METHODS:In July 2023, PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for studies comparing CTOs treated with CABG versus MT. A sub-analysis of CABG patients, comparing complete surgical revascularization, including CTO bypass, to CABG without CTO bypass, was performed. A pooled odds ratio meta-analysis assessed four main outcomes: mortality, myocardial infarction (MI), stroke, and major adverse cardiovascular events (MACE). The primary outcome was all-cause mortality. RESULTS:Ten observational studies (6458 patients) comparing CABG-CTO with MT-CTO showed lower all-cause mortality in the CABG group (OR 0.31, 95% CI 0.24-0.40, p<0.001, I2=36%). Despite heterogeneity, CABG exhibited reduced CV mortality and MACE (OR 0.37, 95% CI 0.24-0.57, p<0.001, I2=59%; OR 0.37, 95% CI 0.15-0.92, p=0.03, I2=80%, respectively). The MI rate was lower in the CABG group (OR 0.41, 95% CI 0.30-0.56, p<0.001, I2=0%). Comparing bypassed to non-bypassed CTO groups (5 studies, 1949 patients), the bypassed-CTO group had considerably lower MACE (OR 0.49, 95% CI 0.30-0.81, p=0.005, I2=44%). CONCLUSION:This study suggests a clinical benefit of bypassing a CTO in multivessel disease patients during CABG, with significantly lower MACE. The improved outcomes of CABG over MT further underscore these findings, warranting careful consideration by the Heart Team during their decision-making process.

Introduction: Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a major complication following hematopoietic stem cell transplantation, resulting from immune and chemical toxicity in the sinusoidal endothelium and hepatocellular damage. In the most severe cases, multiorgan dysfunction occurs, so it is essential to promptly identify patients at greater risk of SOS/VOD and to adopt prophylactic strategies. Objectives: This study aims to systematize the impact of different approaches as primary prophylaxes against SOS/VOD in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods: A systematic review and meta-analysis of randomized clinical trials evaluating different strategies for primary prophylaxis of SOS/VOD was carried out in pairwise fashion and with a consistent network structure. The odds ratio (OR) and corresponding confidence intervals were calculated using the random-effects model. Heterogeneity was assessed by the I2 method and the efficacy of each approach was estimated by SUCRA (surface under the cumulative ranking curve). Results: Considering all patients undergoing HSCT, ursodeoxycholic acid (UDCA) [OR = 0.38, 95%CI 0.14–1.06, SUCRA = 0.720] was associated with a lower incidence of VOD while defibrotide reached a modest reduction in its incidence [OR = 0.64, 95%CI 0.23–1.67; SUCRA = 0.486]. Considering the subgroup of patients undergoing hematopoietic progenitors allotransplantation, defibrotide scored higher [OR = 0.51, 95%CI 0.09–2.85, SUCRA = 0.650] by comparison with UDCA [OR = 0.53, 95%CI 0.14–1.96, SUCRA = 0.639]. Conclusions: This is the first meta-analysis comparing primary prophylaxes against SOS/VOD. UDCA yielded more promising results when considering all patients undergoing hematopoietic stem cell transplantation, yet, in a subgroup analysis of the ones exposed to allogeneic grafts, it becomes not significantly overrun by defibrotide.

We present a case of a 67-year-old Caucasian male, with history of hypertension, obesity, and previous hepatitis B infection. He was diagnosed with chronic lymphocytic B leukemia in 2011, treated with rituximab, cyclophosphamide, and fludarabine. His disease progressed in 2014 and was treated with 6 cycles of R-CHOP. Then, in 2015 a hematopoietic stem cell transplant (HSCT) from a related donor (fludarabin/bussulfan conditioning regimen) was performed. Cyclosporine A and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis and lamivudine for hepatitis B reactivation prophylaxis.

ABSTRACT Background Chronic coronary total occlusion (CTO) is a common finding in patients referred to coronary angiography. To sustain blood flow distally to the occlusion site, collateral circulation is formed from preexisting vessels. While these collaterals may partial or completely preserve perfusion at rest, they may be insufficient when increased blood flow is needed. According to current guidelines, percutaneous coronary intervention (PCI) is recommended solely in patients with resistant angina despite optimal medical therapy or when a large area of documented ischemia in the territory of the occluded vessel is present. Randomised controlled trials (RCTs) suggest its benefit in the improvement of patients’ quality of life and symptoms, despite their conflicting results concerning prognosis and left ventricular function. However, most of these studies often lack data regarding myocardial ischemic burden and viability, assessed by imaging methods. Therefore, the purpose of the systematic review is to comprise and analyse the literature on whether viability or ischemia-guided PCI of CTO, identified by imaging methods, has an impact on the clinical outcomes of the patients. Methods We will conduct a thorough research in different databases, including PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science Core Collection, Clinical trials in the European Union, and ClinicalTrials.gov . We will include RCTs, cohort studies, cross-sectional studies, and case-control studies, in which patients with established CTO were tested for viability and/or ischemia before the decision to perform PCI and were evaluated by post-intervention testing or clinical endpoint follow-up. Two authors will independently review the selected studies, and any discrepancies will be solved by a third element. Subsequently, data from the various eligible studies will be extracted and analysed by two different authors. No subgroup analysis is planned. Ethics and disclosure Ethical approval will not be required for this study as it is an analysis of previously published articles (i.e., secondary data). The results will be published in a peer-reviewed journal. PROSPERO registration CRD42023426858.

Severe combined immunodeficiency disorders (SCID) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function that lead to a wide spectrum in clinical manifestations. A subgroup of patients presents a disabling and life-threatening clinical course. In these cases, allogeneic hematopoietic stem cell transplant provides a curative approach. The occurrence of SCID-associated lymphoproliferative disorders is rare and occur mostly in adenosine deaminase-deficient severe combined immunodeficiency disorders, after allogeneic hematopoietic stem cell transplant. Epstein Barr virus infection is present in the majority of individuals with primary immunodeficiency developing lymphoma, revealing compromised anti-tumour surveillance of virally transformed cells. Herein, we report a rare case of diffuse large B cell lymphoma occurring in an Epstein Barr virus negative, non-transplanted X-linked severe combined immunodeficiency 4-months-old infant, successfully treated with immunotherapy and allogeneic stem cell transplantation. This case suggests that Epstein Barr virus -independent mechanism of neoplastic transformation must take action in severe combined immunodeficiency associated lymphoma and unveils the curative potential of donor T cells after allogeneic transplantation.

Abstract Background: Allogenic stem cell transplant (alloSCT) has been used for several decades as a salvage strategy for relapsed/ refractory Hodgkin lymphoma (R/R HL), being a durable disease control method for some patients. Methods: A unicenter retrospective analysis was performed about alloSCT in R/R HL along 21 years. A survival analysis was made in search for prognostic factors with impact in overall survival (OS)/progression free survival (PFS). Results: Thirty-five patients were reviewed: median age 30years [17-46], 57.1% males, 82.9% had an esclero-nodular HL, 54.3% were in stage II of disease, and 42.9% achieved a complete response before the alloSCT. The donor type was matched-related in 54.3% and the stem cell source was peripheral blood in 97.1% of the grafts. All patients did a reduced intensity conditioning regimen. The overall response rate was 85.7% (complete in 68.6%, partial in 17.1%). Acute graft versus host disease grade II-IVwas seen in 45.7%. Transplant related mortality at day 360 was 17.9%. The median OS was 61 months (95% confidente interval: 33.6-88.3). The median PFS was 1Omonths (95% confidente interval: 3.1-16.9). Patients with >3Oyears at the alloSCT time and a previous autologous SCT showed better OS/PFS in the univariate analysis; having a matched donor and absence of infections along the alloSCT also improved PFS. Conclusions: AlloSCT is a feasible procedure in patients with R/R HL, being able to stabilize the disease in a large number of patients. However, it has a relevant toxicity in patients highly pre-treated.

Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.

Pull-the-Strings presents a mapping model for digital puppetry based on a transparent framework to support generic device controllers and generic tools. Digital puppetry requires a creative interaction design, in particular in the way designers map the puppet to the puppeteer using specific devices. This process depends on a constantly changing interface technology, which limits the reuse of devices and mappings. This paper proposes a methodology and a set of tools that facilitate the mapping process, and promote the recycling of technologies. A flexible and generic environment independent from device specifications. By abstracting the hardware layer, the artist is motivated to think in terms of signal flow, establishing relations through meaningful mappings instead of handling the diverse specifications of each device and application. Pull-the-Strings is a data-flow ecosystem that focus on the functional usage of control signals. It provides a scalable environment for building semantic blocks that connect, transform and generate signals for the manipulation of virtual objects. Its goal is to make technology as transparent as possible, facilitating connections and reducing the obstacles between the performer and the performing object. On the other hand, it proposes an interaction design space that takes into account the manipulation and perception distance, responding to the specifications of the digital puppetry medium. This model was evaluated comparing a set of tools and methods with experienced and non-experienced users.

Collateral development in chronic total occlusions (CTO) is crucial to perfuse the distal myocardium and its angiographic evaluation is frequently used to assess the need for revascularization. We aimed to analyse the association between the presence of ischemia and hibernating myocardium, evaluated by cardiac [ 13 N]NH3/2-[ 18 F]FDG PET-CT, and the angiographic characterization of the collateral circulation. Prospective study including patients with a CTO who underwent a [ 13 N]NH3 and, when deemed necessary, 2-[ 18 F]FDG PET-CT. Well developed (WD) collaterals were defined as a concomitant angiographic Rentrop grade 3 and Werner collateral connection score 2 or 3, whereas the remaining as poorly developed (PD). 2% thresholds used to identify prognostic benefit of revascularization were applied: ischemia > 10% and hibernating myocardium > 7%. Fifty-nine patients (age 62.9±9.1 years, 58 male) were recruited, WD collaterals were present in 28 (47.5%). No significant differences were found in ischemia (WD 6.4±4.3 vs. PD 7.0±4.1, p = 0.64) and hibernation (WD 1.8±1.9 vs. PD 3.1±3.3, p = 0.18) scores. Most CTO territories demonstrated ischemia, but only 19 (46.3%) were associated with an area > 10% (WD 47.6% vs. PD 45.0%, p = 0.58). Scared non-viable myocardium was limited to 9 (15.3%) patients and was not associated with PD collaterals. Hibernating myocardium was frequent (54.2%), but just 6 (10.2%) CTO patients had an area of > 7% (WD 3.6% vs. PD 16.1%, p = 0.20). Collateral assessment by angiography has a poor association with the ischemic burden and hibernation state of CTO territories. Myocardial viability was present even in most CTO with angiographic PD collaterals.

There have been several approaches to building charts for CV risk, all of which have both strengths and limitations. Identifying early organ damage provides relevant information and should be included in risk charts, although the direct relationship with risk is imprecise, variability between operators at the time to assess, and low availability in some healthcare systems, limits its use. Biomarkers, like troponin (cTns) isoforms cTnI and cTnT, a cardiac specific myocyte injury marker, have the great advantage of being relatively reproducible, more readily accessible, and applicable to different populations. New and improved troponin assays have good analytical performance, can measure very low levels of circulating troponin, and have low intra individual variation, below 10 %. Several studies have analyzed the blood levels in healthy subjects and their predictive value for cardiovascular events in observational, prospective and post-hoc studies. All of them offered relevant information and shown that high sensitivity hs-cTnI has a place as an additional clinical marker to add to current charts, and it also reflects sex- and age-dependent differences. Although few more questions need to be answered before recommend cTnI for assessing CV risk in primary prevention, seems to be a potential strong marker to complement CV risk charts.

Introduction Chronic Graft versus Host Disease (cGvHD) remains a major complication of hematopoietic stem cells transplantation (HSCT) causing significant morbidity and mortality. We performed Phase I/II clinical trials to access the feasibility, safety and efficacy of infusing donor regulatory T cells (Treg) for the treatment of steroid-refractory/dependent cGvHD under the auspices of the EC-funded consortium TREGeneration.This is the first presentation of the Lisbon (iMM) and Seville (SAS) cohorts. Methods Treg were purified using CliniMACS (Miltenyi Biotec®) from fresh leukapharesis from the original HSCT donor by CD8 and CD20 depletion, followed by CD25bright positive selection. The dose escalation protocol comprised sequential groups of 3 (SAS) or 5 (iMM) patients per center receiving 0.5x106 (Dose A), 1x106 (Dose B) or 2-3x106 (Dose C) donor Treg/kg. After Phase I, 5 patients per center were included at the MTD, as a preliminary Phase II trial. We report feasibility and toxicity results on 33 patients (n=19, iMM; n=14, SAS) and efficacy on 31 patients (n=19, iMM; n=12, SAS) evaluable at month 12 post infusion (n=8, moderate; n=23, severe). Patients were classified according to the NIH 2014 cGVHD criteria (Jagasia, MH et al, BBMT, 2015). Scores for the skin, eye, modified oral mucosa, GI tract, liver, lung, joint/fascia and cGvHD severity were used to calculate clinical responses at 3, 6 and 12 months, whereupon the final response was recorded. cGVHD treatment at iMM comprised primarily steroids and MMF, while all patients at SAS were on a ruxolitinib-containing regimen and had not obtained at least a partial response. Blood was collected for lymphocyte subsets monitoring by flow cytometry, evaluation of tissue damage biomarkers, homeostatic, pro-inflammatory and suppressive cytokines (sIL-2Ra, CXCL9/MIG, MMP3, Osteopontin, CXCL10/IP-10, CSTB, sCD13, Elafin, sTM, ST2, BAFF, IL-1R antagonist, IL-2, IL-7, IL-10, IFN-γ, TNF-α, CXCL11/I-TAC, IL-6, IL-17A/CTLA8 and TGF-β) by Multiplex, and tracking of infused Treg clonotypes by deep-level TCR RNA-based Next Generation Sequencing (NGS). Univariate tests were carried out using Fisher's exact test for categorical variables. t-test or Mann-Whitney tests were used for continuous variables as per normality analysis. Since no multiple testing correction was carried out, there were no corrections for multiple comparison or adjustments for other covariates. Results and Conclusions Donor Treg products preparation was feasible. Nevertheless, due to the paucity of circulating Treg, dose C required 2 separate leucapheresis in most patients. At SAS, achieving more than 1.5x106 donor Treg/kg was possible for only 4 patients. At iMM, the QC criteria were met in 20/20 products (mean Treg purity 67%; CD8 depletion 4.5 and 4 times for CD20). At SAS, 1 product did not meet the purity criteria and was not infused, the remaining 14 products were infused (mean purity 73%; CD8 log depletion of 4.9 and of 6.5 times for CD20). Infused cell doses were calculated based on Treg purity (CD4+CD25++CD127lowFoxP3+). There were no dose limiting toxicities and dose C was used whenever reached in the Phase II trial. Efficacy analysis revealed that 22 out of 31 evaluable patients (70.9%) showed either complete response (CR) or partial response (PR) at month 12, whereas 29% progressed (P) or did not respond (NR). The median time from infusion to response was 6 months. The same efficacy trend was observed irrespective of a previous failure to ruxolitinib. Time from cGvHD diagnosis to Treg infusion was significantly associated with response in the iMM cohort (p=0.003). Interestingly, the Treg dose influenced outcomes. Hence, when patients receiving A+B doses (<1 x106Treg/Kg) were compared to patients receiving >1.3x106 Treg/Kg, 10/18 (56%) of patients in lower doses responded versus 12/13 (92%) in higher Treg doses (p=0.045). Furthermore, 39% of patients had the daily dose of prednisolone tapered by at least 50%. Exploratory TCR tracking analysis revealed the persistence of infused Treg clones in 18 of the 20 patients analyzed thus far up to one year after infusion. In summary, we report the feasibility and safety of donor Treg infusion in patients with moderate/severe cGVHD. Meaningful responses were observed in over 2/3 of the patients, further suggesting that early treatment with Treg is associated to improved clinical outcomes. Our results set the stage for larger Phase II trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.

A few years ago, motion capture was a technology used exclusively in high-cost film productions. With technological developments, this type of resource has become more accessible to the general public, and so the need arose to look for appropriate methods that serve as an impetus for the development of 3D animations in real time, either through open source software, through equipment that is more accessible to the general public. The importance here lies in reducing costs and discarding any dependency on rendering in 3D animation.This article aims to expose some areas of study associated with performance animation and film production. As a case study, this article presents the development of a prototype for a multimedia installation within the scope of the short-film Animata. With this prototype, it´s intended to explore the limits of the animated character in real time, through the integration between different devices and software, connected in a multimedia ecosystem.

Supravalvular aortic stenosis is a rare congenital anomaly (less than 0.05% of all congenital heart defects). This aortic root anomaly consists in a narrow aortic lumen immediately above the aortic valve and represents the least common form of left ventricular outflow tract obstruction. Clinical presentation is usually in the first decades of life. In most cases, the aortic valve leaflets are morphologically normal. However, aortic insufficiency due the high systolic pressure proximal to the sinotubular junction is the most commonly abnormality described. There are very few cases described in the literature with concomitant valvular and supra-valvular aortic stenosis.