Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. METHODS: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. RESULTS: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; Pinteraction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. CONCLUSIONS: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single "non-LBBB" category when selecting patients for CRT should be reconsidered. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Mismatched related donor allogeneic haematopoietic cell transplantation compared to other donor types for Ph+ chronic myeloid leukaemia: A retrospective analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.

Reliability of Magseed® marking before neoadjuvant systemic therapy with subsequent contrast-enhanced mammography in patients with non-palpable breast cancer lesions after treatment: the MAGMA study.

PURPOSE: To assess the reliability of excising residual breast cancer lesions after neoadjuvant systemic therapy (NAST) using a previously localized paramagnetic seed (Magseed®) and the subsequent use of contrast-enhanced spectral mammography (CESM) to evaluate response. METHODS: Observational, prospective, multicenter study including adult women (> 18 years) with invasive breast carcinoma undergoing NAST between January 2022 and February 2023 with non-palpable tumor lesions at surgery. Radiologists marked tumors with Magseed® during biopsy before NAST, and surgeons excised tumors guided by the Sentimag® magnetometer. CESMs were performed before and after NAST to evaluate tumor response (Response Evaluation Criteria for Solid Tumors [RECIST]). We considered intraoperative, surgical, and CESM-related variables and histological response. RESULTS: We analyzed 109 patients (median [IQR] age of 55.0 [46.0, 65.0] years). Magseed® was retrieved from breast tumors in all surgeries (100%; 95% CI 95.47-100.0%) with no displacement and was identified by radiology in 106 patients (97.24%), a median (IQR) of 176.5 (150.0, 216.3) days after marking. Most surgeries (94.49%) were conservative; they lasted a median (IQR) of 22.5 (14.75, 40.0) min (95% CI 23.59-30.11 min). Most dissected tumor margins (93.57%) were negative, and few patients (5.51%) needed reintervention. Magseed® was identified using CESM in all patients (100%); RECIST responses correlated with histopathological evaluations of dissected tumors using the Miller-Payne response grade (p < 0.0001) and residual lesion diameter (p < 0.0001). Also 69 patients (63.3%) answered a patient's satisfaction survey and 98.8% of them felt very satisfied with the entire procedure. CONCLUSION: Long-term marking of breast cancer lesions with Magseed® is a reliable and feasible method in patients undergoing NAST and may be used with subsequent CESM.

Benefit of cardiac resynchronization therapy among older patients: A patient-level meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. METHODS: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. RESULTS: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35). CONCLUSION: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT.

The challenge of standardizing CAR-T cell monitoring: A comparison of two flow-cytometry methods and correlation with qPCR technique.

Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough in hematologic malignancies, such as acute B lymphoblastic leukemia (B-ALL). Monitoring this treatment is recommended, although standardized protocols have not been developed yet. This work compares two flow cytometry monitoring strategies and correlates this technique with qPCR method. CAR-T cells were detected by two different flow-cytometry protocols (A and B) in nine blood samples from one healthy donor and five B-ALL patients treated with Tisagenlecleucel (Kymriah®, USA). HIV-1 viral load allowed CAR detection by qPCR, using samples from seven healthy donors and nine B-ALL patients. CAR detection by protocol A and B did not yield statistically significant differences (1.9% vs. 11.8% CD3 + CAR+, p = 0.07). However, protocol B showed a better discrimination of the CD3 + CAR+ population. A strong correlation was observed between protocol B and qPCR (r = 0.7, p < 0.0001). CD3 + CAR+ cells were detected by flow cytometry only when HIV-1 viral load was above 104 copies/mL. In conclusion, protocol B was the most specific flow-cytometry procedure for the identification of CAR-T cells and showed a high correlation with qPCR. Further efforts are needed to achieve a standardized monitoring approach.

Safety and Efficacy of High-Dose Memory CD45RO+ Donor Lymphocyte Infusion in Pediatric Recipients after Hematopoietic Stem Cell Transplantation.

Memory T selected cells (CD45RA-/RO+) as donor lymphocyte infusion are less capable of producing alloreactivity and graft versus host disease (GvHD) compared with naïve T cells. The objective of this study was to evaluate the safety and efficacy of high-dose memory (CD45RA-/RO+) donor lymphocyte infusion (mDLI) after allogeneic hematopoietic cell transplantation (HCT). Indications for mDLI were "as needed" and "as prophylactic regimen." Sixty-one children diagnosed with malignant (82%) and non-malignant diseases (18%) received 241 mDLIs. Patients received a median of three infusions (range 1‒13) of mDLI with a median infused dose of 1.35 × 107/kg CD45RO+ containing 8.96 × 106/kg CD3+CD45RO+ and 3.81 × 103/kg CD3+CD45RA+. De novo GvHD developed in 7 patients following 4% of the mDLI infusions. Among patients with GvHD before mDLI, this condition worsened following 6 infusions (11%) in the 3 patients with grade II-IV acute GvHD. A decrease in cytomegalovirus viral load followed 65% of mDLI infusions. Two-year overall survival (OS) for the total cohort was 64% (95% CI 57%‒72%). For patients receiving prophylactic mDLI, the two-year non-relapse mortality was 10% (95% CI 9%‒11%). In summary, high-dose mDLI is feasible and safe, with a relatively low risk of severe GvHD even in patients with active GvHD. Importantly, mDLI was associated with positive effects, including enhanced control of CMV viremia.

Results of phase 2 randomized multi-center study to evaluate the safety and efficacy of infusion of memory T cells as adoptive therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and/or lymphopenia (RELEASE NCT04578210).

BACKGROUND AIMS: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA- memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. METHODS: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA- memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA- memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. RESULTS: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. CONCLUSIONS: Adoptive cell therapy with off-the-shelf CD45RA- memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. TRIAL REGISTRATION: NCT04578210.

Factors related to the development of high antibody titres against SARS-CoV-2 in convalescent plasma donors from the ConPlas-19 trial.

BACKGROUND AND OBJECTIVES: The efficacy of COVID-19 convalescent plasma (CP) associates with high titres of antibodies. ConPlas-19 clinical trial showed that CP reduces the risk of progression to severe COVID-19 at 28 days. Here, we aim to study ConPlas-19 donors and characteristics that associate with high anti-SARS-CoV-2 antibody levels. MATERIALS AND METHODS: Four-hundred donors were enrolled in ConPlas-19. The presence and titres of anti-SARS-CoV-2 antibodies were evaluated by EUROIMMUN anti-SARS-CoV-2 S1 IgG ELISA. RESULTS: A majority of 80.3% of ConPlas-19 donor candidates had positive EUROIMMUN test results (ratio ≥1.1), and of these, 51.4% had high antibody titres (ratio ≥3.5). Antibody levels decline over time, but nevertheless, out of 37 donors tested for an intended second CP donation, over 90% were still EUROIMMUN positive, and nearly 75% of those with high titres maintained high titres in the second sample. Donors with a greater probability of developing high titres of anti-SARS-CoV-2 antibodies include those older than 40 years of age (RR 2.06; 95% CI 1.24-3.42), with more than 7 days of COVID-19 symptoms (RR 1.89; 95% CI 1.05-3.43) and collected within 4 months from infection (RR 2.61; 95% CI 1.16-5.90). Male donors had a trend towards higher titres compared with women (RR 1.67; 95% CI 0.91-3.06). CONCLUSION: SARS-CoV-2 CP candidate donors' age, duration of COVID-19 symptoms and time from infection to donation associate with the collection of CP with high antibody levels. Beyond COVID-19, these data are relevant to inform decisions to optimize the CP donor selection process in potential future outbreaks.

The green seaweed Ulva: tomorrow's "wheat of the sea" in foods, feeds, nutrition, and biomaterials.

Ulva, a genus of green macroalgae commonly known as sea lettuce, has long been recognized for its nutritional benefits for food and feed. As the demand for sustainable food and feed sources continues to grow, so does the interest in alternative, plant-based protein sources. With its abundance along coastal waters and high protein content, Ulva spp. have emerged as promising candidates. While the use of Ulva in food and feed has its challenges, the utilization of Ulva in other industries, including in biomaterials, biostimulants, and biorefineries, has been growing. This review aims to provide a comprehensive overview of the current status, challenges and opportunities associated with using Ulva in food, feed, and beyond. Drawing on the expertise of leading researchers and industry professionals, it explores the latest knowledge on Ulva's nutritional value, processing methods, and potential benefits for human nutrition, aquaculture feeds, terrestrial feeds, biomaterials, biostimulants and biorefineries. In addition, it examines the economic feasibility of incorporating Ulva into aquafeed. Through its comprehensive and insightful analysis, including a critical review of the challenges and future research needs, this review will be a valuable resource for anyone interested in sustainable aquaculture and Ulva's role in food, feed, biomaterials, biostimulants and beyond.

An artificial intelligence-driven predictive model for pediatric allogeneic hematopoietic stem cell transplantation using clinical variables.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a procedure with high morbidity and mortality. Identifying patients for maximum benefit and risk assessment is crucial in the decision-making process. This has led to the development of predictive risk models for HSCT in adults, which have limitations when applied to pediatric population. Our goal was to develop an automatic learning algorithm to predict survival in children with malignant disorders undergoing HSCT. METHODS: We studied allogenic HSCTs performed on children with malignant disorders at a third-level hospital between 1991 and 2021. Survival was analyzed using the Kaplan-Meier method, log-rank test for the univariate analysis, and Cox regression for the multivariate analysis. A prognostic index was constructed based on these findings. Lastly, we constructed a predictive model using a random forest algorithm to forecast 1-year survival after HSCT. RESULTS: We analyzed 229 HSCTs in 201 patients with a median follow-up of 1.64 years. Variables that impacted on the multivariate analysis were older age (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.76, p = .003), oldest period of HSCT (HR 0.46, 95% CI 0.29-0.73, p < .001), and mismatched donor (HR 2.65, 95% CI 1.51-4.65, p = .001). Our prognostic index was associated with 3-year overall survival (OS; p < .001). A random forest was developed using as variables: diagnosis, age, year of HSCT, time from diagnosis to HSCT, disease stage, donor type, and conditioning. This achieved 72% accuracy in predicting 1-year OS. CONCLUSIONS: Our index and random forest was effective in predicting 1-year survival. However, further validation in diverse populations is necessary to establish their generalizability.

Clinical features and prognosis of prosthetic valve endocarditis due to Staphylococcus aureus.

PURPOSE: Staphylococcus aureus prosthetic valve endocarditis (SAPVE) is a serious infection with high mortality. The main objective of this study was to identify factors associated with in-hospital mortality. METHODS: From January 2008 to December 2021, consecutive patients from a Spanish cohort of infective endocarditis with a definitive diagnosis of SAPVE were analyzed. RESULTS: During the study period, 219 cases of definitive SAPVE were diagnosed, which accounted for 16.7% of a total of 1309 cases of definitive prosthetic valve endocarditis (PVE). Patients presented advanced age and marked comorbidity. There was a higher incidence of persistent bacteremia, septic shock, stroke, and acute kidney injury than in cases of PVE caused by other microorganisms. Methicillin resistance was not associated with differences in clinical presentation, echocardiographic findings, or mortality. Only 50.6% of the patients with surgical indications (88 patients) underwent surgery. Overall, in-hospital mortality was 47.9%. The variables associated with in-hospital mortality were age (OR:1.03, 95% CI: 1.00-1.05; p = 0.016), heart failure (OR:2.86, 95% CI: 1.53-5.32; p = 0.001), acute kidney injury (OR:2.42, 95%CI:1.28-4.58; p = 0.006), stroke (OR:3.53, 95%CI:1.79-6.96; p < 0.001) and surgery indicated but not performed (OR:2.01, 95%CI:1.06-3.8; p = 0.030). On the other hand, the performance of surgery per se in patients with SAPVE, regardless of whether there was a surgical indication according to the guidelines, was not associated with a reduction in in-hospital mortality. CONCLUSIONS: SAPVE is characterized by high mortality, which is more marked in patients who present a surgical indication but do not undergo surgery.

Bezlotoxumab during the first episode of Clostridioides difficile infection in patients at high risk of recurrence.

PURPOSE: To describe a cohort with a high risk of recurrence who received bezlotoxumab during the first episode of Clostridioides difficile infection (CDI) and to compare this cohort with patients with similar characteristics who did not receive the monoclonal antibody. METHODS: A prospective and multicentre study of patients with a high risk of recurrence (expected recurrence rate>35%) who were treated with bezlotoxumab during their first episode of CDI was conducted. A propensity score-matched model 1:2 was used to compare both cohorts that were weighed according to basal characteristics (hospital-acquisition, creatinine value, and fidaxomicin as a CDI treatment). RESULTS: Sixty patients (mean age:72 years) were prospectively treated with bezlotoxumab plus anti-Clostridioides antibiotic therapy. Vancomycin (48 patients) and fidaxomicin (12 patients) were prescribed for CDI treatment, and bezlotoxumab was administered at a mean of 4.2 (SD:2.1) days from the beginning of therapy. Recurrence occurred in nine out of 54 (16.7%) evaluable patients at 8 weeks. Forty bezlotoxumab-treated patients were matched with 69 non-bezlotoxumab-treated patients. Recurrence rates at 12 weeks were 15.0% (6/40) in bezlotoxumab-treated patients vs. 23.2% (16/69) in non-bezlotoxumab-treated patients (OR:0.58 [0.20-1.65]). No adverse effects were observed related to bezlotoxumab infusion. Only one of 9 patients with previous heart failure developed heart failure. CONCLUSION: We observed that patients treated with bezlotoxumab in a real-world setting during a first episode of CDI having high risk of recurrence, presented low rate of recurrence. However, a significant difference in recurrence could not be proved in comparison to the controls. We did not detect any other safety concerns.

Synthesis, Characterization, and Photochemistry of a Ga2L3 Coordination Cage with Dithienylethene-Catecholate Ligands.

Two new photoswitchable dithienylethene (DTE)-catechol ligands, specifically designed for group 13 metal coordination, were synthesized via Suzuki coupling reactions from a dichloro-DTE building block, each with varying longitudinal extensions. The shorter DTE-catechol ligand did not efficiently assemble with Ga3+ metal ions; however, elongation with a phenylene-amide spacer group enabled the successful formation of a novel triply DTE-functionalized coordination [Ga2L3]6- cage. This cage represents a unique example of integrating DTE photoswitches with main group metals in a supramolecular coordination framework. The [Ga2L3]6- cage was thoroughly characterized by NMR spectroscopy, including DOSY hydrodynamic volumetric analyses, high-resolution mass spectrometry, computational DFT, and photochemical analyses. The DFT studies highlighted the structural integrity and dynamic interplay within the helicate and mesocate isomeric forms of the [Ga2L3]6- cage upon photoswitching. While the free ligands exhibited all-photonic reversible switching at up to mM concentrations upon alternating irradiation at 365 and >495 nm, the [Ga2L3]6- cage demonstrated these capabilities under dilute µM conditions, albeit with lower efficiency and fatigue resistance. This behavior highlights the intricate relationship between rigid coordination with main group metals and the flexibility of the photoswitchable DTE ligands within the [Ga2L3]6- cage.

Reversible Redox Ligand-Centered Reactivity in 2,6-Bisiminopyridine Aluminum Systems.

We report the synthesis of cationic 2,6-bisiminopyridine organoaluminum complexes, [(BIP)AlR2]+, as stable BArF4- or PF6- salts, and their reversible single-electron reduction into well-defined paramagnetic species, [(BIP·)AlR2]. Four redox couples, [(BIP)AlR2]+/0, have been fully characterized through structural, spectroscopic, electrochemical and computational techniques.

Complications in Patients with Surgically Altered Gastrointestinal Anatomy Undergoing Endoscopic Retrograde Cholangiopancreatography: 15-Year Experience at a Tertiary Care Center in Latin America.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common procedure, but it poses challenges in patients with surgically altered gastrointestinal anatomy (SAGA). Alternative techniques like single-balloon enteroscopy (SBE), double-balloon enteroscopy (DBE), or push enteroscopy (PE) have been used, albeit with potential complications. Limited Latin American data exists on ERCP complications in SAGA patients. Our goal is to describe complications of ERCP in SAGA at a national referral institution. METHODS: Retrospective, single-center cohort study. All SAGA ERCP procedures performed at the Gastrointestinal Endoscopy Department of the National Institute of Medical Sciences and Nutrition Salvador Zubirán from January 2008 to May 2023 were included. Extracted data from records included procedure specifics, endoscope type, success, and complications. Complications were evaluated during procedure and 28-day post-procedure and classified using the AGREE system. RESULTS: A total of 266 procedures in 174 patients were included, 74% were women, and the median age was 44 years. Predominant modified anatomy was Roux-en-Y biliary reconstruction (79%), followed by Whipple procedure (13%) and subtotal gastrectomy with Roux-en-Y reconstruction (6.0%). The main indications were cholangitis with stricture (31%), stricture (19%), and cholangitis (19%). DBE was used in 89%, PE in 7.5%, and SBE in 3.4%. Success rates were 77% endoscopic, 72% technical, and 69% therapeutic; in 30%, the procedure was unsuccessful. Complications happened in 18% of cases, most commonly cholangitis (7.5%), followed by perforation (2.6%) and hemorrhage (1.9%). According to the AGREE classification, 10.9% were grades 1 and 2, 6.4% were grade 3, and 0.4% were grade 4 complications. No significant differences emerged between groups with and without complications. Procedures increased over time, but complications and unsuccessful procedures remained stable. CONCLUSION: ERCP complications align with international data, often not requiring invasive treatment. Enhanced exposure to such cases correlates with fewer complications and failures. Prospective studies are essential to identify complication and failure predictors.

Synthesis of Marine (-)-Pelorol and Future Perspectives.

Meroterpenoid-type marine natural compounds have attracted an increasing amount of attention due to their peculiar chemical structures and their potential for the development of therapeutically important probes. Within this group of substances pelorol stands out; it is a natural compound isolated from marine organisms with a unique structure and an interesting biological profile. In this article, we summarize and highlight the most interesting aspects of the synthetic procedures towards this compound, which have two common key steps. The first is the coupling of a drimanyl derivative with a compound derived from an arene. The second is a Friedel-Crafts cyclization which forms the C ring of the natural product. Despite the synthetic advances achieved so far, we consider that a more efficient synthetic procedures could be carried out, since their synthetic routes are difficult to scale up due to numerous reaction steps and the limitations imposed by the use of some reagents. In this article, we present a new and versatile retrosynthetic analysis of (-)-pelorol and analogs, which is highly desirable for their easy preparation and subsequent broad study of their biological activities. This is a retrosynthetic route that could improve those reported in the literature in terms of cost-effectiveness.

Evolutionary dynamics at the tumor edge reveal metabolic imaging biomarkers.

Human cancers are biologically and morphologically heterogeneous. A variety of clonal populations emerge within these neoplasms and their interaction leads to complex spatiotemporal dynamics during tumor growth. We studied the reshaping of metabolic activity in human cancers by means of continuous and discrete mathematical models and matched the results to positron emission tomography (PET) imaging data. Our models revealed that the location of increasingly active proliferative cellular spots progressively drifted from the center of the tumor to the periphery, as a result of the competition between gradually more aggressive phenotypes. This computational finding led to the development of a metric, normalized distance from 18F-fluorodeoxyglucose (18F-FDG) hotspot to centroid (NHOC), based on the separation from the location of the activity (proliferation) hotspot to the tumor centroid. The NHOC metric can be computed for patients using 18F-FDG PET-computed tomography (PET/CT) images where the voxel of maximum uptake (standardized uptake value [SUV]max) is taken as the activity hotspot. Two datasets of 18F-FDG PET/CT images were collected, one from 61 breast cancer patients and another from 161 non-small-cell lung cancer patients. In both cohorts, survival analyses were carried out for the NHOC and for other classical PET/CT-based biomarkers, finding that the former had a high prognostic value, outperforming the latter. In summary, our work offers additional insights into the evolutionary mechanisms behind tumor progression, provides a different PET/CT-based biomarker, and reveals that an activity hotspot closer to the tumor periphery is associated to a worst patient outcome.

Clinical and serological characteristics of patients allergic to LTP.

BACKGROUND: Allergy to lipid transfer proteins (LPT) is common in Mediterranean Europe, and it causes severe reactions in patients and affects multiple foods, impairing the quality of life. OBJECTIVE: This study aimed to describe the clinical and sensitization profile of patients with LTP syndrome and to determine a clinical pattern of severity. Molecular diagnosis is shown in a broad population through microarrays. MATERIAL AND METHODS: This study was performed at the LTP Allergy Consultation of the Reina Sofia Hospital in Murcia, Spain. We analyzed the patients' characteristics, reactions, cofactors, food implicated, quality of life, skin prick test to food and aeroallergens, and serologic parameters, such as total immunoglobulin E, peach LTP (Pru p 3 IgE) and immunoglobulin G4, and microarray Immuno Solid-phase Allergen Chip (ISAC). We related the severity of the reactions with other variables. RESULTS: We presented a series of 236 patients diagnosed with LTP allergy, 54.66% suffering from anaphylaxis, 36.02% from urticaria angioedema, and 9.32% from oral allergy syndrome. The most frequently implicated food was peach, producing symptoms in 70% of patients, followed by walnut in 55%, peanut in 45%, hazelnut in 44%, and apple in 38% patients. Regarding the food that provoked anaphylaxis, walnut was the most frequent instigator, along with peach, peanut, hazelnut, almond, sunflower seed, and apple. According to the severity of LPT reaction, we did not discover significant differences in gender, age, food group involved, and serologic parameters. We found differences in the presence of cofactors, with 48.84% of cofactors in patients with anaphylaxis, compared to 27.1% in patients without anaphylaxis and in family allergy background (P < 0.0001). CONCLUSION: In our series of patients, 54% presented anaphylaxis, and the foods that most frequently produced symptoms were peaches, apples, and nuts. Cofactors and family allergy backgrounds were associated with the severity of LPT reaction.

In vitro activity of delafloxacin against anaerobic bacteria compared with other antimicrobials.

The aim of this study was to describe the in vitro activity of delafloxacin against 230 anaerobic isolates and compare it with the activity of other antimicrobials used against infections caused by anaerobic microorganisms. Minimal inhibitory concentrations (MICs) were lower for delafloxacin than for all other antibiotics tested with the exception of piperacillin-tazobactam and meropenem against Gram-positive anaerobic cocci. Only two (0.8 %) isolates of Bacteroides spp. showed a MIC ≥4 µg/mL. With some exceptions, the present results show lower MICs for delafloxacin in comparison to the other antibiotics used against anaerobes.

Inherited human ezrin deficiency impairs adaptive immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. OBJECTIVE: We investigated a patient with an IEI of unknown genetic etiology. METHODS: Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. RESULTS: Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells. CONCLUSIONS: Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.