Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

Analysis of Susceptibility or Resistance to Antimicrobial Agents.

Here were described the main three methods being used for analysis of antibiotic susceptibility or resistance of Streptococcus suis clinical isolates to antimicrobial agents: the Kirby-Bauer disk diffusion, the epsilometer test (E test), and the broth microdilution test. In each case, procedures, results, and interpretation are described, as well as their advantages or limitations when proceeds.

Detection of Macrolide and/or Tetracycline Genetic Resistance Determinants by PCR.

Globally, the main molecular trials being developed to study the genetic determinants responsible for conferring resistance to bacterial organisms are amplification-based methods, hybridization-based methods, and sequence-based methods. In the specific case of Streptococcus suis, polymerase chain reaction is the only test tuned up until now for detecting resistant clinical isolates to macrolides and/or tetracyclines, the two main groups of antibiotics being ineffective against this human and animal pathogen.

Isavuconazole Versus Voriconazole as the First-line Therapy for Solid Organ Transplant Recipients With Invasive Aspergillosis: Comparative Analysis of 2 Multicenter Cohort Studies.

BACKGROUND: Isavuconazole (ISA) and voriconazole (VORI) are recommended as the first-line treatment for invasive aspergillosis (IA). Despite theoretical advantages of ISA, both triazole agents have not been compared in solid organ transplant recipients. METHODS: We performed a post hoc analysis of 2 retrospective multicenter cohorts of solid organ transplant recipients with invasive fungal disease (the SOTIS [Solid Organ Transplantation and ISavuconazole] and DiasperSOT [DIagnosis of ASPERgillosis in Solid Organ Transplantation] studies). We selected adult patients with proven/probable IA that were treated for ≥48 h with ISA (n = 57) or VORI (n = 77) as first-line therapy, either in monotherapy or combination regimen. The primary outcome was the rate of clinical response at 12 wk from the initiation of therapy. Secondary outcomes comprised 12-wk all-cause and IA-attributable mortality and the rates of treatment-emergent adverse events and premature treatment discontinuation. RESULTS: Both groups were comparable in their demographics and major clinical and treatment-related variables. There were no differences in the rate of 12-wk clinical response between the ISA and VORI groups (59.6% versus 59.7%, respectively; odds ratio [OR], 0.99; 95% confidence interval [CI], 0.49-2.00). This result was confirmed after propensity score adjustment (OR, 0.81; 95% CI, 0.32-2.05) and matching (OR, 0.79; 95% CI, 0.31-2.04). All-cause and IA-attributable mortality were also similar. Patients in the ISA group were less likely to experience treatment-emergent adverse events (17.5% versus 37.7%; P = 0.011) and premature treatment discontinuation (8.8% versus 23.4%; P = 0.027). CONCLUSIONS: Front-line treatment with ISA for posttransplant IA led to similar clinical outcomes than VORI, with better tolerability and higher treatment completion.

Exhaled breath condensate contains extracellular vesicles (EVs) that carry miRNA cargos of lung tissue origin that can be selectively purified and analyzed.

Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh-EVs). Using our customizable antibody-purification assay, EV-CATCHER, we initially determined that exh-EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh-EVs harbour lung-specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh-EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV-CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti-CCSP/SFTPC EV-CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh-EV subpopulations from EBC allows non-invasive sampling of EVs produced by lung tissues.

Exploring Reversible Redox Behavior in the 6H-BaFeO3-δ (0 < δ < 0.4) System: Impact of Fe3+/Fe4+ Ratio on CO Oxidation.

This work is devoted to evaluating the relationship between the oxygen content and catalytic activity in the CO oxidation process of the 6H-type BaFeO3-δ system. Strong evidence is provided about the improvement of catalytic performance with increasing Fe average oxidation state, thus suggesting the involvement of lattice oxygen in the catalytic process. The compositional and structural changes taking place in both the anionic and cationic sublattices of the catalysts during redox cycles have been determined by temperature-resolved neutron diffraction. The obtained results evidence a structural transition from hexagonal (P63/mmc) to orthorhombic (Cmcm) symmetry. This transition is linked to octahedra distortion when the Fe3+ concentration exceeds 40% (δ values higher than 0.2). The topotactical character of the redox process is maintained in the δ range 0 < δ < 0.4. This suggests that the cationic framework is only subjected to slight structural modifications during the oxygen exchange process occurring during the catalytic cycle.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors.

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.

Enhancing ASD detection accuracy: a combined approach of machine learning and deep learning models with natural language processing.

Purpose: The main aim of our study was to explore the utility of artificial intelligence (AI) in diagnosing autism spectrum disorder (ASD). The study primarily focused on using machine learning (ML) and deep learning (DL) models to detect ASD potential cases by analyzing text inputs, especially from social media platforms like Twitter. This is to overcome the ongoing challenges in ASD diagnosis, such as the requirement for specialized professionals and extensive resources. Timely identification, particularly in children, is essential to provide immediate intervention and support, thereby improving the quality of life for affected individuals. Methods: We employed natural language processing (NLP) techniques along with ML models like decision trees, extreme gradient boosting (XGB), k-nearest neighbors algorithm (KNN), and DL models such as recurrent neural networks (RNN), long short-term memory (LSTM), bidirectional long short-term memory (Bi-LSTM), bidirectional encoder representations from transformers (BERT and BERTweet). We extracted a dataset of 404,627 tweets from Twitter users using the platform's API and classified them based on whether they were written by individuals claiming to have ASD (ASD users) or by those without ASD (non-ASD users). From this dataset, we used a subset of 90,000 tweets (45,000 from each classification group) for the training and testing of these models. Results: The application of our AI models yielded promising results, with the predictive model reaching an accuracy of almost 88% when classifying texts that potentially originated from individuals with ASD. Conclusion: Our research demonstrated the potential of using AI, particularly DL models, in enhancing the accuracy of ASD detection and diagnosis. This innovative approach signifies the critical role AI can play in advancing early diagnostic techniques, enabling better patient outcomes and underlining the importance of early identification of ASD, especially in children.

Clinical Characteristics and Incidence of Hemorrhagic Complications in Patients Taking Factor Xa Inhibitors in Spain: A Long-Term Observational Study.

Objective. To analyze the clinical characteristics of patients taking Factor Xa inhibitors (FXai), either direct FXai or enoxaparin (only in active cancer patients), and to estimate the incidence of and risk factors for major bleeding during FXai use. Methods. A retrospective cohort study, which included secondary data from computerized health records of primary care centers and hospitals in seven Spanish Autonomous Communities. Results. 9374 patients were analyzed, with 8972 taking direct FXai and 402 enoxaparin. At baseline, the mean age (SD) was 71.8 (9.4) years, 56.0% were women, 76.3% had hypertension, 33.6% had type 2 diabetes, and 25.5% had heart failure. The most common indication for FXai use was atrial fibrillation (72.3%), followed by venous thromboembolism (22.2%) and non-mechanical cardiac-valve replacement (5.6%). At the end of the follow-up period, the incidence rates of major bleeding overall, gastrointestinal, and intracranial were 10.2, 9.0, and 0.8 per 100 person-years, respectively. The total incidence of fatal major bleeding was 0.5 per 100 person-years. Incidence rates of all bleedings progressively decreased over time, with 62.5% of the first events occurring in the initial three months and reaching 76.8% within six months following initiation of treatment. Only 4.8% of the 1st major bleedings led to death, 2.3% in the case of major gastrointestinal bleeding, and 30.8% after an intracranial bleeding. 65.9% of patients discontinued anticoagulation after experiencing major bleeding. Conclusions. In Spain, patients taking FXai were old and had many comorbidities. Despite incidence rates of major bleeding were high, incidence rates of intracranial and fatal bleedings were low, but more efforts are required due to their relevant clinical impact.

Anterior Scleral Thickness and Anterior Segment Biometrics Measured with Swept Source Ocular Coherence Tomography in High Myopic Eyes with and without Glaucoma: A Comparative Study.

Background: To assess the anterior scleral thickness (AST), Schlemm's canal diameter (SCD), trabecular meshwork diameter (TMD) and conjunctiva tenon capsule thickness (CTT) in high myopic (HM) subjects and HM subjects with glaucoma (HMG) compared to control eyes. Methods: One hundred and twenty eyes were included, and AST at 0, 1, 2 and 3 mm from the scleral spur, SCD, TMD and CTT were measured. Results: Mean age was 64.2 ± 11.0 years, and the temporal SCD and temporal TMD were significantly longer in the HMG subjects compared to the controls (380.0 ± 62 µm vs. 316.7 ± 72 µm, p = 0.001) and (637.6 ± 113 µm vs. 512.1 ± 97 µm, p = 0.000), respectively. There were no significant differences between the HM and HMG subjects in SCD and TMD (all p > 0.025). Compared to the HM subjects, the temporal AST0 (432.5 ± 79 µm vs. 532.8 ± 99 µm, p = 0.000), temporal AST1 (383.9 ± 64 µm vs. 460.5 ± 80 µm, p = 0.000), temporal AST2 (404.0 ± 68 µm vs. 464.0 ± 88 µm, p = 0.006) and temporal AST3 (403.0 ± 80 µm vs. 458.1 ± 91 µm, p = 0.014) were significantly thinner in the HMG group. No differences were found between the CTT in the three groups (all p > 0.025). Conclusions: Our data indicate a thinner AST in HMG subjects and no differences in SCD and TMD between HM and HMG subjects.

Streptococcus suis Research Update: Serotype Prevalence and Antimicrobial Resistance Distribution in Swine Isolates Recovered in Spain from 2020 to 2022.

This study aimed to update the Streptococcus suis serotype distribution in Spain by analysing 302 clinical isolates recovered from diseased pigs between 2020 and 2022. The main objectives were to identify prevalent serotypes, differentiate specific serotypes 1, 14, 2, and 1/2, investigate specific genotypic and phenotypic antimicrobial resistance features, and explore associations between resistance genes and phenotypic resistances. Serotypes 9 (21.2%), 1 (16.2%), 2 (15.6%), 3 (6%), and 7 (5.6%) were the most prevalent, whereas serotypes 14 and 1/2 corresponded with 4.3% and 0.7% of all isolates. Antimicrobial resistance genes, including tet(O), erm(B), lnu(B), lsa(E), tet(M), and mef(A/E), were analysed, which were present in 85.8%, 65.2%, 7%, 7%, 6.3%, and 1% of the samples, respectively. Susceptibility testing for 18 antimicrobials revealed high resistance levels, particularly for clindamycin (88.4%), chlortetracycline (89.4%), and sulfadimethoxine (94.4%). Notably, seven significant associations (p < 0.0001) were detected, correlating specific antimicrobial resistance genes to the observed phenotypic resistance. These findings contribute to understanding the S. suis serotype distribution and its antibiotic resistance profiles in Spain, offering valuable insights for veterinary and public health efforts in managing S. suis-associated infections.

An intronic RNA element modulates Factor VIII exon-16 splicing.

Pathogenic variants in the human Factor VIII (F8) gene cause Hemophilia A (HA). Here, we investigated the impact of 97 HA-causing single-nucleotide variants on the splicing of 11 exons from F8. For the majority of F8 exons, splicing was insensitive to the presence of HA-causing variants. However, splicing of several exons, including exon-16, was impacted by variants predicted to alter exonic splicing regulatory sequences. Using exon-16 as a model, we investigated the structure-function relationship of HA-causing variants on splicing. Intriguingly, RNA chemical probing analyses revealed a three-way junction structure at the 3'-end of intron-15 (TWJ-3-15) capable of sequestering the polypyrimidine tract. We discovered antisense oligonucleotides (ASOs) targeting TWJ-3-15 partially rescue splicing-deficient exon-16 variants by increasing accessibility of the polypyrimidine tract. The apical stem loop region of TWJ-3-15 also contains two hnRNPA1-dependent intronic splicing silencers (ISSs). ASOs blocking these ISSs also partially rescued splicing. When used in combination, ASOs targeting both the ISSs and the region sequestering the polypyrimidine tract, fully rescue pre-mRNA splicing of multiple HA-linked variants of exon-16. Together, our data reveal a putative RNA structure that sensitizes F8 exon-16 to aberrant splicing.

Security-differentiated Water Pricing as a Mechanism for Mitigating Drought Impacts. Insights from a Case Study in the Mediterranean Basin.

Water is becoming an increasingly scarce resource due to growing multi-sector demand and the effects of climate change. During droughts, the proportional rule is the most widespread water allocation method applied in irrigation systems. However, this method fails to guarantee efficient water allocation or to provide a fair method of water allocation. This paper aims to verify whether by replacing the water allocation methods based on a proportional rule with methods based on a priority rule could improve the allocation of water resources and minimize the negative economic impacts of water shortages. The ultimate objective of this research is to design a water pricing scheme capable of guaranteeing efficient water reallocation during drought conditions. Therefore, an experiment was carried out for the largest irrigated area in southern Italy, covered by the Capitanata Reclamation and Irrigation board (CBC). A positive mathematical programming model was implemented in order to simulate the effects of the proposed mechanism. The findings show that priority mechanisms have the potential to improve overall economic efficiency in the event of water shortages. However, results also point to the need for optimal design of a differentiated water pricing scheme.

Effectiveness of a specific strength program of the gluteus maximus muscle to improve dynamic postural control in female basketball players. A randomized controlled trial.

BACKGROUND: Basketball is a team sport in which players perform multidirectional movements, jumps and landings, experiencing abrupt accelerations and decelerations and numerous changes of rhythm. In this sport, speed and intensity are two key factors that are associated with an increased risk of injury. The aim of this randomized controlled trial was to determine the effectiveness of a specific gluteus maximus strength programme as preventive work for young female basketball players, to improve dynamic postural stability and to observe its impact in the rate of lower limb injuries, vertical jump, dynamic knee valgus and pain. RESEARCH QUESTION: Is effective a strength programme to improve dynamic postural stability, vertical jump and dynamic valgus in female basketball players? METHODS: A hundred and thirteen female basketball players that play in professional clubs were recruited, reaching the final stage 92 (46 per group). One group (CG) received conventional injury prevention training while the experimental group (EG) added to the conventional team prevention program, a gluteus maximus strength programme of 5 months composed of 4 exercises/2 days per week/2 sets of 10 repetitions per leg. RESULTS: The total injury incidence decreased from 0.33 to 0.16 cases (control group pre=0.43 to post=0.14 cases, EG pre=022 to post=0.19). The EG improved overall (p = 0.000), posterior (p = 0.001), posteromedial (p = 0.001) and posterolateral (p = 0.000) dynamic stability of the right leg; anterior (p = 0.024), medial (p = 0.07) and posteromedial (p = 0.01) of the left leg. Both groups improved vertical jump (GC: p = 0.045 and GE: p = 0.000). There was no significant improvement in pain or valgus. SIGNIFICANCE: This strength programme is effective in improving dynamic stability especially of the dominant leg and jump height.

Evolution of economic burden of heart failure by ejection fraction in newly diagnosed patients in Spain.

OBJECTIVE: To describe healthcare resource utilization (HCRU) and costs, in patients with newly diagnosed heart failure (HF) according to ejection fraction (EF) in Spain. METHODS: Retrospective cohort study that analyzed anonymized, integrated and computerised medical records in Spain. Patients with ≥ 1 new HF diagnosis between January 2013 and September 2019 were included and followed-up during a 4-year period. Rates per 100 person-years of HCRU and costs were estimated. RESULTS: Nineteen thousand nine hundred sixty-one patients were included, of whom 43.5%, 26.3%, 5.1% and 25.1% had HF with reduced, preserved, mildly reduced and unknown EF, respectively. From year 1 to 4, HF rates of outpatient visits decreased from 1149.5 (95% CI 1140.8-1159.3) to 765.5 (95% CI 745.9-784.5) and hospitalizations from 61.7 (95% CI 60.9-62.7) to 15.7(14.7-16.7) per 100 person-years. The majority of HF-related healthcare resource costs per patient were due to hospitalizations (year 1-4: 63.3-38.2%), followed by indirect costs (year 1-4: 12.2-29.0%), pharmacy (year 1-4: 11.9-19.9%), and outpatient care (year 1-4: 12.6-12.9%). Mean (SD) per patient HF-related costs decreased from 2509.6 (3518.5) to 1234.6 (1534.1) Euros (50% cost reduction). At baseline, 70.1% were taking beta-blockers, 56.3% renin-angiotensin system inhibitors, 11.8% mineralocorticoid receptor antagonists and 8.9% SGLT2 inhibitors. At 12 months, these numbers were 72.3%, 65.4%, 18.9% and 9.8%, respectively. CONCLUSIONS: Although the economic burden of HF decreased over time since diagnosis, it is still substantial. This reduction could be partially related to a survival bias (sick patients died early), but also to a better HF management. Despite that, there is still much room for improvement.

Estimulación cerebral profunda combinada del núcleo subtalámico y el globo pálido interno en la enfermedad de Parkinson / Combined subthalamic nucleus and globus pallidus internus deep brain stimulation in Parkinson’s disease

Introducción: La estimulación cerebral profunda (ECP) del núcleo subtalámico (NST) y el globo pálido interno (GPi) son los principales abordajes quirúrgicos en la enfermedad de Parkinson avanzada. La estimulación suele aplicarse de forma bilateral en la misma estructura cerebral. Sin embargo, cuando diferentes síntomas motores se presentan concomitantemente en el mismo paciente, la modulación simultánea de diferentes estructuras cerebrales puede ser una alternativa eficaz. Caso clínico: Presentamos un paciente con enfermedad de Parkinson avanzada en el que se realizó ECP combinada en NST y el GPi. La ECP del NST izquierdo controló de manera óptima la sintomatología del hemicuerpo derecho, mientras que las discinesias problemáticas que presentaba en el hemicuerpo izquierdo se redujeron con éxito mediante la estimulación del GPi derecho. Discusión. La estimulación combinada del NST/GPi puede considerarse un enfoque neuroquirúrgico adecuado cuando surge una sintomatología motora desafiante en pacientes con enfermedad de Parkinson avanzada.(AU)

Introduction: Subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) are the main surgical approaches for advanced Parkinson’s disease. Stimulation is usually applied bilaterally in the same brain structure. However, when various motor symptoms concomitantly present in the same patient, simultaneous modulation of different brain structures may be a suitable alternative. Case report: We present a patient with advanced Parkinson’s disease with a combined DBS neurosurgery. Left STN DBS optimally controlled the off right hemibody symptomatology while left side troublesome dyskinesias were successfully relieved by right GPi stimulation. Discussion: Combined STN/GPi stimulation can be considered a suitable approach when challenging motor symptomatology arises in advanced Parkinson’s disease patients.(AU)

Brazilian Clinical Strains of Actinobacillus pleuropneumoniae and Pasteurella multocida: Capsular Diversity, Antimicrobial Susceptibility (In Vitro) and Proof of Concept for Prevention of Natural Colonization by Multi-Doses Protocol of Tildipirosin.

One hundred Actinobacillus pleuropneumoniae (App) and sixty Pasteurella multocida subsp. multocida serogroup A (PmA) isolates were recovered from porcine pneumonic lungs collected from eight central or southern states of Brazil between 2014 and 2018 (App) or between 2017 and 2021 (PmA). A. pleuropneumoniae clinical isolates were typed by multiplex PCR and the most prevalent serovars were 8, 7 and 5 (43, 25% and 18%, respectively). In addition, three virulence genes were assessed in P. multocida isolates, all being positive to capA (PmA) and kmt1 genes, all negative to capD and toxA, and most of them (85%) negative to pfhA gene. The susceptibility of both pathogens to tildipirosin was investigated using a broth microdilution assay. The percentage of isolates susceptible to tildipirosin was 95% for App and 73.3% for PmA. The MIC50 values were 0.25 and 1 µg/mL and the MIC90 values were 4 and >64 µg/mL for App and PmA, respectively. Finally, a multiple-dose protocol of tildipirosin was tested in suckling piglets on a farm endemic for both pathogens. Tildipirosin was able to prevent the natural colonization of the tonsils by App and PmA and significantly (p < 0.0001) reduced the burden of Glaesserella parasuis in this tissue. In summary, our results demonstrate that: (i) tildipirosin can be included in the list of antibiotics to control outbreaks of lung disease caused by App regardless of the capsular type, and (ii) in the case of clinical strains of App and PmA that are sensitive to tildipirosin based on susceptibility testing, the use of this antibiotic in eradication programs for A. pleuropneumoniae and P. multocida can be strongly recommended.

Exploring the Occurrence of Organic Contaminants in Human Semen through an Innovative LC-HRMS-Based Methodology Suitable for Target and Nontarget Analysis.

Understanding the potential impact of organic contaminants on male fertility is crucial, yet limited studies have examined these chemicals in semen, with most focusing on urine and blood. To address this gap, we developed and validated a robust LC-HRMS methodology for semen analysis, with a focus on polar and semipolar chemicals. Our methodology enables the quantitative (or semiquantitative) analysis of >2000 chemicals being compatible with suspect and nontarget strategies and providing unprecedented insights into the occurrence and potential bioaccumulation of diverse contaminants in this matrix. We comprehensively analyzed exogenous organic chemicals and associated metabolites in ten semen samples from Spanish participants collected in an area with a large presence of the chemical industry included in the LED-FERTYL Spanish study cohort. This investigation revealed the presence of various contaminants in semen, including plastic additives, PFAS, flame retardants, surfactants, and insecticides. Notably, prevalent plastic additives such as phthalic acid esters and bisphenols were identified, indicating potential health risks. Additionally, we uncovered previously understudied chemicals like the tire additive 2-mercaptobenzothiazole and specific organophosphate flame retardants. This study showcases the potential of our methodology as a valuable tool for large-scale cohort studies, providing insights into the association between contaminant exposure and the risk of male fertility impairments.

Comprehensive profiling and semi-quantification of exogenous chemicals in human urine using HRMS-based strategies.

Chemicals infiltrate our daily experiences through multiple exposure pathways. Human biomonitoring (HBM) is routinely used to comprehensively understand these chemical interactions. Historically, HBM depended on targeted screening methods limited to a relatively small set of chemicals with triple quadrupole instruments typically. However, recent advances in high-resolution mass spectrometry (HRMS) have facilitated the use of broad-scope target, suspect, and non-target strategies, enhancing chemical exposome characterization within acceptable detection limits. Despite these advancements, establishing robust and efficient sample treatment protocols is still essential for trustworthy broad-range chemical analysis. This study sought to validate a methodology leveraging HRMS-based strategies for accurate profiling of exogenous chemicals and related metabolites in urine samples. We evaluated five extraction protocols, each encompassing various chemical classes, such as pharmaceuticals, plastic additives, personal care products, and pesticides, in terms of their extraction recoveries, linearity, matrix effect, sensitivity, and reproducibility. The most effective protocol was extensively validated and subsequently applied to 10 real human urine samples using wide-scope target analysis encompassing over 2000 chemicals. We successfully identified and semi-quantified a total of 36 chemicals using an ionization efficiency-based model, affirming the methodology's robust performance. Notably, our results dismissed the need for a deconjugation step, a typically labor-intensive and time-consuming process.

Phase 1b dose-finding study of rituximab, lenalidomide, and ibrutinib (R2I) in patients with relapsed/refractory mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n = 25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1-21) and ibrutinib 560 mg (days 1-28) of 28-day cycles. The MTD for lenalidomide was 20 mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92 months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67 > 30%). R2I was safe and tolerable in patients with R/R MCL.