Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.

COPD: systemic proteomic profiles in frequent and infrequent exacerbators.

Background: Some patients with COPD suffer frequent exacerbations (FE). We hypothesised that their systemic proteomic profile would be different from that of non-frequent exacerbators (NFE). The objective of the present study was to contrast the systemic proteomic profile in FE versus NFE. As a reference, we also determined the systemic proteomic profile of healthy controls (HC) and COPD patients during an actual episode of exacerbation (AE). Methods: In the analysis we included 40 clinically stable COPD patients (20 FE and 20 NFE), and 20 HC and 10 AE patients. Their plasma samples were analysed by combining two complementary proteomic approaches: label-free liquid chromatography-tandem mass spectrometry and multiplex immunoassays. Gene Ontology annotation, pathway enrichment and network analyses were used to investigate molecular pathways associated with differentially abundant proteins/peptides (DAPs). Results: Compared with HC, we identified 40 DAPs in FE, 10 in NFE and 63 in AE. Also compared to HC, pathway functional and protein-protein network analyses revealed dysregulation of inflammatory responses involving innate and antibody-mediated immunity in COPD, particularly in the FE group, as well as during an AE episode. Besides, we only identified alterations in the complement and coagulation cascades in AE. Conclusion: There are specific plasma proteome profiles associated with FE, which are partially shared with findings observed during AE, albeit others are uniquely present during the actual episode of AE.

A Step towards understanding coronary artery disease: a complication in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a relatively rare disease with increasing incidence trends. Cardiovascular disease is a significant complication in IPF patients due to the role of common proatherogenic immune mediators. The prevalence of coronary artery disease (CAD) in IPF and the association between these distinct pathologies with overlapping pathophysiology remain less studied. RESEARCH QUESTION: We hypothesised that IPF is an independent risk factor for CAD. METHODS: We conducted a retrospective case-control study using the national inpatient sample (2017-2019). We included adult hospitalisations with IPF after excluding other interstitial lung diseases and other endpoints of CAD, acute coronary syndrome and old myocardial infarction. We examined their baseline characteristics, such as demographic data, hospital characteristics and socioeconomic status. The prevalence of cardiac risk factors and CAD was also compared between hospitalisations with and without IPF. Univariate and multivariate regression analysis was further performed to study the odds of CAD with IPF. The cases of IPF in the study population were propensity-matched, after which generalised linear modelling analysis was performed to validate the findings. RESULTS: A total of 116 010 admissions were hospitalised in 2017-2019 with IPF, of which 55.6% were men with a mean age of 73 years. Adult hospitalisations with IPF were found to have a higher prevalence of diabetes mellitus (29.3% vs 24.0%; p<0.001), hypertension (35.6% vs 33.8%; p<0.001), hyperlipidaemia (47.7% vs 30.2%; p<0.0001) and tobacco abuse (41.7% vs 20.9%; p<0.001), while they had a lower prevalence of obesity (11.7% vs 15.3%; p<0.0001) compared with hospitalisations without IPF. Multivariate logistic regression analysis revealed 28% higher odds of developing CAD in IPF hospitalisations (OR -1.28; CI 1.22 to 1.33; p<0.001). Postpropensity matching, generalised linear modelling analysis revealed even higher odds of CAD with IPF (OR -1.77; CI 1.54 to 2.02; p<0.001) CONCLUSIONS: Our study found a higher prevalence of CAD in IPF hospitalisations and significantly higher odds of CAD among IPF cases. IPF remains a terminal lung disease that portends a poor prognosis, but addressing the cardiovascular risk factors in these patients can help reduce the case fatality rate due to the latter and potentially add to quality-adjusted life years.

Post hoc analysis of daratumumab plus lenalidomide, bortezomib and dexamethasone in Black patients from final data of the GRIFFIN study.

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients.

Biological and ecological traits rather than geography control mercury (Hg) in scutes of marine turtles from the Southwest Atlantic.

The use of sentinel species in monitoring programs for toxic metals such as mercury (Hg) is essential to understand these pollutants' impact on the environment. For this purpose, it is essential to use organisms that have a lifespan compatible with the residence time of Hg in the oceans, and preferably with a wide geographical distribution, such as sea turtles. Here, we assess the regional variability of Hg concentrations using carapace scutes of four sea turtle species along the foraging and spawning area in the northeast coastline of Brazil. Mercury concentrations in samples showed no relationship with the environmental Hg levels (obtained from literature). Rather, Hg concentrations varied according to species-specific biological, and ecological traits. Characteristics such as the ontogenetic shift in the diet of Chelonia mydas, capital breeding in females, depth of foraging in oceanic waters, and selectivity of food items, such as in Eretmochelys imbricata, significantly influenced Hg concentrations.

Trophic ecology of sympatric sea turtles in the tropical Atlantic coast of Brazil.

The Tropical Atlantic coast of Brazil is a hotspot area for multiple sea turtle species at all life stages. The multiple nearshore reefs and beaches, oceanic islands, and the only atoll in the south Atlantic Ocean, are suitable for year-round foraging, migration corridors, and nesting activities of five sea turtle species. Still, relatively few studies have assessed trophic niche among sympatric sea turtles which can provide a better understanding of how closely related species compete/partition the available resources. Using multiple biogeochemical tracers (i.e., nitrogen (δ15N) and carbon (δ13C) stable isotopes, and mercury (Hg)), we disentangled the trophic niches of four sea turtle species - the green turtle (Chelonia mydas), the loggerhead turtle (Caretta), the hawksbill turtle (Eretmochelys imbricata), and the olive ridley turtle (Lepidochelys olivacea) - co-occurring in nesting and foraging habitats along the northeastern coast of Brazil. We found interspecific differences in isotopic and contamination niches, as well as intraspecific niche variation associated with life stage. Differences in the estimation niche models associated to life-stage in C. caretta support the notion of ontogenetic shift in habitat and diet composition previously reported for this species. Oceanic habitat signatures were observed in juvenile green turtles and adult olive turtles, while nearshore habitat signatures were observed in adult hawksbill turtles.

Safety profile of trastuzumab deruxtecan in advanced breast cancer: Expert opinion on adverse event management.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) and has shown promising results in the treatment of advanced/metastatic breast cancer. The objective of this report is to provide guidance on the prophylaxis, monitoring, and management of adverse events (AEs) in patients with breast cancer treated with T-DXd, and to emphasize that proper management of AEs is needed to optimize the effectiveness of T-DXd treatment and reduce the number of discontinuations. The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical recommendations for managing AEs, such as nausea/vomiting, interstitial lung disease, and hematologic toxicity. Although there are still many knowledge gaps about the cause and incidence of AEs in real-world patients, this document may serve as a valuable resource for clinicians who are involved in the care of breast cancer patients receiving T-DXd treatment.

Evolutionary history of the cytochrome P450s from Colletotrichum species and prediction of their putative functional roles during host-pathogen interactions.

The genomes of species belonging to the genus Colletotrichum harbor a substantial number of cytochrome P450 monooxygenases (CYPs) encoded by a broad diversity of gene families. However, the biological role of their CYP complement (CYPome) has not been elucidated. Here, we investigated the putative evolutionary scenarios that occurred during the evolution of the CYPome belonging to the Colletotrichum Graminicola species complex (s.c.) and their biological implications. The study revealed that most of the CYPome gene families belonging to the Graminicola s.c. experienced gene contractions. The reductive evolution resulted in species restricted CYPs are predominant in each CYPome of members from the Graminicola s.c., whereas only 18 families are absolutely conserved among these species. However, members of CYP families displayed a notably different phylogenetic relationship at the tertiary structure level, suggesting a putative convergent evolution scenario. Most of the CYP enzymes of the Graminicola s.c. share redundant functions in secondary metabolite biosynthesis and xenobiotic metabolism. Hence, this current work suggests that the presence of a broad CYPome in the genus Colletotrichum plays a critical role in the optimization of the colonization capability and virulence.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation.

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

BACKGROUND: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study. METHODS: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. RESULTS: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1]). CONCLUSION: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. CLINICAL TRIAL REGISTRATION: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Regional differences in Hg contents in the liver and muscle of the green turtle (Chelonia mydas) from three foraging grounds in Northeast Brazil.

Mercury (Hg) is a highly toxic pollutant that endangers several marine animals, including green sea turtles (Chelonia mydas), particularly in their foraging grounds along Brazilian coastal waters. Environmental Hg levels differ along this extensive littoral, rendering mandatory Hg long-term assessments of the different Hg fate in different sectors of the Brazilian coast. This study quantifies total Hg concentrations in the liver and muscle of green sea turtle populations from three foraging coastal regions in northeastern Brazil and analyzes Hg concentration differences given the locality and size of 61 juvenile individuals sampled. The results showed wide variations in Hg concentrations in the liver (81-3135 ng g-1) and muscle (10.1-8569 ng g-1). There was no significant correlation between animal size and Hg concentrations. Also, no difference was found among areas, reflecting the opportunistic feeding habit of juveniles of this species. This suggests that, in the case of green turtles, the ontogenetic change of diet plays an important role in influencing Hg concentrations found in this species.

Inhibitors of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Decrease the Growth, Ergosterol Synthesis and Generation of petite Mutants in Candida glabrata and Candida albicans.

Candida glabrata and Candida albicans, the most frequently isolated candidiasis species in the world, have developed mechanisms of resistance to treatment with azoles. Among the clinically used antifungal drugs are statins and other compounds that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), resulting in decreased growth and ergosterol levels in yeasts. Ergosterol is a key element for the formation of the yeast cell membrane. However, statins often cause DNA damage to yeast cells, facilitating mutation and drug resistance. The aim of the current contribution was to synthesize seven series of compounds as inhibitors of the HMGR enzyme of Candida ssp., and to evaluate their effect on cellular growth, ergosterol synthesis and generation of petite mutants of C. glabrata and C. albicans. Compared to the reference drugs (fluconazole and simvastatin), some HMGR inhibitors caused lower growth and ergosterol synthesis in the yeast species and generated fewer petite mutants. Moreover, heterologous expression was achieved in Pichia pastoris, and compounds 1a, 1b, 6g and 7a inhibited the activity of recombinant CgHMGR and showed better binding energy values than for α-asarone and simvastatin. Thus, we believe these are good candidates for future antifungal drug development.

Beneficios del entrenamiento multicomponente en el aprendizaje motor y cognitivo de los adultos mayores / Benefits of multicomponent training on motor and cognitive learning in older adults / Benefícios do treinamento multicomponente para o aprendizado motor e cognitivo em adultos mais velhos

Un problema reiterativo en adultos mayores son las caídas, afectando notablemente su salud y generando morbimortalidad elevada por la lesión y por las secuelas producidas en el aspecto psicológico y social. Objetivo. Analizar los beneficios de los ejercicios multicomponentes en el aprendizaje motor y cognitivo del adulto mayor. Metodología. Se realizó una revisión sistemática de artículos experimentales que se centraron en los ejercicios multicomponentes como intervención o tratamiento publicados en revistas indexadas en las bases de datos Scopus y Scielo entre 2015 y 2020. Como resultado preliminar se obtuvo 183 artículos con la aplicación de la cadena de búsqueda: TITLE-ABS-KEY (multicomponent AND exercises AND older AND adults). Después de la selección, se analizaron 12 artículos relevantes que cumplían con los criterios establecidos. Conclusión. La prueba de condición física multidimensional, mostró su eficacia para predecir cambios en el rendimiento físico; Los ejercicios de resistencia redujeron la ocurrencia de caídas al mejorar la funcionalidad. Asimismo, los ejercicios multicomponentes fueron eficaces para restablecer la función cognitiva de los adultos mayores, la prevención de caídas y la mejoría de sus labores cotidianas. Los programas de intervención con ejercicios multicomponentes, redujeron sustancialmente los riesgos de caídas, comparados con programas de ejercicios únicos, del mismo modo se evidenció mejoras relevantes en la función cognitiva y en labores cotidianas, evidenciando mejor funcionamiento general que a su vez originó mejoras en su productividad.

Falls are a recurrent problem in older adults, notably affecting their health and generating high morbimortality due to the injury and the psychological and social sequelae. Objective. To analyze the benefits of multicomponent exercises in motor and cognitive learning in the elderly. Methodology. A systematic review of experimental articles focusing on multicomponent exercises as an intervention or treatment published in journals indexed in the Scopus and Scielo databases between 2015 and 2020 was performed. As a preliminary result, 183 articles were obtained with the application of the search string: TITLE-ABS-KEY (multicomponent AND exercises AND older AND adults). After selection, 12 relevant articles that met the established criteria were analyzed. Conclusion. The multidimensional physical fitness test showed its efficacy in predicting changes in physical performance; resistance exercises reduced the occurrence of falls by improving functionality. Likewise, multicomponent exercises were effective in restoring the cognitive function of older adults, preventing falls and improving their daily tasks. Intervention programs with multicomponent exercises substantially reduced the risk of falls, compared to single exercise programs, and also showed significant improvements in cognitive function and daily tasks, resulting in better overall functioning, which in turn led to improvements in productivity.

As quedas são um problema recorrente em adultos mais velhos, afetando sua saúde e gerando alta morbimortalidade devido à lesão e às sequelas psicológicas e sociais. Objetivos. Analisar os benefícios dos exercícios multicomponentes na aprendizagem motora e cognitiva em idosos. Metodologia. Realizamos uma revisão sistemática de artigos experimentais que enfocaram os exercícios multicomponentes como intervenção ou tratamento publicados em periódicos indexados nas bases de dados Scopus e Scielo entre 2015 e 2020. Como resultado preliminar, 183 artigos foram obtidos com a aplicação da string de busca: TITLE-ABS-KEY (multicomponent AND exercises AND older AND adults). Após a seleção, foram analisados 12 artigos relevantes que atenderam aos critérios estabelecidos. Conclusões. O teste multidimensional de condicionamento físico demonstrou ser eficaz na previsão de mudanças no desempenho físico; os exercícios de resistência reduziram a ocorrência de quedas, melhorando a funcionalidade. Os exercícios multicomponentes também foram eficazes na restauração da função cognitiva dos idosos, na prevenção de quedas e na melhoria de suas tarefas diárias. Os programas de intervenção de exercícios multicomponentes reduziram substancialmente o risco de quedas em comparação com os programas de exercícios individuais e também apresentaram melhorias significativas na função cognitiva e nas tarefas diárias, resultando em melhor funcionamento geral, o que, por sua vez, levou a melhorias na produtividade.

Update on metabolomic findings in COPD patients.

COPD is a heterogeneous disorder that shows diverse clinical presentations (phenotypes and "treatable traits") and biological mechanisms (endotypes). This heterogeneity implies that to carry out a more personalised clinical management, it is necessary to classify each patient accurately. With this objective, and in addition to clinical features, it would be very useful to have well-defined biological markers. The search for these markers may either be done through more conventional laboratory and hypothesis-driven techniques or relatively blind high-throughput methods, with the omics approaches being suitable for the latter. Metabolomics is the science that studies biological processes through their metabolites, using various techniques such as gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance. The most relevant metabolomics studies carried out in COPD highlight the importance of metabolites involved in pathways directly related to proteins (peptides and amino acids), nucleic acids (nitrogenous bases and nucleosides), and lipids and their derivatives (especially fatty acids, phospholipids, ceramides and eicosanoids). These findings indicate the relevance of inflammatory-immune processes, oxidative stress, increased catabolism and alterations in the energy production. However, some specific findings have also been reported for different COPD phenotypes, demographic characteristics of the patients, disease progression profiles, exacerbations, systemic manifestations and even diverse treatments. Unfortunately, the studies carried out to date have some limitations and shortcomings and there is still a need to define clear metabolomic profiles with clinical utility for the management of COPD and its implicit heterogeneity.

Phenotypic and Genomic Characterization of Streptomyces pakalii sp. nov., a Novel Species with Anti-Biofilm and Anti-Quorum Sensing Activity in ESKAPE Bacteria.

The increasing number of infections caused by antimicrobial multi-resistant microorganisms has led to the search for new microorganisms capable of producing novel antibiotics. This work proposes Streptomyces pakalii sp. nov. as a new member of the Streptomycetaceae family. The strain ENCB-J15 was isolated from the jungle soil in Palenque National Park, Chiapas, Mexico. The strain formed pale brown, dry, tough, and buried colonies in the agar with no diffusible pigment in GAE (glucose-asparagine-yeast extract) medium. Scanning electron micrographs showed typical mycelium with long chains of smooth and oval-shaped spores (3-10 m). The strain grew in all of the International Streptomyces Project (ISP)'s media at 28-37 °C with a pH of 6-9 and 0-10% NaCl. S. pakalii ENCB-J15 assimilated diverse carbon as well as organic and inorganic nitrogen sources. The strain also exhibited significant inhibitory activity against the prodigiosin synthesis of Serratia marcescens and the inhibition of the formation and destruction of biofilms of ESKAPE strains of Acinetobacter baumannii and Klebsiella pneumoniae. The draft genome sequencing of ENCB-J15 revealed a 7.6 Mb genome with a high G + C content (71.6%), 6833 total genes, and 6746 genes encoding putative proteins. A total of 26 accessory clusters of proteins associated with carbon sources and amino acid catabolism, DNA modification, and the antibiotic biosynthetic process were annotated. The 16S rRNA gene phylogeny, core-proteome phylogenomic tree, and virtual genome fingerprints support that S. pakalii ENCB-J15 is a new species related to Streptomyces badius and Streptomyces globisporus. Similarly, its average nucleotide identity (ANI) (96.4%), average amino acid identity (AAI) (96.06%), and virtual DNA-DNA hybridization (67.3%) provide evidence to recognize it as a new species. Comparative genomics revealed that S. pakalli and its closest related species maintain a well-conserved genomic synteny. This work proposes Streptomyces pakalii sp. nov. as a novel species that expresses anti-biofilm and anti-quorum sensing activities.

Unlocking the hidden potential of Mexican teosinte seeds: revealing plant growth-promoting bacterial and fungal biocontrol agents.

The bacterial component of plant holobiont maintains valuable interactions that contribute to plants' growth, adaptation, stress tolerance, and antagonism to some phytopathogens. Teosinte is the grass plant recognized as the progenitor of modern maize, domesticated by pre-Hispanic civilizations around 9,000 years ago. Three teosinte species are recognized: Zea diploperennis, Zea perennis, and Zea mays. In this work, the bacterial diversity of three species of Mexican teosinte seeds was explored by massive sequencing of 16S rRNA amplicons. Streptomyces, Acinetobacter, Olivibacter, Erwinia, Bacillus, Pseudomonas, Cellvibrio, Achromobacter, Devosia, Lysobacter, Sphingopyxis, Stenotrophomonas, Ochrobactrum, Delftia, Lactobacillus, among others, were the bacterial genera mainly represented. The bacterial alpha diversity in the seeds of Z. diploperennis was the highest, while the alpha diversity in Z. mays subsp. mexicana race was the lowest observed among the species and races. The Mexican teosintes analyzed had a core bacteriome of 38 bacterial genera, including several recognized plant growth promoters or fungal biocontrol agents such as Agrobacterium, Burkholderia, Erwinia, Lactobacillus, Ochrobactrum, Paenibacillus, Pseudomonas, Sphingomonas, Streptomyces, among other. Metabolic inference analysis by PICRUSt2 of bacterial genera showed several pathways related to plant growth promotion (PGP), biological control, and environmental adaptation. The implications of these findings are far-reaching, as they highlight the existence of an exceptional bacterial germplasm reservoir teeming with potential plant growth promotion bacteria (PGPB). This reserve holds the key to cultivating innovative bioinoculants and formidable fungal antagonistic strains, thereby paving the way for a more sustainable and eco-friendly approach to agriculture. Embracing these novel NGS-based techniques and understanding the profound impact of the vertical transference of microorganisms from seeds could revolutionize the future of agriculture and develop a new era of symbiotic harmony between plants and microbes.

Prediabetes is an incremental risk factor for adverse cardiac events: A nationwide analysis.

Background and aims: Prediabetes is defined as a state of impaired glucose metabolism with hemoglobin A1c (HbA1c) levels that precede those of a diabetic state. There is increasing evidence that suggests that hyperglycemic derangement in prediabetes leads to microvascular and macrovascular complications even before progression to overt diabetes mellitus. We aim to identify the association of prediabetes with acute cardiovascular events. Methods: We utilized the National inpatient sample 2018-2020 to identify adult hospitalizations with prediabetes after excluding all hospitalizations with diabetes. Demographics and prevalence of other cardiovascular risk factors were compared in hospitalizations with and without prediabetes using the chi-square test for categorical variables and the t-test for continuous variables. Multivariate regression analysis was further performed to study the impact of prediabetes on acute coronary syndrome, acute ischemic stroke, intracranial hemorrhage, and acute heart failure. Results: Hospitalizations with prediabetes had a higher prevalence of cardiovascular risk factors like hypertension, hyperlipidemia, obesity, and tobacco abuse. In addition, the adjusted analysis revealed that hospitalizations with prediabetes were associated with higher odds of developing acute coronary syndrome (OR-2.01; C.I:1.94-2.08; P<0.001), acute ischemic stroke (OR-2.21; 2.11-2.31; p<0.001), and acute heart failure (OR-1.41; C.I.: 1.29-1.55; p<0.001) as compared to hospitalizations without prediabetes. Conclusions: Our study suggests that prediabetes is associated with a higher odds of major cardiovascular events. Further prospective studies should be conducted to identify prediabetes as an independent causative factor for these events. In addition, screening and lifestyle modifications for prediabetics should be encouraged to improve patient outcomes.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.