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PURPOSE: Tamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival. METHODS: We enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment. RESULTS: The analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance. CONCLUSION: An early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.

Background Antiretroviral therapy has revolutionized HIV treatment, increasing quality and life expectancy of people living with HIV (PLWH). However, the expansion of treatment has resulted in an increase in antiretroviral-resistant viruses, which can be an obstacle to maintenance of successful ART. Objectives This study analysed the genetic composition of the HIV near full-length genome (NFLG) from archived proviruses of PLWH under successful ART, and determined the presence/frequency of drug resistance mutations (DRMs) and viral subtype. Patients and methods Forty-six PLWH from Rio de Janeiro (RJ) and 40 from Rio Grande (RS) had proviral HIV NFLG PCR-amplified and ultradeep sequenced. The presence/frequency of DRMs were analysed in Geneious. Phylogenetic analyses were performed using PhyML and SimPlot. Results All samples included in the study were sequenced and 69 (80.2%) had the HIV NFLG determined. RJ and RS showed a predominance of HIV subtypes B (78.3%) and C (67.5%), respectively. Overall, 168 DRMs were found in 63 (73.3%) samples, and 105 (62.5%) of them were minority variants. Among DRMs, 41 (39.0%) minority variants and 33 (52.4%) variants with frequency above 20.0% in the viral population were able to confer some degree of resistance to at least one drug in use by respective patients, yet no one showed signs of therapeutic failure. Conclusions Our study contributes to the understanding of the impact of DRMs on successful therapy and supports the sustainability of combinatorial ART, because all patients maintained their successful treatment despite the high prevalence of DRMs at low (62.5%) or high (37.5%) frequency.

This work provide objective measures of foveal avascular zone area and macular vascular density by swept-source optical coherence tomography angiography during the follow-up of a patient with papilledema due to secondary intracranial hypertension.

In this ongoing study we aim at using machine learning algorithms to better understand and improve southern Europe summer heatwave prediction on sub-seasonal to seasonal timescales (S2S). Summer heatwaves are extreme events that have large socio-economic impacts on mortality rate, crop yields, energy demand or water resources and southern Europe is particularly prone and vulnerable to such events. To do this, we train a convolutional network coupled with a multilayer perceptron to forecast with a 15-day and 1-month lead times the occurrence and intensity of heatwave in summer. This forecast model is trained with ERA5 data. The predictors fed to this model are monthly means of the SST, local soil moisture, outgoing longwave radiation, snow cover and sea-ice cover. The target is a monthly-mean heatwave index integrated over a sub-area of southern Europe. Here, we will present the initial results of this ongoing work and the next steps, focusing first on the Iberian Peninsula only.

Risk of overdose, suicide, and other adverse outcomes are elevated among sub-populations prescribed opioid analgesics. To address this, the Veterans Health Administration (VHA) developed the Stratification Tool for Opioid Risk Mitigation (STORM)-a provider-facing dashboard that utilizes predictive analytics to stratify patients prescribed opioids based on risk for overdose/suicide.To evaluate the impact of the case review mandate on serious adverse events (SAEs) and all-cause mortality among high-risk Veterans.A 23-month stepped-wedge cluster randomized controlled trial in all 140 VHA medical centers between 2018 and 2020.A total of 44,042 patients actively prescribed opioid analgesics with high STORM risk scores (i.e., percentiles 1% to 5%) for an overdose or suicide-related event.A mandate requiring providers to perform case reviews on opioid analgesic-prescribed patients at high risk of overdose/suicide.Nine serious adverse events (SAEs), case review completion, number of risk mitigation strategies, and all-cause mortality.Mandated review inclusion was associated with a significant decrease in all-cause mortality within 4 months of inclusion (OR: 0.78; 95% CI: 0.65-0.94). There was no detectable effect on SAEs. Stepped-wedge analyses found that mandated review patients were five times more likely to receive a case review than non-mandated patients with similar risk (OR: 5.1; 95% CI: 3.64-7.23) and received more risk mitigation strategies than non-mandated patients (0.498; CI: 0.39-0.61).Among VHA patients prescribed opioid analgesics, identifying high risk patients and mandating they receive an interdisciplinary case review was associated with a decrease in all-cause mortality. Results suggest that providers can leverage predictive analytic-targeted population health approaches and interdisciplinary collaboration to improve patient outcomes.ISRCTN16012111.

Structural and functional characterization of 4-1BBN/CEGFR after conjugation with p-SCN-Bn-deferoxamine (Df).

Oligonucleotides used in this study

Purpose:The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell–mediated antitumor response. Systemic administration of anti-4-1BB–agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.Experimental Design:Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo.Results:In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non–small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8+ T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFNγ secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer.Conclusions:These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.

BACKGROUND Within chronic diseases, cognitive, neurological, and cardiovascular impairments are becoming increasingly prevalent, generating a shift in health and social needs. Technology can create an ecosystem of care integrated with microtools based on biosensors for motion, location, voice, and expression detection that can help people with chronic diseases. A technological system capable of identifying symptoms, signs or behavioral patterns could alert patients with chronic diseases to the development of complications, aid them in self-care and save healthcare costs. As a result, the autonomy and empowerment of patients and their caregivers would be promoted, improving their quality of life, and health professionals would be provided with monitoring tools. OBJECTIVE The main objective of this study is to evaluate the effectiveness of a technological system (the TeNDER System) to improve quality of life in patients with chronic diseases: Alzheimer’s, Parkinson’s and cardiovascular disease. METHODS A multicenter, randomized, parallel-group, clinical trial will be conducted with a follow-up of 2 months. The scope of the study will be the primary care health centers in Madrid belonging to Spain’s Public Health System. The study population will be patients diagnosed with Parkinson’s, Alzheimer’s and cardiovascular disease, their caregivers and health professionals. The total sample size will be 534 patients (380 in the intervention group). The intervention will consist of the use of the TeNDER System. The system will monitor patients by means of biosensors, and their data will be integrated into the TeNDER application. With the information provided, the TeNDER system will generate health reports that can be viewed by patients, caregivers and health professionals. The primary outcome will be the difference in quality of life (measured with the SF36 questionnaire) between T0 and T1 and the corresponding 95% confidence interval (CI). Adjustment for confounding factors will be performed by multilevel analysis. RESULTS Recruitment of participants started in April 2021 and is ongoing. It is expected to end in April 2023. By 2023, the results will be disseminated in the form of scientific articles for publication. CONCLUSIONS This clinical trial of patients with highly prevalent chronic illnesses and the people most involved in their care will provide a more realistic view of the situation experienced by the long-term sick and their support networks. The TeNDER System is in continuous development based on results from the study of the target population and feedback from patients, caregivers and primary care health professionals. CLINICALTRIAL ClinicalTrials.gov NCT05681065. Registered on 11 January 2023.

Introducción: La endocarditis infecciosa (EI) es una patología que conlleva una elevada morbimortalidady representa un problema creciente de salud pública. El tratamiento quirúrgico es necesario en más dela mitad de los casos, y su principal finalidad es eliminar totalmente el tejido infectado y reconstruir laanatomía cardiaca normal, incluyendo la reparación o la sustitución de la/s válvula/s afectada/s.Objetivo y métodos: El presente estudio se centra en describir el procedimiento más apropiado para lacirugía de reparación mitral en casos de EI, atendiendo a la literatura y a la amplia experiencia adquiridapor parte del equipo quirúrgico. De igual modo, hemos recopilado a través de una búsqueda sistemáticade la literatura los resultados que se han ido reportando sobre la cirugía reparadora en comparación conel reemplazo valvular mitral.Resultados: La técnica quirúrgica descrita requiere de un estudio minucioso del grado de afectación ydesestructuración de los distintos segmentos valvulares. Consideramos que la resección con interposi-ción de parche de pericardio y/o implante de neocuerdas de Goretex®es la técnica estándar que permiteobtener resultados reproducibles. La revisión estructurada de las evidencias científicas disponibles veri-fica la seguridad de la reparación mitral para el tratamiento de la EI, aportando beneficios significativosen comparación con el reemplazo valvular.Conclusión: Los resultados quirúrgicos evaluados sugieren que la cirugía de reparación mitral deberíaser considerada el procedimiento de elección para el tratamiento quirúrgico de la EI, siempre que seatécnicamente posible., Introduction: Infective endocarditis (IE) is a pathology with a high morbidity and mortality rate andrepresents a growing public health problem. Surgical treatment is necessary in more than half of thecases, and its main purpose is to completely remove the infected tissue and reconstruct normal cardiacanatomy, including repair or replacement of the affected valve(s).Objectives and methods: The present study focuses on describing the most appropriate procedure formitral repair surgery in cases of IE, based on the literature and the extensive experience gained by thesurgical team. Likewise, we have compiled through a systematic search of the literature the results thathave been reported on reparative surgery compared to mitral valve replacement. Results: The surgical technique described requires a thorough study of the degree of involvement anddestructuring of the different valve segments. We consider resection with pericardial patch interpositionand/or Goretex®neochord implantation to be the standard technique that allows reproducible results. Thestructured review of the available scientific evidence verifies the safety of mitral repair for the treatmentof IE, providing significant benefits compared to valve replacement.Conclusion: The evaluated surgical results suggest that mitral repair surgery should be considered theprocedure of choice for the surgical treatment of IE, whenever technically feasible.

Genome-wide association studies (GWAS) have identified host genetic variants associated with paratuberculosis (PTB) susceptibility. Most of the GWAS-identified SNPs are in non-coding regions. Connecting these non-coding variants and downstream affected genes is a challenge and, up to date, only a few functional mutations or expression quantitative loci (cis-eQTLs) associated with PTB susceptibility have been identified. In the current study, the associations between imputed whole-genome sequence genotypes and whole RNA-Sequencing data from peripheral blood (PB) and ileocecal valve (ICV) samples of Spanish Holstein cows (N= 16) were analyzed with TensorQTL. This approach allowed the identification of 88 and 37 cis-eQTLs regulating the expression levels of 90 and 37 genes in PB and ICV samples, respectively (FDR ≤ 0.05). Next, we applied summary-based data Mendelian randomization (SMR) to integrate the cis-eQTL dataset with GWAS data obtained from a cohort of 813 culled cattle that were classified according to the presence or absence of PTB-associated histopathological lesions in gut tissues. After multiple testing corrections (False discovery rate, FDR ≤ 0.05), we identified two novel cis-eQTLs affecting the expression of the early growth response factor 4(EGR4) and the bovine neuroblastoma breakpoint family member 6-like protein isoform 2 (MGC134040) that showed pleiotropic associations with the presence of multifocal and diffuse lesions in gut tissues; P = 0.002 and P = 0.017, respectively. While EGR4acts as a brake on T-cell proliferation and cytokine production through interaction with the nuclear factor Kappa β (NF-κß), MGC134040 is a target gene of NF-κß. Although no other genes were pleiotropically associated with PTB susceptibility after correction for multiple testing, several genes involved in splicing, innate immune response, apoptosis, blood coagulation, and regulation of epithelial cell adhesion were significantly associated with the presence of multifocal and diffuse lesions (nominal P-value ≤ 0.05). Our findings provide a better understanding of the genetic factors influencing PTB outcomes, confirm that the multifocal lesions are localized/confined lesions that have different underlying host genetics than the diffuse lesions, and highlight regulatory SNPs and regulated-gene targets to design future functional studies.