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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

Serum stability of the 4-1BBN/CEGFR trimerbody.

Representative images of CD3+ and FoxP3+ TIL immunostaining

Kinetic constants

Pharmacokinetic parameters.

SAXS Data Collection and derived parameters

Binding assays of 4-1BB IgG and urelumab.

Co-stimulatory activity of control antibodies.

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.

Commercial antibodies

Effect of 4-1BBN/CEGFR trimerbody on EGFR-mediated signaling

Experimental and theoretical SAXS scattering.

Analysis by SAXS of the arrangement in solution of the 4-1BBN trimerbody.

Schematic diagrams showing the protein structure of the anti-hu4-1BB IgG (a), and the gene layout (b) and protein structure (c) of the anti-hu4-1BB trimerbody.

Structural characterization of 4-1BBN and 4-1BBN/CEGFR trimerbodies.

Species specificity of the 4-1BBN/CEGFR trimerbody.

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.

Materials by the modified proteic method based on calcium doped LaMnO3 and LaNiO3, with perovskite structure were prepared. The X-ray diffraction patterns revealed the presence of the perovskite phase in all materials, whose specific surface area values varied between 27 and 37 m2.g-1. The materials presented efficiency for the removal of Congo red dye and those with site B occupied by nickel presented better adsorptive efficiency. The incorporation of calcium on LaMnO3 or LaNiO3 materials caused an improvement in the performance of the materials for the dye removal from water. The materials maintained perovskite structure after the adsorption tests, allowing their reuse in new adsorption tests with high efficiency.

Insurance disruptions before, during, and after pregnancy are common in the United States, but little is known about the enrollment patterns of pregnant people in the Affordable Care Act Marketplaces. Data from the Pregnancy Risk Assessment Monitoring System from the period 2016-18 show that among respondents enrolled in Marketplace coverage, approximately one-third reported continuous Marketplace enrollment from preconception through the postpartum period. Compared with respondents who were continuously enrolled in Marketplace coverage from preconception through postpartum, respondents who enrolled in Marketplace plans during pregnancy had a 10.8 percent lower rate of adequate prenatal care, a 6.4 percent lower rate of timely prenatal care initiation, and a 13.2 percent lower rate of having twelve or more prenatal care visits. Policies that promote continuity of coverage during pregnancy, such as designating pregnancy as a qualifying event for a Marketplace open enrollment period, may enable pregnant people to enroll in Marketplace coverage early in their pregnancies and thus enhance access to prenatal care.

To investigate the relationship between community care (CC) treatment and a postoperative surgical complication in elective hernia surgery among Veterans using multiple approaches to control for potential selection bias.Veterans Health Administration (VHA) data sources included Corporate Data Warehouse (VHA encounters and patient data), the Program Integrity Tool and Fee tables (CC encounters), the Planning Systems Support Group (geographic information), and the Paid file (VHA primary care providers).Prior works suggest patient outcomes are better in VHA than in CC settings; however, these studies may not have appropriately accounted for the selection of higher-risk cases into CC. We estimated (1) a naïve logistic regression model to calculate the effect of CC setting on the probability of a complication, controlling for facility fixed effects and patient and procedure characteristics, and (2) a 2-stage model using the hernia patient's primary care provider's 1-year prior CC referral rate as the instrument.We identified patients residing ≤40 miles from a VHA surgical facility with elective VHA or CC hernia surgery from 2018 to 2019.Of 7991 hernia surgeries, 772 (9.7%) were in CC. The overall complication rate was 4.2%; 286/7219 (4.0%) among VHA surgeries versus 51/5772 (6.6%, p 0.05) in CC. We observed a 2.8 percentage point increase in the probability of postoperative complication given CC surgery (95% confidence interval: 0.7, 4.8) in the naïve model. After accounting for the VHA provider's historical rate of CC referral, we no longer observed a relationship between surgery setting and risk of postoperative complication.After accounting for the selection of higher-risk patients to CC settings, we found no difference in hernia surgery postoperative complications between CC and VHA. Future VHA and non-VHA comparisons should account for unobserved as well as observed differences in patients seen in each setting.

Westervelt's equation is a nonlinear wave equation that is widely used to model the propagation of sound waves in a compressible medium, with one important application being ultra-sound in human tissue. Two fundamental aspects of this equation -- symmetries and conservation laws -- are studied in the present work by modern methods. Numerous results are obtained: new conserved integrals; potential systems yielding hidden symmetries and nonlocal conservation laws; mapping of Westervelt's equation in the undamped case into a linear wave equation; exact solutions arising from the mapping; hidden variational structures, including a Lagrangian and a Hamiltonian; a recursion operator and a Noether operator; contact symmetries; higher-order symmetries and conservation laws., 23 pages; published version

Copyright © 2021 Elsevier B.V. All rights reserved., Background and aims: Overdiagnosis of prostate cancer (PCa) should be minimized. We wanted to evaluate the diagnostic performance of the prostate health index density (PHID) and compare it with that of the prostate health index (PHI) alone and of the prostate-specific antigen density (PSAD). Materials and methods: 232 men scheduled for a prostate biopsy (prostate-specific antigen level: 2-10 µg/L), were enrolled. PHI, PHID and PSAD were evaluated considering PCa and clinically significant PCa (csPCa) as the outcomes. Results: For PCa, the area under the curve (AUC) was higher for PHID (0.823) than for PHI (0.779) and PSAD (0.776). For csPCa, the AUC was also higher for PHID (0.851) but closer to that of PSAD (0.819) and PHI (0.813). For equal sensitivities (90%) for PCa, PHID and PSAD offered the highest specificities (37%), missing the same number of cancers (n=11). Considering csPCa, PHI and PHID had similar specificities. PSAD reached the highest specificity (50.0%), sparing 32.8% of biopsies, while missing 9 cases of csPCa. Conclusions: PHID has a better diagnostic performance than PHI for overall PCa detection, but very close to the PSAD performance. Considering csPCa, PHI and PHID perform almost equally, but PSAD has a better diagnostic performance.

Although prostate-specific antigen-based prostate cancer screening had a positive impact in reducing prostate cancer mortality, it also led to overdiagnosis, overtreatment and a significant number of unnecessary biopsies. In the post-prostate-specific antigen era, new biomarkers have emerged that can complement the information given by prostate-specific antigen, towards a better cancer diagnostic specificity, and also allowing a better estimate of the aggressiveness of the disease and its clinical outcome. That means those markers have the potential to assist the clinician in the decision-making processes, such as whether or not to perform a biopsy, and to make the best treatment choice among the new therapeutic options available, including active surveillance in lower risk disease. In this article, we will review several of those more recent diagnostic markers (4Kscore®, [-2]proPSA and Prostate Health Index, SelectMDx®, ConfirmMDx®, Progensa® Prostate Cancer Antigen 3, Mi-Prostate Score, ExoDx™ Prostate Test, the Stockholm3 test and ERSPC risk calculators) and prognostic markers (OncotypeDX® Genomic Prostate Score, Prolaris®, Decipher® and ProMark®). We will also address some new liquid biopsy approaches – circulating tumour cells and cell-free DNA – with a potential role in metastatic castration-resistant prostate cancer and will briefly give some future perspectives, mostly outlooking epigenetic markers. The author(s) received no financial support for the research, authorship, and/or publication of this article.

BACKGROUND: Development and prioritization of quality measures typically relies on experts in clinical medicine, but patients and their caregivers may have different perspectives on quality measurement priorities. OBJECTIVE: To inform priorities for health system implementation of palliative cancer and end-of-life care quality measures by eliciting perspectives of patients and caregivers. DESIGN: Using modified RAND-UCLA Appropriateness Panel methods and materials tailored for knowledgeable lay participants, we convened a panel to rate cancer palliative care process quality measure concepts before and after a 1-day, in-person meeting. PARTICIPANTS: Nine patients and caregivers with experience living with or caring for patients with cancer. MAIN MEASURES: Panelists rated each concept on importance for providing patient- and family-centered care on a nine-point scale and each panelist nominated five highest priority measure concepts (“top 5”). KEY RESULTS: Cancer patient and caregiver panelists rated all measure concepts presented as highly important to patient- and family- centered care (median rating ≥ 7) in pre-panel (mean rating range, 6.9–8.8) and post-panel ratings (mean rating range, 7.2–8.9). Forced choice nominations of the “top 5” helped distinguish similarly rated measure concepts. Measure concepts nominated into the “top 5” by three or more panelists included two measure concepts of communication (goals of care discussions and discussion of prognosis), one measure concept on providing comprehensive assessments of patients, and three on symptoms including pain management plans, improvement in pain, and depression management plans. Patients and caregivers nominated one additional measure concept (pain screening) back into consideration, bringing the total number of measure concepts under consideration to 21. CONCLUSIONS: Input from cancer patients and caregivers helped identify quality measurement priorities for health system implementation. Forced choice nominations were useful to discriminate concepts with the highest perceived importance. Our approach serves as a model for incorporating patient and caregiver priorities in quality measure development and implementation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-07041-8.

The build-up of pollutants to harmful levels can occur when meteorological conditions favour their production or accumulation near the surface. Such conditions can arise when a region experiences air stagnation. The link between European air stagnation, air pollution and the synoptic- to large-scale circulation is investigated in this article across all seasons and the 1979–2018 period. Dynamical indices identifying atmospheric blocking, Rossby wave breaking, subtropical ridges, and the North Atlantic eddy-driven and subtropical jets are used to describe the synoptic- to large-scale circulation as predictors in statistical models of air stagnation and pollutant variability. It is found that the large-scale circulation can explain approximately 60 % of the variance in monthly air stagnation, ozone and wintertime particulate matter (PM) in five distinct regions within Europe. The variance explained by the model does not vary strongly across regions and seasons, apart from for PM when the skill is highest in winter. However, the dynamical indices most related to air stagnation do depend on region and season. The blocking and Rossby wave breaking predictors tend to be the most important for describing air stagnation and pollutant variability in northern regions, whereas ridges and the subtropical jet are more important to the south. The demonstrated correspondence between air stagnation, pollution and the large-scale circulation can be used to assess the representation of stagnation in climate models, which is key for understanding how air stagnation and its associated climatic impacts may change in the future.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma (STS) in children and adolescents. In Spain the annual incidence is 4.4 cases per million children