BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12. An X-ray cocrystal structure inspired us to exploit amino acid differences in the binding site of MMP12 and ADAMTS7 to improve selectivity. Further optimization composed of employing 5-membered heteroaromatic groups as hydantoin substituents to become more potent on ADAMTS7. Finally, fine-tuning of DMPK properties yielded BAY-9835, the first orally bioavailable ADAMTS7 inhibitor. Further optimization to improve selectivity vs ADAMTS12 seems possible, and a respective starting point could be identified.

Arthrodesis vs arthroplasty for moderate and severe Hallux rigidus: Systematic review.

Hallux rigidus is the most frequent arthritis of the foot, due to multiple factors. Arthrodesis and interposition arthroplasty are treatments considered in advanced stages of the disease, when conservative treatment has failed. Although arthrodesis may be considered the technique recommended by multiple authors, for patients in whom joint mobility is to be preserved, arthroplasty could represent a reliable alternative. The purpose of this systematic review is to investigate and compare the clinical outcomes and complications of arthrodesis and interposition arthroplasty for moderate and severe stages of hallux rigidus. METHODS: For this systematic review we searched COCHRANE, EMBASE, PUBMED databases. Twenty-six research papers were obtained, with a total of 1348 feet, which were included for qualitative analysis. The following groups were included: Cartiva hemiarthroplasty (286), double stem silicone arthroplasty (276), total metallic arthroplasty (394) and arthrodesis (392). RESULTS: In the arthrodesis group, the AOFAS-HMI score was the most used, ranging from 36 to 45 in the preoperative period and from 79 to 89 in the postoperative period. The greatest improvement in the VAS PAIN score was from 86 to 4. The fusion rate was 98.6% of the total number of cases, the most frequent complication was pain due to material discomfort. In the total metallic arthroplasty group, the ROTO-GLIDE system reported an AOFAS score of 95 points, with low complication rates; but, with the TOEFIT-PLUS and BIOMED-MERCK systems, despite the good postoperative value, they report 37% and 15% revision due to aseptic loosening in the series with the longest follow-up, respectively. The Cartiva group showed a significative increase in FAAM ADL and FAAM SPORT from 59.4 to 90.4 and from 60.9 to 89.7, respectively; similarly, 20.5% implant removal and conversion to arthrodesis were reported. Finally, the double stem silicone arthroplasty group, in the series with the longest follow-up, it manages to improve the MOXFQ score from 78.1 to 11.0, with an average range of mobility of 22.3 degrees. Lysis was reported in 10% of cases. CONCLUSIONS: Arthrodesis has proven to be the best option for the treatment of advanced hallux rigidus. Arthroplasty can be a valid option for patients who demand to maintain the range of mobility of the joint; however, it is important to inform about the complications that may arise in the short and medium term. LEVEL OF CLINICAL EVIDENCE: II.

Validation of prognostic and predictive value of total tumoral load after primary systemic therapy in breast cancer using OSNA assay.

PURPOSE: This study aimed to validate the classification of breast cancer (BC) patients in progression risk groups based on total tumor load (TTL) value to predict lymph node (LN) affectation after neo-adjuvant systemic therapy (NAST) obtained in the NEOVATTL study. METHODS/PATIENTS: This was an observational, retrospective, international, multicenter study including patients with infiltrating BC who received NAST followed by sentinel lymph node biopsy (SLNB) analyzed with one-step nucleic acid amplification (OSNA) from nine Spanish and two Italian hospitals. Patients were classified into three groups according to the progression risk, measured as disease-free survival (DFS), based on TTL values (> 250, 250-25,000, and > 25,000 copies/µL). The previous (NEOVATTL study) Cox regression model for prognosis was validated using prognostic index (PI) and Log ratio test (LRT) analyses; the value of TTL for axillary non-SLN affectation was assessed using receiver operating characteristic (ROC) curves. RESULTS: We included 263 patients with a mean age of 51.4 (± SD 10.5) years. Patients with TTL > 25,000 copies/µL had a shorter DFS (HR 3.561 [95% CI 1.693-7.489], p = 0.0008 vs. TTL ≤ 25,000). PI and LRT analyses showed no differences between the two cohorts (p = 0.2553 and p = 0.226, respectively). ROC analysis showed concordance between TTL and non-SLN involvement (area under the curve 0.828), with 95.7% sensitivity and 92.9% specificity at a TTL cut-off of > 15,000 copies/µL. CONCLUSIONS: In BC patients who had received NAST and underwent SLNB analysis using OSNA, a TTL value of > 25,000 copies/µL was associated with a higher progression risk and > 15,000 copies/µL was predictive of non-SLN involvement.

In situ and in vitro evaluation of two antiseptics for blood bank based on chlorhexidine gluconate/isopropyl alcohol and povidone-iodine.

BACKGROUND: Poor disinfection is the main cause of blood contamination, so its elimination is key to limiting the entry of bacteria into the collection system. With the advancement of antiseptic technology, antiseptics with sterile, disposable applicators are now available. AIM: To evaluate in situ two antiseptics (with and without applicators) for blood banks and to demonstrate in vitro antiseptic activity on bacterial biofilms of importance in transfusion medicine. METHODS: Antiseptic A (2% sterile solution of chlorhexidine gluconate/70% isopropyl alcohol provided with applicator) and bulk antiseptic B (10% povidone-iodine) were evaluated. The deferred blood donor arms were subjected to disinfection with antiseptics A and B and the contralateral arms were cultured to determine the baseline bacterial load (control). Antiseptic activity was assessed by ANOVA and logaritmic reduction values (LRV) and percentage reduction values (PRV) were calculated. Finally, the in vitro activity of antiseptic A was analyzed by confocal laser scanning microscopy (CLSM) on biofilm models. RESULTS: Prior to disinfection tests, commensal and clinically important bacteria were identified; antiseptic A showed post-disinfection bacterial growth rates of zero compared to controls (p < 0.0001). The frequency of bacterial growth with antiseptic B was 74%. A significant difference was identified between both antiseptics, where antiseptic A showed higher activity (p < 0.5468). LRV and PRV were 0.6-2.5/100% and 0.3-1.7/66.7-99.7% for antiseptics A and B, respectively. Through CLSM, disinfectant A (without applicator) showed lower in vitro antiseptic activity on the tested biofilms at the exposure times recommended by the manufacturer. CONCLUSIONS: Sterile solution of chlorhexidine gluconate/isopropyl alcohol with applicator showed advantages disinfection in deferred blood donors over povidone-iodine.

3D model of the bronchial epithelial barrier to study repeated exposure to xenobiotics: Application to silver nanoparticles.

There is still a lack of in vitro human models to evaluate the chronic toxicity of drugs and environmental pollutants. Here, we used a 3D model of the human bronchial epithelium to assess repeated exposures to xenobiotics. The Calu-3 human bronchial cell line was exposed to silver nanoparticles (AgNP) 5 times during 12 days, at the air-liquid interface, to mimic single and repeated exposure to inhaled particles. Repeated exposures induced a stronger induction of the metal stress response and a steady oxidative stress over time. A sustained translocation of silver was observed after each exposure without any loss of the epithelial barrier integrity. The proteomic analysis of the mucus revealed changes in the secreted protein profiles associated with the epithelial immune response after repeated exposures only. These results demonstrate that advanced in vitro models are efficient to investigate the adaptive response of human cells submitted to repeated xenobiotic exposures.

Violence and Clinical Learning Environments in Medical Residencies.

INTRODUCTION: The objective of this study was to describe and analyze residents' perceptions of characteristics on the expansive/restrictive continuum of their clinical learning environment. METHODS: We conducted a quantitative, descriptive and cross-sectional study. A self-administered questionnaire was designed, programmed and applied to residents at the Faculty of Medicine of the National Autonomous University of Mexico. The instrument was structured in eight sections, and for this article, Section 3, which referred to clinical environments and violence was considered. The questionnaire had an 85% response rate, with 12,612 residents from 113 medical units and 78 specialties participating. The reliability and internal consistency measured with alpha omega obtained a value of ω 0.835 (CI; 0.828-0.843). RESULTS: Unpleasant, competitive, tense and conflictive contexts were related to restrictive environments. Sexual orientation influenced the perception of intolerance in the clinical setting with respect to discriminatory comments, such that for gender minorities, the environment was experienced as exclusionary. First-year residents perceived environments as more aggressive, a perception that tended to decrease in later years of residency. DISCUSSION: Abuses in power relations, rigid hierarchical positions and offensive clinical interactions may foster restrictive environments. In such settings, the reproduction of socio-culturally learned violence is feasible; however, asymmetrical relationships may be deconstructed and transformed.

Psychosocial Interventions for the Treatment of Cancer-Related Fatigue: An Umbrella Review.

Cancer-related fatigue is one of the most common symptoms of cancer and one of those referred by patients as the most disabling. However, we still do not have enough evidence to allow us to recommend effective and personalized approaches. GOAL: To provide evidence on the efficacy of ASCO-recommended psychosocial interventions for reducing cancer-related fatigue. METHODOLOGY: A general quantitative systematic review for nonprimary clinical interventions that allows the collection, synthesis and analysis of already published reviews. Systematic reviews of RTCs were selected as these make up the body of knowledge that provides the most evidence in an umbrella format. The results do not provide clear or comparable evidence regarding the different interventions, with moderate evidence standing out for cognitive interventions and mindfulness. CONCLUSIONS: Research gaps, study biases and the need for further research to ask more precise questions and to make reliable recommendations to mitigate the impact of cancer-related fatigue are evident.

Mediterranean songbirds show pronounced seasonal variation in thermoregulatory traits.

Addressing the patterns of variation in thermal traits is crucial to better predict the potential effects of climate change on organisms. Here, we assessed seasonal (winter vs summer) adjustments in key thermoregulatory traits in eight Mediterranean-resident songbirds. Overall, songbirds increased whole-animal (by 8%) and mass-adjusted (by 9%) basal metabolic rate and decreased (by 56%) thermal conductance below the thermoneutral zone during winter. The magnitude of these changes was within the lower values found in songbirds from northern temperate areas. Moreover, songbirds increased (by 11%) evaporative water loss within the thermoneutral zone during summer, while its rate of increase above the inflection point of evaporative water loss (i.e., the slope of evaporative water loss versus temperature) decreased by 35% during summer - a value well above that reported for other temperate and tropical songbirds. Finally, body mass increased by 5% during winter, a pattern similar to that found in many northern temperate species. Our findings support the idea that physiological adjustments might enhance the resilience of Mediterranean songbirds to environmental changes, with short-term benefits by saving energy and water under thermally stressful conditions. Nevertheless, not all species showed the same patterns, suggesting different strategies in their thermoregulatory adaptations to seasonal environments.

Eosinophils Recruited during Pulmonary Vaccination Regulate Mucosal Antibody Production.

Eosinophils have been previously shown to be able to regulate early humoral responses during systemic vaccination. Here we investigated the role of eosinophils during pulmonary vaccination, comparing vaccine-induced responses in eosinophil-deficient (ΔdblGATA) and wild-type mice using a Th2 adjuvant. We observed that eosinophils were needed to induce a complete vaccine response, thereby eliciting specific antibody-secreting plasma cells in the regional lymph nodes and antibody secretion in the BAL at the early stage of the immune response. Reintroduction of eosinophils in the lungs of ΔdblGATA mice during the priming stage enhanced both specific IgM and IgG plasma cells but not specific IgA plasma cells. Upon vaccination, eosinophils migrated to the lungs and secreted cytokines involved in B-cell activation, which might promote antibody production. Importantly, however, the absence of eosinophils did not impair late immune responses in a prime/boost protocol because, in that setup, we uncovered a compensating mechanism involving a Th17 pathway. In conclusion, our data demonstrate for the first time a new role for eosinophils during lung mucosal vaccination, whereby they accelerate early immune responses (IgM and IgG) while regulating IgA production at the late stages.

Belongingness among first-generation students at Stanford School of Medicine.

Background: Nationally, underrepresented minorities represent a significant proportion of the first-generation student population. These students also tend to report lower levels of belongingness compared to their peers, which may impact their wellness and be an important factor in their academic success. This study aimed to explore whether status as a first-generation student was associated with belongingness amongst medical students. Methods: In 2019, a previously validated 16-item survey was used to examine potential disparities in belongingness amongst groups of first-generation medical students. Differences between groups were assessed using a Mann-Whitney U-test for each individual item and three composite groupings of items regarding social belonging, academic belonging, and institutional support. Results: First-generation to college and first-generation to graduate school students reported lower belongingness across most individual items as well as in all three composite groups. Conclusions: Given that peer relationships and institutional support play an important role in medical student belonging, these findings represent an opportunity to address the specific needs of individuals from underrepresented groups in medicine. Doing so can support the academic and professional success of first-generation students and help close the diversity gap in medicine.

La Huamanripa (Senecio tephrosioides Turcz) como alternativa saludable para afecciones respiratorias durante la pandemia COVID-19 / Huamanripa (Senecio tephrosioides Turcz) as a healthy alternative for respiratory conditions during the COVID-19 pandemic / Huamanripa (Senecio tephrosioides Turcz) como alternativa saudável para problemas respiratórios durante a pandemia de COVID-19

Desde tiempo histórico las plantas medicinales se han empleado como ingrediente principal para preparación de diferentes recetas. Motivo que se investigó sobre la Huamanripa como alternativa saludable para afecciones respiratorias durante la pandemia COVID-19 en Barranca. Objetivo. El objetivo fue determinar la eficiencia de la Huamanripa como alternativa saludable para las afecciones respiratorias en la pandemia. Materiales y Método. La metodología se basa en investigación descriptiva con enfoque cuantitativo prospectivo, por lo que se cuestionó sobre la preparación, frecuencia de consumo y para que enfermedades se consumen. Obtenidos los datos se procesaron mediante estadísticas básicas y regresión. Resultados. Se determinó que la Huamanripa lo usan para tratamiento casero medicinal y consume con frecuencia 4 a 5 veces por semana para afecciones respiratorias y COVID-19, consumo de Huamanripa por mes con 23 % de la población, porcentaje de alivio de afecciones respiratorias con 84 %, correlación entre el consumo de Huamanripa y porcentaje de alivio r = 0.99 y en análisis de varianza del consumo de Huamanripa y el porcentaje de alivio no hubo significancia. Conclusiones. Concluye que la Huamanripa es una alternativa eficiente y se puede complementar con otros tratamientos para las afecciones respiratorias y síntomas de COVID-19; ya sea por sus propiedades como aceites especiales y terpenos que tienen efectos antimicrobiana, antiinflamatoria, aliviante, lo cual favorece a la salud.

Since historical times, medicinal plants have been used as the main ingredient for the preparation of different recipes. For this reason, Huamanripa was investigated as a healthy alternative for respiratory diseases during the COVID-19 pandemic in Barranca. Objective. The objective was to determine the efficiency of Huamanripa as a healthy alternative for respiratory diseases during the pandemic. Materials and Method. The methodology is based on descriptive research with a prospective quantitative approach, so that the preparation, frequency of consumption and the diseases for which it is consumed were questioned. Data were obtained and processed by means of basic statistics and regression. Results. It was determined that Huamanripa is used for medicinal home treatment and consumed 4 to 5 times a week for respiratory diseases and COVID-19, consumption of Huamanripa per month with 23% of the population, percentage of relief of respiratory diseases with 84%, correlation between consumption of Huamanripa and percentage of relief r = 0.99 and in variance analysis of Huamanripa consumption and percentage of relief there was no significance. Conclusions. It is concluded that Huamanripa is an efficient alternative and can be complemented with other treatments for respiratory conditions and symptoms of COVID-19; either by its properties such as special oils and terpenes that have antimicrobial, anti-inflammatory, relieving effects, which favors health.

Desde tempos históricos as plantas medicinais têm sido utilizadas como ingrediente principal para a preparação de diferentes receitas. Por esta razão, Huamanripa foi investigado como uma alternativa saudável para doenças respiratórias durante a pandemia da COVID-19 em Barranca. Objetivo. O objetivo era determinar a eficiência de Huamanripa como uma alternativa saudável para as doenças respiratórias durante a pandemia. Materiais e Método. A metodologia é baseada em pesquisa descritiva com uma abordagem quantitativa prospectiva, de modo que foram feitas perguntas sobre a preparação, a freqüência do consumo e para quais doenças é consumida. Os dados foram obtidos e processados utilizando estatísticas básicas e regressão. Resultados. Foi determinado que Huamanripa é usado para tratamento medicinal domiciliar e consumido 4 a 5 vezes por semana para doenças respiratórias e COVID-19, consumo de Huamanripa por mês com 23% da população, porcentagem de alívio de doenças respiratórias com 84%, correlação entre consumo de Huamanripa e porcentagem de alívio r = 0,99 e na análise de variância do consumo de Huamanripa e da porcentagem de alívio não houve significância. Conclusões. Conclui que Huamanripa é uma alternativa eficiente e pode ser complementada com outros tratamentos para condições respiratórias e sintomas da COVID-19; seja por suas propriedades como óleos especiais e terpenos que têm efeitos antimicrobianos, anti-inflamatórios, aliviadores, o que favorece a saúde.

Heat tolerance limits of Mediterranean songbirds and their current and future vulnerabilities to temperature extremes.

Songbirds are one of the groups most vulnerable to extreme heat events. Although several recent studies have assessed their physiological responses to heat, most of them have focused solely on arid-zone species. We investigated thermoregulatory responses to heat in eight small-sized songbirds occurring in the Mediterranean Basin, where heatwaves are becoming more frequent and intense. Specifically, we determined their heat tolerance limits (HTLs) and evaporative cooling efficiency, and evaluated their current and future vulnerabilities to heat in southwestern Iberia, a Mediterranean climate warming hotspot. To do this, we exposed birds to an increasing profile of air temperatures (Ta) and measured resting metabolic rate (RMR), evaporative water loss (EWL), evaporative cooling efficiency (the ratio between evaporative heat loss and metabolic heat production) and body temperature (Tb). HTL ranged between 40 and 46°C across species, and all species showed rapid increases in RMR, EWL and Tb in response to increasing Ta. However, only the crested lark (Galerida cristata) achieved an evaporative cooling efficiency greater than 1. The studied songbirds currently experience summer Ta maxima that surpass the upper critical temperatures of their thermoneutral zone and even their HTL. Our estimates indicate that five of the eight species will experience moderate risk of lethal dehydration by the end of the century. We argue that the limited heat tolerance and evaporative cooling efficiency of small-sized Mediterranean songbirds make them particularly vulnerable to heatwaves, which will be exacerbated under future climate change scenarios.

Resident training in psychopathology and uncertainty in a clinical situation.

The central theme of this article is the way in which psychiatry physicians-in-training deal with uncertainty in the discussion of clinical cases in Mexico. Methodologically, it is approached from the field of clinical ethnography and the narrative interpretation of plots in performative actions where there are sequences of communicative exchanges. In this way, it focuses on a detailed description of situations where clinical cases are reviewed to decipher, explain, and understand intersubjective meanings in the face of the emergence of uncertainty, its management, and the implications on decisions and actions. The study finds that limitations within the field of psychiatry lie in the nosographic construction of disease and its translation into the diagnostic hypotheses made by clinicians, where there are wide margins of ambiguity. The strategies implemented in the face of uncertainty are use of drugs, the collegiate review of the case, and utilization of intuition as a spontaneous, preconscious daily practice. The specific case described here provides a microscopic observation of the complex scenarios in which uncertainty occurs in educational and teaching processes, clearly revealing how patient care is articulated. The narratives and their interpretation are materials for training/curriculum and psychiatric clinical practice.

Exploratory study on gastrostomy in patients with neurological diseases: usefulness and impact.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a useful intervention for patients with impaired swallowing and a functional gastrointestinal system. Neurological diseases that cause neuromotor dysphagia, brain tumors, and cerebrovascular disease are the most frequent indications; complications are rare, and morbidity and mortality rates are low. OBJECTIVE: To describe the usefulness of PEG in patients with neurological diseases, and its impact on care, survival, and costs and benefits. MATERIAL AND METHODS: We performed a retrospective observational study, reviewing clinical files of patients hospitalised at the National Institute of Neurology and Neurosurgery (years 2015-2017) who underwent PEG placement. RESULTS: The sample included 51 patients: 62.7% were women and the mean (SD) age was 54.4 (18.6) years (range, 18-86). Diagnosis was tumor in 37.3% of cases and cerebrovascular disease in 33.3%. Sixteen patients (33.3%) died and 11 presented minor complications. The PEG tube remained in place for a mean of 9.14 months; in 52.9% of patients it was removed due to lack of improvement and/or tolerated oral intake, with removal occurring after a mean of 5.1 (4.4) months. Among patients' family members, 78.4% reported a great benefit, 43.1% reported difficulty caring for the PEG, and 45.1% reported complicated care in general. The monthly cost of maintaining the PEG was €175.78 on average (range, 38.38-293.45). DISCUSSION AND CONCLUSIONS: This preliminary study reveals that PEG was well indicated in patients with neurological diseases, with survival rates similar to those reported in other studies with long follow-up periods. In patients with cerebrovascular disease, the PEG tube remained in place a mean of 9.14 months, during recovery of swallowing function; however, the cost is high for our population.

Intimate Partner Violence in Persons With Parkinson's Disease.

Recent studies have reported that older adults with cognitive or physical disabilities are at risk to suffer intimate partner violence. This article investigates the intimate partner violence among caregivers and persons with Parkinson's disease (PD). We used qualitative methods to investigate whether the presence of violence was related to the type of couple relationship before the disease onset. We used a survey, in-depth interviews, and focus groups in 20 dyads of caregivers and patients. Twelve (60%) persons with PD and nine (45%) caregivers reported receiving violence. Considering their relationships previous to disease onset, we describe three typologies of violence in PD: (a) disease and history of violence, (b) disease as a buffer of violence, and (c) the burden of disease as an inductor of violence. Previous relationships and the couple's biographical trajectories influence the types of violence and its nature. This study is relevant as it considers time as a crucial factor in both the violence and suffering of PD and its caregiving.

The Performance and Trajectory of Medical Students With Disabilities: Results From a Multisite, Multicohort Study.

PURPOSE: To conduct a post-Americans with Disabilities Act Amendments Act of 2008 multisite, multicohort study called the Pathways Project to assess the performance and trajectory of medical students with disabilities (SWDs). METHOD: From June to December 2020, the authors conducted a matched cohort study of SWDs and nondisabled controls from 2 graduating cohorts (2018 and 2019) across 11 U.S. MD-granting medical schools. Each SWD was matched with 2 controls, one from their institution and, whenever possible, one from their cohort for Medical College Admission Test score and self-reported gender. Outcome measures included final attempt Step 1 and Step 2 Clinical Knowledge scores, time to graduation, leave of absence, matching on first attempt, and matching to primary care. RESULTS: A total of 171 SWDs and 341 controls were included; the majority of SWDs had cognitive/learning disabilities (118/171, 69.0%). Compared with controls, SWDs with physical/sensory disabilities had similar times to graduation (88.6%, 95% confidence interval [CI]: 77.0, 100.0 vs 95.1%, 95% CI: 90.3, 99.8; P = .20), Step 1 scores (229.6 vs 233.4; P = .118), and match on first attempt (93.9%, 95% CI: 86.9, 100.0 vs 94.6%, 95% CI: 91.8, 97.4; P = .842), while SWDs with cognitive/learning disabilities had lower Step 1 scores (219.4; P < .001) and were less likely to graduate on time (81.2%, 95% CI: 69.2, 93.2; P = .003) and match on first attempt (85.3%, 95% CI: 78.0, 92.7; P = .009). Accommodated SWDs had Step 1 scores that were 5.9 points higher than nonaccommodated SWDs (95% CI: -0.7, 12.5; P = .08). CONCLUSIONS: Structural barriers remain for SWDs with cognitive/learning disabilities, which could be partially mitigated by accommodations on high-stakes exams.

The thermoregulatory role of relative bill and leg surface areas in a Mediterranean population of Great tit (Parus major).

There is growing evidence on the role of legs and bill as 'thermal windows' in birds coping with heat stress. However, there is a lack of empirical work examining the relationship between the relative bill and/or leg surface areas and key thermoregulatory traits such as the limits of the thermoneutral zone (TNZ) or the cooling efficiency at high temperatures. Here, we explored this relationship in a Mediterranean population of Great tit (Parus major) facing increasing thermal stress in its environment. The lower and upper critical limits of the TNZ were found to be 17.7 ± 1.6ºC and 34.5 ± 0.7°C, respectively, and the basal metabolic rate was 0.96 ± 0.12 ml O2 min-1 on average. The evaporative water loss (EWL) inflection point was established at 31.85 ± 0.27°C and was not significantly different from the value of the upper critical limit. No significant relationship was observed between the relative bill or tarsi size and TNZ critical limits, breadth, mass-independent VO2, or mass-independent EWL at any environmental temperature (from 10 to 40°C). However, Great tit males (but not females) with larger tarsi areas (a proxy of leg surface area) showed higher cooling efficiencies at 40°C. We found no support for the hypothesis that the bill surface area plays a significant role as a thermal window in Great tits, but the leg surface areas may play a role in males' physiological responses to high temperatures. On the one hand, we argue that the studied population occupies habitats with available microclimates and fresh water for drinking during summer, so active heat dissipation by EWL might be favored instead of dry heat loss through the bill surface. Conversely, male dominance behaviors could imply a greater dependence on cutaneous EWL through the upper leg surfaces as a consequence of higher exposure to harsh environmental conditions than faced by females.

Long-term evolution of the epithelial cell secretome in preclinical 3D models of the human bronchial epithelium.

The human bronchial epithelium is the first line of defense against atmospheric particles, pollutants, and respiratory pathogens such as the novel SARS-CoV-2. The epithelial cells form a tight barrier and secrete proteins that are major components of the mucosal immune response. Functional in vitro models of the human lung are essential for screening the epithelial response and assessing the toxicity and barrier crossing of drugs, inhaled particles, and pollutants. However, there is a lack of models to investigate the effect of chronic exposure without resorting to animal testing. Here, we developed a 3D model of the human bronchial epithelium using Calu-3 cell line and demonstrated its viability and functionality for 21 days without subculturing. We investigated the effect of reduced Fetal Bovine Serum supplementation in the basal medium and defined the minimal supplementation needed to maintain a functional epithelium, so that the amount of exogenous serum proteins could be reduced during drug testing. The long-term evolution of the epithelial cell secretome was fully characterized by quantitative mass spectrometry in two preclinical models using Calu-3 or primary NHBE cells. 408 common secreted proteins were identified while significant differences in protein abundance were observed with time, suggesting that 7-10 days are necessary to establish a mature secretome in the Calu-3 model. The associated Reactome pathways highlight the role of the secreted proteins in the immune response of the bronchial epithelium. We suggest this preclinical 3D model can be used to evaluate the long-term toxicity of drugs or particles on the human bronchial epithelium, and subsequently to investigate their effect on the epithelial cell secretions.

Survival analysis of bevacizumab plus taxane treatment in luminal metastatic breast cancer.

BACKGROUND: The treatment of luminal metastatic breast cancer is based on endocrine therapy and chemotherapy treatment is limited to the progression of this treatment. MATERIALS & METHODS: We analyzed the efficacy of treatment with bevacizumab plus paclitaxel in 43 patients with hormone receptor-positive and HER2-negative metastatic breast cancer. DISCUSSION: Paclitaxel plus bevacizumab combination is a useful treatment in metastatic luminal breast cancer with an impressive overall survival of 31 months, similar to combination to endocrine therapy and targeted therapy in first line. In patients with hormone resistance, endocrine therapy saw worse results thus the taxol plus bevacizumab combination could be a better option. This combination does not influence the results of subsequent treatments; therefore, it could provide a good option for patients.