Quantum mechanics insights into melatonin and analogs binding to melatonin MT1 and MT2 receptors.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.

Association of Meal Timing with Sleep Quality and Anxiety According to Chronotype: A Study of University Students.

There are several determinants of mental health symptoms, ranging from individual characteristics to social factors. Consistent with patterns in the general population, students with evening characteristics tend to exhibit more anxiety symptoms and poorer sleep quality compared to morning students. Meal timing also appears to affect sleep and may be associated with mental health symptoms. In this context, the aim of the present study was to investigate the association of the timing of the main and last meals of the day with sleep quality and anxiety levels, according to the chronotype of university students. This study was conducted in colleges in São Paulo, Brazil, and involved application of a questionnaire to 162 university students. The questionnaire collected sociodemographic information meal and study times, and included scales assessing eveningness and morningness, sleep quality, and anxiety. Students demonstrating a phase delay in both chronotype and dinner timing exhibited higher levels of anxiety compared to morning-type students. Although no associations were observed between meal timing and sleep quality, sleeping later was associated with poorer sleep quality. The study suggests that evening students and those who eat late at night are more prone to presenting mental health symptoms. More studies are needed to further investigate this association.

External Validation of a Prognostic Model of Overall Survival in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: We have previously developed and externally validated a prognostic model of overall survival (OS) in men with metastatic, castration-resistant prostate cancer (mCRPC) treated with docetaxel. We sought to externally validate this model in a broader group of men with docetaxel-naïve mCRPC and in specific subgroups (White, Black, Asian patients, different age groups, and specific treatments) and to classify patients into validated two and three prognostic risk groupings on the basis of the model. METHODS: Data from 8,083 docetaxel-naïve mCRPC men randomly assigned on seven phase III trials were used to validate the prognostic model of OS. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low and high) and three-risk prognostic groups (low, intermediate, and high). RESULTS: The tAUC was 0.74 (95% CI, 0.73 to 0.75), and when adjusting for the first-line androgen receptor (AR) inhibitor trial status, the tAUC was 0.75 (95% CI, 0.74 to 0.76). Similar results were observed by the different racial, age, and treatment subgroups. In patients enrolled on first-line AR inhibitor trials, the median OS (months) in the low-, intermediate-, and high-prognostic risk groups were 43.3 (95% CI, 40.7 to 45.8), 27.7 (95% CI, 25.8 to 31.3), and 15.4 (95% CI, 14.0 to 17.9), respectively. Compared with the low-risk prognostic group, the hazard ratios for the high- and intermediate-risk groups were 4.3 (95% CI, 3.6 to 5.1; P < .0001) and 1.9 (95% CI, 1.7 to 2.1; P < .0001). CONCLUSION: This prognostic model for OS in docetaxel-naïve men with mCRPC has been validated using data from seven trials and yields similar results overall and across race, age, and different treatment classes. The prognostic risk groups are robust and can be used to identify groups of patients for enrichment designs and for stratification in randomized clinical trials.

Impact of COVID-19 pandemic on cardiometabolic patients without SARS-CoV-2 infection in Latin America.

BACKGROUND AND OBJECTIVES: A cross-sectional survey including 38 questions about demography, clinical condition, changes in health habits, and medical treatments for cardiometabolic patients in outpatient follow-up was conducted. From June 15 to July 15, 2020, a total of 13 Latin-American countries participated in enrolling patients. METHODS: These countries were divided into 3 geographic regions: Region 1 including North, Central, and Caribbean Regions (NCCR), Region 2 including the Andean Region (AR), and Region 3 including the Southern Cone Region (SCR). 4.216 patients were analyzed, resulting in a coefficient of 33.82%, 32.23%, and 33.94% for NCCR, AR, and SCR, respectively. RESULTS: Significant differences were found between the AR, SCR, and NCCR regions. The analysis of habitual medication usage showed that discontinued use of medication was more present in AR, reaching almost 30% (p < 0.001). The main finding of this study was the negative impact that restrictive measures have on adherence to medications and physical activity: Rs = 0.84 (p = 0.0003) and Rs = 0.61 (p = 0.0032), respectively. AR was the most vulnerable region. CONCLUSION: Restrictive quarantine measures imposed by the different countries showed a positive correlation with medication discontinuation and a negative correlation with physical activity levels in patients analyzed. These findings characterize the impact of the consequences left by this pandemic. Undoubtedly, restrictive measures have been and will continue to have reverberating negative effects in most Latin-American countries.

ANTECEDENTES Y OBJETIVOS: Se realizó una encuesta transversal que incluyó 38 preguntas sobre demografía, estado clínico, cambio de hábitos de salud, tratamientos médicos a pacientes cardiometabólicos en seguimiento ambulatorio. Un total de 13 países latinoamericanos inscribieron pacientes del 15 de junio al 15 de julio de 2020. MÉTODO: Los países se dividieron en 3 regiones geográficas Región 1 (NCCR): Región Norte, Centro y Caribe; Región 2 (AR): Región Andina; Región 3 (SCR): Región Cono Sur. Las medidas de aislamiento se estimaron a partir de informes nacionales y se correlacionaron utilizando el coeficiente R de Spearman. Se analizaron 4.216 pacientes, NCCR (33.82%); AR (32.23%) SCR (33.94%). RESULTADOS: Se encontraron diferencias significativas entre regiones. Este análisis de la medicación habitual mostró que la discontinuación de la medicación fue mayor en RA, llegando a casi el 30% (p < 0.001). El principal hallazgo de este estudio fue el impacto negativo que tienen las medidas restrictivas sobre la adherencia a la medicación y la actividad física, Rs = 0.84 (p = 0.0003) y Rs = 0.61 (p = 0.0032), respectivamente. Se encontraron diferencias significativas entre regiones. AR es la región más vulnerable. CONCLUSIONES: Las medidas restrictivas impuestas por los diferentes países (cuarentena) mostraron una correlación positiva con la interrupción de la medicación y una correlación negativa con la cantidad de actividad física. El impacto de las consecuencias que deja esta pandemia será muy profundo en la mayoría de los países latinoamericanos.

Different sleep patterns during the COVID-19 pandemic: association with mood, exercise and light exposure.

The aim was to evaluate the sleep-wake cycle pattern, mood, perceived stress and some behaviors, such as physical exercise and exposure to natural light of college students during the COVID-19 pandemic. This is a cross-sectional study conducted between June and August 2020 using an electronic form provided by Google. The sample consisted of undergraduate students aged between 18 and 30 years old and residents of the northeast region of Brazil. The students generally had sleepiness and poor sleep quality, high levels of anxiety, mild to moderate depressive symptoms and moderate perceived stress. Some of these aspects were worse in women. The college students showed three sleep patterns: one group had good sleep quality without excessive daytime sleepiness; another group had poor sleep quality, but no excessive daytime sleepiness; and a third group had high daytime sleepiness, and less expressive sleep quality impairment. Greater exposure to sunlight and practicing physical exercise predominated in individuals with better sleep quality, suggesting that they are protective factors. In addition, excessive daytime sleepiness and poor sleep quality were separately associated with higher anxiety, depression and stress perception levels, proving to be important aspects for care in order to favor mental health during the pandemic. In conclusion, it is suggested that the COVID-19 pandemic affected the sleep of college students in a heterogeneous way. The differentiated sleep patterns are associated with exposure to natural light and exercising.

Changes in the rest-activity rhythm in migraine patients are associated with anxiety symptoms

Objective: To characterize rest-activity rhythm in chronic migraine (CM) and to investigate the relationship between this rhythm and depressive and anxiety symptoms in patients with CM. Methods: This was a study of adults aged 20 to 40 years. The rest-activity rhythm of patients with CM (n=23) and non-headache controls (NH, n=23) was assessed by actigraphy for 15 days, and they completed the following assessments: Visual Analogue Scale for pain intensity; Headache Diary; Headache Impact Test-6; Morningness-Eveningness Questionnaire; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Beck Depression Inventory; and State-Trait Anxiety Inventory. Results: Patients with CM showed less activity over 24 hours and more fragmented sleep. Reduced interdaily stability of the rest-activity rhythm was observed, with less robustness of this rhythm in the CM group. Multiple linear regressions revealed a significant association between the rest-activity rhythm and trait anxiety variables in patients with CM, specifically regarding the relative amplitude of the cycle, activity throughout 24 hours and during sleep, and robustness of the rest-activity rhythm. Conclusions: Our findings provide evidence that the robustness of the rest-activity rhythm, activity throughout 24 hours, and sleep fragmentation are associated with trait anxiety in patients with CM. Clinical trial registration: Brazilian Clinical Trials Registry (registration number: RBR-4M5J4S).

Predictors of stress in college students during the COVID-19 pandemic.

Background: College students experience high stress levels during emergency remote classes in the COVID-19 pandemic. However, it is not clear whether this is due to the summation effect of both stressors (classes and pandemic). Therefore, the aim of this study was to investigate predictors of stress in college students before and during remote classes five months after the beginning of the COVID-19 pandemic. Methods: The study was conducted before (BRC, July-August 2020) and during remote classes (DRC, October-November 2020). The sample consisted of 177 individuals (80 in BRC, 97 in DRC). Students were asked to self-collect saliva for cortisol analysis at each moment of the study, and to fill out a form to characterize the individual and assess the chronotype (Morningness-Eveningness Questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and the stress (Perceived Stress Scale-10). Results: There was no difference between the evaluated periods for cortisol, perceived stress or sleep quality. Predictors for cortisol levels were gender, academic semester, chronotype, sleep quality and sadness due to pandemic (p<0.001). Limitations: Short interval between BRC and DRC assessments of perceived stress and salivary cortisol. Conclusions: Age, sex, income, academic semester, chronotype, and the impact of the pandemic on mood are predictors of stress among college students. In addition, emergency remote classes and sleep quality contribute to less stress.

Changes in the rest-activity rhythm in migraine patients are associated with anxiety symptoms.

OBJECTIVE: To characterize rest-activity rhythm in chronic migraine (CM) and to investigate the relationship between this rhythm and depressive and anxiety symptoms in patients with CM. METHODS: This was a study of adults aged 20 to 40 years. The rest-activity rhythm of patients with CM (n=23) and non-headache controls (NH, n=23) was assessed by actigraphy for 15 days, and they completed the following assessments: Visual Analogue Scale for pain intensity; Headache Diary; Headache Impact Test-6; Morningness-Eveningness Questionnaire; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Beck Depression Inventory; and State-Trait Anxiety Inventory. RESULTS: Patients with CM showed less activity over 24 hours and more fragmented sleep. Reduced interdaily stability of the rest-activity rhythm was observed, with less robustness of this rhythm in the CM group. Multiple linear regressions revealed a significant association between the rest-activity rhythm and trait anxiety variables in patients with CM, specifically regarding the relative amplitude of the cycle, activity throughout 24 hours and during sleep, and robustness of the rest-activity rhythm. CONCLUSIONS: Our findings provide evidence that the robustness of the rest-activity rhythm, activity throughout 24 hours, and sleep fragmentation are associated with trait anxiety in patients with CM.

Abiraterone acetate plus prednisone in non-metastatic biochemically recurrent castration-naïve prostate cancer.

BACKGROUND: Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery. METHODS: This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy. RESULTS: Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events. CONCLUSIONS: In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.

Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel.

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

The circadian rest-activity pattern predicts cognitive decline among mild-moderate Alzheimer's disease patients.

BACKGROUND: Alterations in circadian rhythms are present in the presymptomatic stage of Alzheimer's disease (AD), possibly contributing to its pathogenesis. However, it is unknown whether such alterations are associated with worse outcomes once individuals are diagnosed with symptomatic disease. We aimed to evaluate the association between the circadian rest-activity pattern and AD-related features in patients with mild-moderate AD. METHODS: We assessed the circadian rest-activity pattern of consecutive patients with mild-moderate AD through actigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of important pathological markers including amyloid-beta protein (Aß42), phosphorylated tau (P-tau), total tau (T-tau), and neurofilament light (NF-L). Neuropsychological evaluation was conducted at the beginning of the study and after 12 months of follow-up. Linear regression models were performed considering the global population and Aß42+ patients only. RESULTS: The cohort included 100 patients with mild-moderate AD. The median age [p25;p75] was 76.0 [73.0;80.0] years and 63.0% were female. Older age (effect size [SE] of 0.324 [0.096]; p = 0.001) and male sex (0.780 [0.193]; p = 0.001) were associated with increased fragmentation and decreased synchronization of the rhythm, respectively. After adjusting for age, sex, and season of the year, increased levels of T-tau (effect size [95% CI] of 0.343 [0.139 to 0.547]; p = 0.001) and NF-L (0.444 [0.212 to 0.676]; p = 0.001) were associated with a higher amplitude of the rest-activity rhythm. Increased fragmentation of the rhythm at baseline was associated with greater cognitive decline after one year of follow-up independent of age, sex, T-tau/Aß42 ratio, educational level, and season of the year (- 0.715 [- 1.272 to - 0.157]; p = 0.013). Similar findings were obtained considering only the Aß42+ patients. CONCLUSIONS: Our results suggest a potential role of the circadian rest-activity pattern in predicting the cognitive decline of patients with mild-moderate AD. Further studies are warranted to confirm these findings and to elucidate whether there is causality among the observed associations.

Transition to adulthood and transfer to adult care of adolescents with congenital heart disease: a global consensus statement of the ESC Association of Cardiovascular Nursing and Allied Professions (ACNAP), the ESC Working Group on Adult Congenital Heart Disease (WG ACHD), the Association for European Paediatric and Congenital Cardiology (AEPC), the Pan-African Society of Cardiology (PASCAR), the Asia-Pacific Pediatric Cardiac Society (APPCS), the Inter-American Society of Cardiology (IASC), the Cardiac Society of Australia and New Zealand (CSANZ), the International Society for Adult Congenital Heart Disease (ISACHD), the World Heart Federation (WHF), the European Congenital Heart Disease Organisation (ECHDO), and the Global Alliance for Rheumatic and Congenital Hearts (Global ARCH).

The vast majority of children with congenital heart disease (CHD) in high-income countries survive into adulthood. Further, paediatric cardiac services have expanded in middle-income countries. Both evolutions have resulted in an increasing number of CHD survivors. Expert care across the life span is necessitated. In adolescence, patients transition from being a dependent child to an independent adult. They are also advised to transfer from paediatrics to adult care. There is no universal consensus regarding how transitional care should be provided and how the transfer should be organized. This is even more challenging in countries with low resources. This consensus document describes issues and practices of transition and transfer of adolescents with CHD, accounting for different possibilities in high-, middle-, and low-income countries. Transitional care ought to be provided to all adolescents with CHD, taking into consideration the available resources. When reaching adulthood, patients ought to be transferred to adult care facilities/providers capable of managing their needs, and systems have to be in place to make sure that continuity of high-quality care is ensured after leaving paediatric cardiology.

COVID-19 in Adults With Congenital Heart Disease.

BACKGROUND: Adults with congenital heart disease (CHD) have been considered potentially high risk for novel coronavirus disease-19 (COVID-19) mortality or other complications. OBJECTIVES: This study sought to define the impact of COVID-19 in adults with CHD and to identify risk factors associated with adverse outcomes. METHODS: Adults (age 18 years or older) with CHD and with confirmed or clinically suspected COVID-19 were included from CHD centers worldwide. Data collection included anatomic diagnosis and subsequent interventions, comorbidities, medications, echocardiographic findings, presenting symptoms, course of illness, and outcomes. Predictors of death or severe infection were determined. RESULTS: From 58 adult CHD centers, the study included 1,044 infected patients (age: 35.1 ± 13.0 years; range 18 to 86 years; 51% women), 87% of whom had laboratory-confirmed coronavirus infection. The cohort included 118 (11%) patients with single ventricle and/or Fontan physiology, 87 (8%) patients with cyanosis, and 73 (7%) patients with pulmonary hypertension. There were 24 COVID-related deaths (case/fatality: 2.3%; 95% confidence interval: 1.4% to 3.2%). Factors associated with death included male sex, diabetes, cyanosis, pulmonary hypertension, renal insufficiency, and previous hospital admission for heart failure. Worse physiological stage was associated with mortality (p = 0.001), whereas anatomic complexity or defect group were not. CONCLUSIONS: COVID-19 mortality in adults with CHD is commensurate with the general population. The most vulnerable patients are those with worse physiological stage, such as cyanosis and pulmonary hypertension, whereas anatomic complexity does not appear to predict infection severity.

Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.

Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.

Influenza and Pneumococcal Vaccination in Non-Infected Cardiometabolic Patients from the Americas during the COVID-19 Pandemic. A Sub-Analysis of the CorCOVID-LATAM Study.

BACKGROUND: Influenza vaccination (IV) and Pneumococcus vaccination (PV) are recommended for patients with cardiometabolic diseases. This study aimed to evaluate the immunization rate of ambulatory cardiometabolic patients during the COVID-19 pandemic in the Americas. METHODS: Electronic surveys were collected from 13 Spanish speaking countries between 15 June and 15 July 2020. RESULTS: 4216 patients were analyzed. Mean age 60 (±15) years and 49% females. Global IV rate was 46.5% and PV 24.6%. Vaccinated patients were older (IV = 63 vs. 58 years; PV = 68 vs. 59, p < 0.01) but without gender difference. Vaccination rates were greater in higher-risk groups (65+, diabetics, heart failure), but not in coronary artery disease patients. In the Southern cone, the rate of IV and PV was approximately double that in the tropical regions of the Americas. In a multivariate model, geographic zone (IV = OR 2.02, PV = OR 2.42, p < 0.001), age (IV = OR 1.023, PV = OR 1.035, p < 0.001), and incomes (IV = OR 1.28, PV = OR 1.58, p < 0.001) were predictors for vaccination. CONCLUSIONS: During the COVID-19 pandemic, ambulatory patients with cardiometabolic diseases from the Americas with no evidence of COVID-19 infection had lower-than-expected rates of IV and PV. Geographic, social, and cultural differences were found, and they should be explored in depth.

A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. PATIENTS AND METHODS: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. RESULTS: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. CONCLUSION: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

Disruption of neocortical synchronisation during slow-wave sleep in the rotenone model of Parkinson's disease.

Parkinson's disease motor dysfunctions are associated with improperly organised neural oscillatory activity. The presence of such disruption at the early stages of the disease in which altered sleep is one of the main features could be a relevant predictive feature. Based on this, we aimed to investigate the neocortical synchronisation dynamics during slow-wave sleep (SWS) in the rotenone model of Parkinson's disease. After rotenone administration within the substantia nigra pars compacta, one group of male Wistar rats underwent sleep-wake recording. Considering the association between SWS oscillatory activity and memory consolidation, another group of rats underwent a memory test. The fine temporal structure of synchronisation dynamics was evaluated by a recently developed technique called first return map. We observed that rotenone administration decreased the time spent in SWS and altered the power spectrum within different frequency bands, whilst it increased the transition rate from a synchronised to desynchronised state. This neurotoxin also increased the probability of longer and decreased the probability of shorter desynchronisation events. At the same time, we observed impairment in object recognition memory. These findings depict an electrophysiological fingerprint represented by a disruption in the typical oscillatory activity within the neocortex at the early stages of Parkinson's disease, concomitant with a decrease in the time spent in SWS and impairment in recognition memory.