Somatic Activating ESR1 Mutation in an Aggressive Prolactinoma.

CONTEXT AND OBJECTIVE: The genetic profile of prolactinomas remains poorly understood. Our objective is to identify somatic genetic alterations associated with prolactinomas and to report the identification of an activating ESR1 mutation (ESR1Y537S) in an aggressive prolactinoma. SETTING: Brigham and Women's Hospital. DESIGN: Massively parallel-sequencing panel (OncoPanel) was performed in a cohort of patients with prolactinomas to identify mutations and copy number variation (CNV). RESULTS: Twenty subjects (mean age 38.6 years; 12 women and 8 men) were included in this study. A somatic ESR1Y537S mutation was identified in an aggressive prolactinoma in a post-menopausal woman. No SF3B1 or other somatic mutations were identified. The median number of CNV events identified in our samples was 46; the prolactinoma with ESR1Y537S had the highest number with 233 events. In breast cancer, ESR1Y537S has been shown to activate estrogen receptor alpha independent of ligand binding. In patients with resistant breast cancer and ESR1Y537S, elacestrant, a second-line ER degrader, improves progression-free survival. Therefore, given the lack of response to multimodality therapies, elacestrant was initiated in this patient after the third cycle of radiotherapy. Elacestrant, along with radiotherapy, controlled tumor growth and significantly reduced prolactin levels. CONCLUSION: Molecular profiling allowed the identification of ESR1Y537S, in an aggressive prolactinoma. ESR1Y537S was not detected early in the course of the disease and is likely conferring tumor aggressiveness. This finding emphasizes the significance of estrogen receptor signaling in prolactinomas. It also allowed the use of targeted therapy with successful control of disease progression.

Impact of gastrointestinal inoculation and benznidazole treatment on infection by Trypanosoma cruzi (Y strain, DTU TcII) in Swiss mice.

In Brazil, where Chagas disease is endemic, the most frequent form of transmission of the parasite is the oral route, associated with greater severity and worse response to benznidazole (BZ), the drug used in its treatment. This study aimed to evaluate the impact of gastrointestinal infection (GI) and BZ treatment on the parasitological and histopathological parameters in mice inoculated with a strain of T. cruzi II. Swiss mice were inoculated by GI and intraperitoneal (IP) routes with 2x106 culture-derived metacyclic trypomastigotes of the Y strain (TcII) of T. cruzi and were treated with BZ in the acute phase of the infection. Fresh blood examination, qPCR, histopathological and biochemical evaluations (enzymatic dosages and oxidative stress-OS) were performed. BZ treatment of uninfected animals caused changes in the liver, increased the activity of aspartate aminotransferase and alanine aminotransferase enzymes and OS, showing that the drug alone affects this organ. Inflammation and necrosis in the cardiac tissue were less intense and deaths occurred later in animals inoculated via the GI route than the animals inoculated via the IP route. BZ reduced the intensity of tissue lesions and avoided lethality in animals inoculated via the GI route, and decreased parasitemia and OS in those inoculated via both routes. Although BZ alone caused liver damage, it was less intense than that caused by both routes of inoculation. Infection with the Y strain of T. cruzi II via the GI route proved to be less virulent and pathogenic and responded better to treatment than the infection acquired via the IP route.

Impact and Correction of an Anterior Phakic Intraocular Lens on Swept-Source Optical Coherence Tomography Biometry.

PURPOSE: To evaluate the impact of anterior chamber phakic intraocular lens (pIOL) on swept-source optical coherence tomography (SS-OCT) biometric measurements and IOL power calculation. METHODS: This retrospective analysis of 67 eyes of 49 patients with previous anterior chamber pIOL implantation analyzed the accuracy of automatic segmentation of the anterior surface of the crystalline lens and its impact on anterior chamber depth (ACD, measured from epithelium to lens), lens thickness measurements, and IOL power calculation. The sample was divided into two groups: correct detection of the anterior surface of the crystalline lens and inaccurate detection. Segmentation of eyes from the inaccurate detection group was manually corrected and ACD and lens thickness were calculated using ImageJ software. IOL power was calculated using 7 formulas for both measurements. RESULTS: The anterior surface of the crystalline lens was mis-identified in 13 (19.4%) eyes. ACD was underestimated (Δ -0.85 ± 0.33 mm, P < .001) and lens thickness was overestimated (Δ +0.81 ± 0.25 mm, P < .001). Manual correction changed the target spherical equivalent only in the Haigis formula (P = .009). After correction for segmentation bias, the Pearl DGS, Cooke K6, and EVO 2.0 formulas showed the lowest prediction error, with the Pearl DGS showing greatest accuracy within ±1.00 diopters of prediction error range (81.0%). CONCLUSIONS: SS-OCT biometry misidentifies the anterior surface of the crystalline lens in a significant proportion, resulting in significant IOL power calculation error in the Haigis formula. Manual proofing of segmentation is mandatory in every patient with anterior chamber pIOL implantation. After correct segmentation, the Pearl DGS, Cooke K6, and EVO seem to be the best formulas. [J Refract Surg. 2024;40(8):e562-e568.].

Impact of an exercise-based cardiac rehabilitation program on cardiopulmonary test parameters.

INTRODUCTION: The exercise-based cardiac rehabilitation program (CRP) represent a multidisciplinary therapeutic approach tailored to improving cardiorespiratory fitness and overall health-related quality of life, while reducing cardiovascular hospitalizations and mortality. Our aim is to determine changes in exercise capacity and cardiac events according to the left ventricular ejection fraction (LVEF) following a CRP. METHODS: This single-center cohort study of 131 patients who completed a center-based CRP from 2015 to 2022. Cardiopulmonary exercise testing (CPET), transthoracic echocardiography, and laboratory analysis were conducted before and after program completion. RESULTS: Of 232 enrolled patients, 131 were included in our cohort analysis, with 36.6% having a reduced LVEF. These patients exhibited higher rates of atrial fibrillation (p=0.019) and NT-proBNP values (p<0.001). Patients with reduced LVEF had lower peak VO2 (p=0.046), ppVO2 (p<0.001) and VO2 at anaerobic threshold (p=0.015) during baseline CPET. Completion of the CRP lead to comparable improvements in exercise performance between groups, assessed through Δ pVO2 (p=0.990), Δ ppVO2 (p=0.610), and Δ VE/VCO2 slope (p=0.200). In the study population, male gender and hypertension independently predicted variation in VE/VCO2 slope (p=0.017) and oxygen uptake efficiency slope (p=0.048), respectively, post-CRP. During follow-up, 9.2% of all patients had hospital admissions for cardiac events, and 3.8% died, with no group differences. CONCLUSION: Patients with reduced LVEF admitted to our CRP showed lower functional status based on specific CPET parameters. After CRP, both reduced and preserved LVEF groups experienced similar functional improvements. Therefore, strategies to increase participation of patients with reduced LVEF in such programs are warranted.

Variation in Secondary Prevention of Coronary Heart Disease: The INTERASPIRE Study.

BACKGROUND AND AIMS: INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner. METHODS: Between 2020-2023, adults hospitalized in the preceding 6-24 months with incident or recurrent CHD were sampled in 14 countries from all 6 World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation. RESULTS: Overall, 4548 (21.1% female) CHD patients were interviewed a median of 1.05 (interquartile range 0.76-1.45) years after index hospitalization. Among all participants, 24% were obese (40% centrally). Only 38.5% achieved a blood pressure (BP) <130/80 mmHg and 19.2% a low-density lipoprotein cholesterol (LDL-C) of <1.4 mmol/l. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 56% achieved glycated hemoglobin (HbA1c) of <7.0%. A further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. Females were less likely to achieve targets: BP (females 37.4% males 38.6%), LDL-C (females 13.7% males 18.6%) and HbA1c in diabetes (females 47.7% males 57.5%). Overall, just 9.0% (inter-country range 3.8%-20.0%) reported attending cardiac rehabilitation and 1.0% (inter-country range 0.0%-2.4%) achieved the study definition of optimal guideline adherence. CONCLUSIONS: INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. Investment aimed at reducing between-country and between-individual variability in secondary prevention will promote equity in global efforts to reduce the burden of CHD.

Molecular signatures of Haemonchus contortus infection in sheep: A comparative serum proteomic study on susceptible and resistant sheep breeds.

Due to the negative impact of Haemonchus contortus in the tropics and subtropics, the detection of serum protein profiles that occur in infected sheep is of high relevance for targeted selective treatment strategies (TST). Herein, we integrated proteomics with phenotypic traits to elucidate physiological mechanisms associated to H. contortus infection in susceptible (Dorper - D) and resistant (Santa Inês - S) sheep breeds. Naïve female lambs were infected with H. contortus third-stage larvae on day zero (D0), and samples were collected weekly, for 28 days. Feces were used for individual fecal egg counts (FEC) blood for packed cell volume (PCV) and serum for specific antibody quantification through ELISA. Sera was collected on D0 (-) and D21 (+), and analyzed using a LC-MS/MS based proteomics approach. FEC, PCV, and anti-H. contortus antibody levels confirmed the absence of infection on D0. On D28 there was a significant difference between the two breeds for logFEC means (D = 3774 and S = 3141, p=0.033) and PCV means (D = 16.3 % and S = 24.3 %, p=0.038). From a total of 754 proteins identified, 68 differentially abundant proteins (DAPs) were noted. Phosphopyruvate hydratase (ENO3) was a DAP in all comparisons, while S+ vs D+ and S- vs D- shared the highest number of DAPs (8). Each of the four experimental groups clustered separately in a principal component analysis (PCA) of protein profile. Among the DAPs, proteins associated with the innate and adaptive immune system were detected when comparing S- vs D- and S+ vs D+. In D-, some proteins were linked to stress response to handling, sampling and heat. Focusing on the consequences of infection in each breed, in the D+ vs D- comparison, upregulated proteins were associated with inflammation control and immune response, where downregulated proteins pointed to a negative impact of infection on tissue anabolism, compromising muscle growth and fat deposition. In the S+ vs S- comparison, upregulated proteins were related to immune response, while the downregulated proteins were possibly linked to muscular development and growth, impaired by infection. Collectively, it can be concluded that ENO3 regulation emerges as a potential factor underlying the differential immune response observed between Santa Inês and Dorper sheep infected with H. contortus. In turn, detected acute phase proteins (APPs) reinforce their relation with infection, inflammation and stress conditions, whereas THEMIS-like may contribute to the immune system in Dorper. GSDMD, Guanylate-binding protein and ACAN warrant further investigation as possible biomarkers for TST strategy development.

Measurement invariance of the Facebook intrusion questionnaire across 25 countries.

Facebook is one of the most popular social networking sites. However, Facebook intrusion or addiction is a growing concern as it involves an excessive attachment to Facebook, which disrupts daily functioning. To date, few studies have examined whether cross-cultural differences in the measurement of Facebook addiction exist. The aim of this study was to investigate the cross-cultural validity and measurement invariance of the Facebook Intrusion Questionnaire (FIQ), one of the most widely used measures of Facebook addiction, across 25 countries (N = 12,204, 62.3% female; mean age = 25 years). Multigroup confirmatory factor analyses (MGCFA) assessed cross-cultural validity as well as invariance. Additionally, individual confirmatory factor analyses evaluated the factorial structure and measurement invariance across genders in each country. The FIQ demonstrated partial metric invariance across countries and metric (13 countries), scalar (11 countries) or residual (10 countries) invariance across genders within individual countries. A one-factor model indicated a good fit in 18 countries. Cronbach's alpha for the entire sample was .85. Our findings suggest that the FIQ may provide an adequate assessment of Facebook addiction that is psychometrically equivalent across cultures. Moreover, the questionnaire seems to be universal and suitable for studying different social media in distinct cultural environments. Consequently, this robust tool can be used to explore behaviours related to specific media that are particularly popular in any given country.

Estimated reduction in obesity prevalence and costs of a 20% and 30% ad valorem excise tax to sugar-sweetened beverages in Brazil: A modeling study.

BACKGROUND: The consumption of sugar-sweetened beverages (SSBs) is associated with obesity, metabolic diseases, and incremental healthcare costs. Given their health consequences, the World Health Organization (WHO) recommended that countries implement taxes on SSB. Over the last 10 years, obesity prevalence has almost doubled in Brazil, yet, in 2016, the Brazilian government cut the existing federal SSB taxes to their current 4%. Since 2022, a bill to impose a 20% tax on SSB has been under discussion in the Brazilian Senate. To simulate the potential impact of increasing taxes on SSB in Brazil, we aimed to estimate the price-elasticity of SSB and the potential impact of a new 20% or 30% excise SSB tax on consumption, obesity prevalence, and cost savings. METHODS AND FINDINGS: Using household purchases data from the Brazilian Household Budget Survey (POF) from 2017/2018, we estimated constant elasticity regressions. We used a log-log specification by income level for all beverage categories: (1) sugar-sweetened beverages; (2) alcoholic beverages; (3) unsweetened beverages; and (4) low-calorie or artificially sweetened beverages. We estimated the adult nationwide baseline intake for each beverage category using 24-h dietary recall data collected in 2017/2018. Taking group one as the taxed beverages, we applied the price and cross-price elasticities to the baseline intake data, we obtained changes in caloric intake. The caloric reduction was introduced into an individual dynamic model to estimate changes in weight and obesity prevalence. No benefits on cost savings were modeled during the first 3 years of intervention to account for the time lag in obesity cases to reduce costs. We multiplied the reduction in obesity cases during 7 years by the obesity costs per capita to predict the costs savings attributable to the sweetened beverage tax. SSB price elasticities were higher among the lowest tertile of income (-1.24) than in the highest income tertile (-1.13), and cross-price elasticities suggest SSB were weakly substituted by milk, water, and 100% fruit juices. We estimated a caloric change of -17.3 kcal/day/person under a 20% excise tax and -25.9 kcal/day/person under a 30% tax. Ten years after implementation, a 20% tax is expected to reduce obesity prevalence by 6.7%; 9.1% for a 30% tax. These reductions translate into a -2.8 million and -3.8 million obesity cases for a 20% and 30% tax, respectively, and a reduction of $US 13.3 billion and $US 17.9 billion in obesity costs over 10 years for a 20% and 30% tax, respectively. Study limitations include using a quantile distribution method to adjust self-reported baseline weight and height, which could be insufficient to correct for reporting bias; also, weight, height, and physical activity were assumed to be steady over time. CONCLUSIONS: Adding a 20% to 30% excise tax on top of Brazil's current federal tax could help to reduce the consumption of ultra-processed beverages, empty calories, and body weight while avoiding large health-related costs. Given the recent cuts to SSB taxes in Brazil, a program to revise and implement excise taxes could prove beneficial for the Brazilian population.

World Heart Federation Cholesterol Roadmap: The Portuguese case.

Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability; effective cardiovascular (CV) risk prevention is fundamental. The World Heart Federation (WHF) Cholesterol Roadmap provides a framework for national policy development and aims to achieve ASCVD prevention. At the invitation of the WHF, a group of experts from the Portuguese Society of Cardiology (SPC), addressed the cholesterol burden at nationally and discussed possible strategies to include in a Portuguese cholesterol roadmap. The literature review showed that the cholesterol burden in Portugal is high and especially uncontrolled in those with the highest CV risk. An infographic scorecard was built to include in the WHF collection, for a clear idea about CV risk and cholesterol burden in Portugal, which would also be useful for health policy advocacy. The expert discussion and preventive strategies proposal followed the five pillars of the WHF document: awareness improvement; population-based approaches for CV risk and cholesterol; risk assessment/population screening; system-level approaches; surveillance of cholesterol and ASCVD outcomes. These strategies were debated by all the expert participants, with the goal of creating a national cholesterol roadmap to be used for advocacy and as a guide for CV prevention. Several key recommendations were outlined: include all stakeholders in a multidisciplinary national program; create a structured activities plan to increase awareness in the population; improve the quality of continuous CV health education; increase the interaction between different health professionals and non-health professionals; increment the referral of patients to cardiac rehabilitation; screen cholesterol levels in the general population, especially high-risk groups; promote patient self-care, engage with patients' associations; use specific social networks to spread information widely; create a national database of cholesterol levels with systematic registry of CV events; redefine strategies based on the evaluation of results; create and involve more patients' associations - invert the pyramid order. In conclusion, ASCVD and the cholesterol burden remain a strong global issue in Portugal, requiring the involvement of multiple stakeholders in prevention. The Portuguese cholesterol roadmap can provide some solutions to help urgently mitigate the problem. Population-based approaches to improve awareness and CV risk assessment and surveillance of cholesterol and ASCVD outcomes are key factors in this change. A call to action is clearly needed to fight hypercholesterolemia and ASCVD burden.

Primary Dengue and Long-Term Health Status in Madeira Island, Portugal: A Retrospective Questionnaire-Based Study.

Dengue is among the most important mosquito-borne viral diseases worldwide. Although its acute manifestations are well known, little is known about the long-term impact of dengue on the population's health status. Madeira Island experienced a single outbreak of autochthonous dengue from September 2012 to March 2013. To extend our knowledge about the clinical impact of the outbreak on this naive population, we applied an online questionnaire to 168 adults diagnosed with dengue at the time to characterize retrospectively their symptoms during the infection and to identify long-term manifestations, possibly triggered by dengue. The most frequent symptoms during the clinical period, reported by more than three-quarters of our participants, were fever, myalgia, extreme tiredness, and headaches, whereas vomiting, pruritus, nausea, retro-orbital pain, and arthralgia occurred in 35% to 50% of participants. In the 8 years after dengue, 61.5% of participants reported at least one recurrent previously nonexistent symptom, the most frequent being headaches, abundant hair loss, extreme tiredness, arthralgia, and myalgia, experienced by 25% to 35% of participants. Nearly 20% of the participants with persistent symptoms reported the onset of chronic illness in the 4 years after dengue, most frequently ophthalmological and autoimmune diseases (5.6% each), versus only 2.2% of chronic disease onset in participants without persistent symptoms. Our results suggest that the occurrence of persistent symptoms after primary dengue might be more frequent than anticipated and may persist for several years, having an impact on the health status and well-being of a considerable proportion of the infected population.

Effects of High-Intensity Interval Training vs Moderate-Intensity Continuous Training on Body Composition and Blood Biomarkers in Coronary Artery Disease Patients: A Randomized Controlled Trial.

Background: Cardiac rehabilitation (CR) is essential in reducing cardiovascular mortality and morbidity. High-intensity interval training (HIIT) has emerged as a promising exercise intervention for enhancing clinical outcomes in cardiac patients. This study aimed to investigate the effects of two short-term exercise-based programs employing HIIT and moderate-intensity continuous training (MICT) in comparison to a control group concerning blood pressure, body composition, and blood biomarkers in patients diagnosed with coronary artery disease (CAD). Methods: Seventy-two CAD patients (14% women) underwent randomization into three groups: HIIT, MICT, and control. The training programs encompassed six weeks of supervised treadmill exercises, conducted thrice weekly. MICT targeted ≈ 70-75% of peak heart rate (HRpeak), while HIIT was tailored to ≈ 85-95% of HRpeak. The control group received guidance on adopting healthy lifestyles. Outcome measurements included evaluations of blood pressure, body composition, and blood biomarkers. Results: In contrast to MICT, the HIIT exhibited superior improvements in body fat mass ( Δ %HIIT: 4.5%, p < 0.001 vs. Δ %MICT: 3.2%, p < 0.001), waist circumference ( Δ %HIIT: 4.1%, p = 0.002 vs. Δ %MICT: 2.5%, p = 0.002), hemoglobin A1c (HbA1c) ( Δ %HIIT: 10.4%, p < 0.001 vs. Δ %MICT: 32.3%, p < 0.001) and thyrotropin (TSH) ( Δ %HIIT: 16.5%, p = 0.007 vs. Δ %MICT: 3.1%, p = 0.201). Both HIIT and MICT induced significant enhancements across all variables compared to the control group. Conclusions: HIIT and MICT emerged as effective modalities for enhancing systolic and diastolic function, body composition, and blood biomarkers in CAD patients, with HIIT demonstrating incremental improvements over MICT. The absence of participation in exercise-based programs following cardiovascular events yielded less favorable outcomes. HIIT holds promise as an adjunct intervention in CR programs for CAD patients. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03538119.

Reliability and Validity of the Global Physical Activity Questionnaire for Portuguese Adults.

The Global Physical Activity Questionnaire (GPAQ) has been used often to assess physical activity (PA) patterns. However, the European Portuguese version of this instrument has not been validated. We aimed to validate the self-administered GPAQ, version 2, (GPAQv2) for Portuguese adults. We included 32 participants in a pilot study of a Portuguese adaptation of the test and 108 participants in an assessment of their PA patterns and sedentary behavior (SB) through the GPAQv2. For its validation, we compared the GPAQv2 to the International PA Questionnaire-Long Form (IPAQ-LF) (concurrent validity) and the ActiGraph wGT3X-BT accelerometer (criterion validity). We evaluated PA and SB at baseline and after seven consecutive days. Test-retest reliability with the Kappa test (k) and the Intraclass Correlation Coefficient (ICC) ranged from strong to almost perfect (k: 0.864-0.976) and from moderate to excellent (ICC: 0.56-0.994), respectively. Concurrent validity, assessed by Spearman's Correlation Coefficient, was moderate to substantial (rho: 0.471-0.680), and there was fair to substantial criterion validity (rho: 0.226-0.672). Bland-Altman plots showed that the GPAQv2 overestimated vigorous and moderate to vigorous PA and underestimated moderate PA. The largest difference values were related to SB, since the GPAQv2 underestimated sitting time. In sum, we found the GPAQv2 to have acceptable validity and reliability for assessing PA and SB patterns, and we recommend its use for Portuguese adults.

Exploring microbiota-gut-brain axis biomarkers linked to autism spectrum disorder in prenatally chlorpyrifos-exposed Fmr1 knock-out and wild-type male rats.

Fmr1 (fragile X messenger ribonucleoprotein 1)-knockout (KO) rats, modeling the human Fragile X Syndrome (FXS), are of particular interest for exploring the ASD-like phenotype in preclinical studies. Gestational exposure to chlorpyrifos (CPF) has been associated with ASD diagnosis in humans and ASD-like behaviors in rodents and linked to the microbiota-gut-brain axis. In this study, we have used both Fmr1-KO and wild-type male rats (F2 generation) at postnatal days (PND) 7 and 40 obtained after F1 pregnant females were randomly exposed to 1 mg/kg/mL/day of CPF or vehicle. A nuclear magnetic resonance (NMR) metabolomics approach together with gene expression profiles of these F2 generation rats were employed to analyze different brain regions (such as prefrontal cortex, hippocampus, and cerebellum), whole large intestine (at PND7) and gut content (PND40). The statistical comparison of each matrix spectral profile unveiled tissue-specific metabolic fingerprints. Significant variations in some biomarker levels were detected among brain tissues of different genotypes, including taurine, myo-inositol, and 3-hydroxybutyric acid, and exposure to CPF induced distinct metabolic alterations, particularly in serine and myo-inositol. Additionally, this study provides a set of metabolites associated with gastrointestinal dysfunction in ASD, encompassing several amino acids, choline-derived compounds, bile acids, and sterol molecules. In terms of gene expression, genotype and gestational exposure to CPF had only minimal effects on decarboxylase 2 (gad2) and cholinergic receptor muscarinic 2 (chrm2) genes.