PERK inhibition in zebrafish mimics human Wolcott-Rallison syndrome phenotypes.

Wolcott-Rallison Syndrome (WRS) is the most common cause of permanent neonatal diabetes mellitus among consanguineous families. The diabetes associated with WRS is non-autoimmune, insulin-requiring and associated with skeletal dysplasia and growth retardation. The therapeutic options for WRS patients rely on permanent insulin pumping or on invasive transplants of liver and pancreas. WRS has a well identified genetic cause: loss-of-function mutations in the gene coding for an endoplasmic reticulum kinase named PERK (protein kinase R-like ER kinase). Currently, WRS research is facilitated by cellular and rodent models with PERK ablation. While these models have unique strengths, cellular models incompletely replicate the organ/system-level complexity of WRS, and rodents have limited scalability for efficiently screening potential therapeutics. To address these challenges, we developed a new in vivo model of WRS by pharmacologically inhibiting PERK in zebrafish. This small vertebrate displays high fecundity, rapid development of organ systems and is amenable to highly efficient in vivo drug testing. PERK inhibition in zebrafish produced typical WRS phenotypes such as glucose dysregulation, skeletal defects, and impaired development. PERK inhibition in zebrafish also produced broad-spectrum WRS phenotypes such as impaired neuromuscular function, compromised cardiac function and muscular integrity. These results show that zebrafish holds potential as a versatile model to study WRS mechanisms and contribute to the identification of promising therapeutic options for WRS.

Multiple mask and boundary scoring R-CNN with cGAN data augmentation for bladder tumor segmentation in WLC videos.

Automatic diagnosis systems capable of handling multiple pathologies are essential in clinical practice. This study focuses on enhancing precise lesion localization, classification and delineation in transurethral resection of bladder tumor (TURBT) to reduce cancer recurrence. Despite deep learning models success, medical applications face challenges like small and limited datasets and poor image characterization, including the absence lack of color/texture modeling. To address these issues, three solutions are proposed: (1) an improved texture-constrained version of the pix2pixHD cGAN for data augmentation, addressing the tradeoff of generating high-quality images with enough stochasticity using the Fréchet Inception Distance (FID) measure. (2) Introducing the Multiple Mask and Boundary Scoring R-CNN (MM&BS R-CNN), a new mask sub-net scheme where multiple masks are generated from the different levels of the mask sub-net pipeline, improving segmentation accuracy by including a new scoring module to refine object boundaries. (3) A novel accelerated training strategy based on the SGD optimizer with the second momentum. Experimental results show significant mAP improvements: the data generation scheme improves by more than 12 %; MM&BS R-CNN proposed architecture is responsible for an improvement of about 1.25 %, and the training algorithm based on the second-order momentum increases mAP by 2-3 %. The simultaneous use of all three proposals improved the state-of-the-art mAP by 17.44 %.

Effects of the pyriproxyfen and fenthion on the gonadal morphology of Nile tilapia (Oreochromis niloticus: Perciformes, Cichlidae).

Commercially available insecticides present acute toxicity to the health of fish and other aquatic organisms, which may impair the local aquaculture. This study evaluated the gonadal morphology of freshwater fish exposed to pyriproxyfen and fenthion. Forty-five juvenile male Nile tilapias (Oreochromis niloticus) were divided into control, pyriproxyfen-exposed (0.01 g/L), and fenthion-exposed (0.001 g/L) groups. They were evaluated in three moments (30, 60, and 90 days). The variables analyzed were the gonadosomatic index (GSI), weight to length ratio, seminiferous tubules morphometry (diameter and height), tissue damage, and immunohistochemical analysis for caspase-3, tumor necrosis factor alpha (TNF-α), and vascular endothelial growth factor (VEGF). Pyriproxyfen and fenthion injured the seminiferous tubule tissue, and the damage progressed according to the exposure time. In addition, the GSI gradually reduced over time in all groups compared with the first moment (30 days), while caspase-3, TNF-α, and VEGF values increased only in the fenthion-exposed group. Therefore, pyriproxyfen and fenthion changed the gonadal morphology of male Oreochromis niloticus, which may affect their reproduction in the wild or captivity.

Association between sociodemographic and clinical features, health behaviors, and health literacy of patients with prostate cancer and prostate cancer prognostic stage.

Patient characteristics may influence access and acceptance of Prostate Specific Antigen test, and therefore, the timing of prostate cancer (PCa) diagnosis. A group of 361 patients from a cohort (n = 451) diagnosed with PCa in 2018-2020 at the Portuguese Institute of Oncology of Porto was evaluated before treatment, using a structured interview, the Medical Term Recognition Test, and the EORTC Quality of Life Questionnaire QLQ-PR25. PCa prognostic stages (I, II, III, IV) were attributed according to the American Joint Committee on Cancer eighth edition. Multinomial logistic regression was used to compute the odds ratio and 95% confidence interval (OR [95% CI]), considering PCa stage II, the most frequent, as reference. Older age (OR = 4.21 [2.24-7.93]), living outside the Porto Metropolitan Area while having low income (OR = 6.25 [1.53-25.62]), and erectile dysfunction (OR = 2.22 [0.99-4.99]) were associated with stage III, while urination during the night (OR = 3.02 [1.42-6.41]) was associated with stage IV. Urine leakage was less frequent in stage III (OR = 0.23 [0.08-0.68]), and living with a partner (OR = 0.41 [0.19-0.88]) and family history of cancer (OR = 0.25 [0.07-0.86]) in stage IV. Health literacy was not associated with PCa stage but lower education was less frequent in stage I (OR = 0.27 [0.11-0.69]). Patient sociodemographic and clinical characteristics should be considered as targets to improve PCa early detection and prognosis.

Exercise Training Benefits Health-Related Quality of Life and Functional Capacity during Breast Cancer Chemotherapy: A Randomized Controlled Trial.

PURPOSE: To examine the effectiveness of a supervised exercise training program (SETP) on health-related quality of life (HRQoL) and functional capacity in women with breast cancer (BC) undergoing chemotherapy. METHODS: Ninety-three women with early-stage BC were randomly allocated to a SETP plus usual care (exercise, n = 47) or usual care alone (UC, n = 46). The SETP included three sessions per week, combining aerobic and resistance training, conducted concurrently over the chemotherapy. The EORTC Cancer Quality-of-Life-Questionnaire-Core-30 (QLQ-C30) and the BC-specific module (QLQ-BR23) were used to assess HRQoL. Functional capacity was analyzed by maximum voluntary handgrip strength (MVHS) and by the 30-s chair sit-to-stand test (30-s CST). These endpoints were assessed at baseline (t0); middle (t1; after 8 or 12 wk of t0); and at the end of chemotherapy (t2; after 20 wk of t0). Mean changes from baseline were assessed by an intention-to-treat approach. RESULTS: Mixed linear model analyses showed that Exercise group experienced less deterioration in several domains of QLQ-C30 at t2, including in global health status/QoL (Δ = 9.39 units; P = 0.034), QLQ-C30 summary score (Δ = 8.08 units; P < 0.001), physical (Δ = 15.14 units; P < 0.001), role ( Δ = 21.81 units; P < 0.001), cognitive (Δ = 9.16 units; P = 0.032) and social functioning (Δ = 11.67 units; P = 0.038), compared with the UC group. Similarly, Exercise group exhibited significant lower levels of fatigue (Δ = -20.19 units; P < 0.001) and appetite loss (Δ = -13.69 units; P = 0.034), compared with the UC group. Significant between-group differences were observed on MVHS of the tumor/surgery upper limb side (Δ = 2.64 kg; P < 0.001) and contralateral limb (Δ = 2.22 kg; P < 0.001), and on the 30-s CST score (Δ = 3.56repetitions; P < 0.001), favoring the Exercise group. No differences were observed on QLQ-BR23 domains. CONCLUSIONS: Exercise training was an effective complementary therapy to prevent the deterioration of HRQoL and functional capacity during chemotherapy in women with early-stage BC.

Perfil sociodemográfico e citológico de mulheres em investigação de neoplasia cérvico-uterina em um serviço secundário / Sociodemographic and cytological profile of women undergoing investigation for cervical-uterine neoplasia in a secondary service

Objetivo: analisar o perfil sociodemográfico e comparar as diferenças das características de mulheres com alterações citológicas de alto grau em um serviço da atenção secundária. Método: estudo transversal retrospectivo de 2017 a 2021 realizado em 160 prontuários (CAAE 51800621.3.0000.5240). Resultados: predominaram mulheres com média de idade 40,7 anos, escolaridade abaixo do ensino médio, tiveram um a três filhos, não utilizavam preservativos e anticoncepcionais, não tabagistas e com alterações citopatológicas alto grau. As características com maiores percentuais para lesões citopatológicas de alto grau foram mulheres com quatro ou mais gestações, idade do parto menor ou igual a 18 anos, coitarca menor ou igual a 15 anos e tabagistas. Conclusão: serviços da rede de atenção, especialmente da atenção primária à saúde, devem capacitar permanentemente os profissionais visando cumprimento de fluxos assistenciais preconizadas pelas recomendações das diretrizes brasileiras de rastreamento da neoplasia cérvico-uterina atentando ao perfil encontrado de mulheres encaminhadas a atenção secundária.(AU)

Objective: analyzes the sociodemographic profile and compare the differences in the characteristics of women with high-grade cytological alterations in a secondary care service. Method: retrospective cross-sectional study from 2017 to 2021 carried out in 160 medical records (CAAE 51800621.3.0000.5240). Results: women predominated with a mean age of 40.7 years, education below high school, had one to three children, did not use condoms and contraceptives, non-smokers and with high-grade cytopathological alterations. The characteristics with the highest percentages for high-grade cytopathological lesions were women with four or more pregnancies, age at birth less than or equal to 18 years, coitarche less than or equal to 15 years, and smokers. Conclusion: services of the care network, especially primary health care, should permanently train professionals in order to comply with the care flows recommended by the recommendations of the Brazilian guidelines for screening cervical uterine neoplasia, paying attention to the profile found of women referred to secondary care.(AU)

Objetivo: analizar el perfil sociodemográfico y comparar las diferencias en las características de mujeres con alteraciones citológicas de alto grado en un servicio de segundo nivel de atención. Método: estudio transversal retrospectivo de 2017 a 2021 realizado en 160 historias clínicas (CAAE 51800621.3.0000.5240). Resultados: predominaron las mujeres con edad media de 40,7 años, escolaridad inferior a la secundaria, con uno a tres hijos, no usuarias de preservativo y anticonceptivos, no fumadoras y con alteraciones citopatológicas de alto grado. Las características con mayor porcentaje de lesiones citopatológicas de alto grado fueron mujeres con cuatro o más embarazos, edad al nacer menor o igual a 18 años, coitarquia menor o igual a 15 años y fumadoras. Conclusión: servicios de la red de atención, especialmente la atención primaria a la salud, deben capacitar permanentemente a los profesionales para cumplir con los flujos de atención recomendados por las recomendaciones de las directrices brasileñas para el tamizaje de la neoplasia cérvico-uterina, prestando atención al perfil encontrado de las mujeres referidas atención secundaria.(AU)

Stress response mechanisms in protein misfolding diseases: Profiling a cellular model of Huntington's disease.

Stress response pathways like the integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt) and the heat shock response (HSR) have emerged as part of the pathophysiology of neurodegenerative diseases, including Huntington's disease (HD) - a currently incurable disease caused by the production of mutant huntingtin (mut-Htt). Previous data from HD patients suggest that ISR is activated while UPRmt and HSR are impaired in HD. The study of these stress response pathways as potential therapeutic targets in HD requires cellular models that mimic the activation status found in HD patients of such pathways. PC12 cells with inducible expression of the N-terminal fragment of mut-Htt are among the most used cell lines to model HD, however the activation of stress responses remains unclear in this model. The goal of this study is to characterize the activation of ISR, UPRmt and HSR in this HD cell model and evaluate if it mimics the activation status found in HD patients. We show that PC12 HD cell model presents reduced levels of Hsp90 and mitochondrial chaperones, suggesting an impaired activation or function of HSR and UPRmt. This HD model also presents increased levels of phosphorylated eIF2α, the master regulator of the ISR, but overall similar levels of ATF4 and decreased levels of CHOP - transcription factors downstream to eIF2α - in comparison to control, suggesting an initial activation of ISR. These results show that this model mimics the ISR activation and the impaired UPRmt and HSR found in HD patients. This work suggests that the PC12 N-terminal HD model is suitable for studying the role of stress response pathways in the pathophysiology of HD and for exploratory studies investigating the therapeutic potential of drugs targeting stress responses.

Cost-effectiveness of hypofractionated versus conventional fractionated radiotherapy for the treatment of men with early glottic cancer: a study in the Brazilian public and private health system.

BACKGROUND: This study aims to evaluate whether hypofractionated radiotherapy (HYPOFRT) is a cost-effective strategy than conventional fractionated radiotherapy (CFRT) for early-stage glottic cancer (ESGC) in the Brazilian public and private health systems. METHODS: Adopting the perspective of the Brazilian public and private health system as the payer, a Markov model with a lifetime horizon was built to delineate the health states for a cohort of 65-year-old men after with ESGC treated with either HYPOFRT or CFRT. Probabilities of controlled disease, local failure, distant metastasis, and death and utilities scores were extracted from randomized clinical trials. Costs were based on the public and private health system reimbursement values. RESULTS: In the base case scenario, for both the public and private health systems, HYPOFRT dominated CFRT, being more effective and less costly, with a negative ICER of R$264.32 per quality-adjusted life-year (QALY) (public health system) and a negative ICER of R$2870.69/ QALY (private health system). The ICER was most sensitive to the probability of local failure, controlled disease, and salvage treatment costs. For the probabilistic sensitivity analysis, the cost-effectiveness acceptability curve indicates that there is a probability of 99.99% of HYPOFRT being cost-effective considering a willingness-to-pay threshold of R$2,000 ($905.39) per QALY (public sector) and willingness-to-pay threshold of R$16,000 ($7243.10) per QALY (private sector). The results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Considering a threshold of R$ 40,000 per QALY, HYPOFRT was cost-effective compared to CFRT for ESGC in the Brazilian public health system. The Net Monetary Benefit (NMB) is approximately 2,4 times (public health system) and 5,2 (private health system) higher for HYPOFRT than CFRT, which could open the opportunity of incorporating new technologies.

3% polidocanol foam sclerotherapy versus hemorrhoidal artery ligation with recto anal repair in hemorrhoidal disease grades II-III: a randomized, pilot trial.

PURPOSE: Polidocanol foam sclerotherapy (SP) versus doppler-guided hemorrhoidal artery ligation with recto-anal repair (HAL-RAR) in the treatment of hemorrhoidal disease (HD) was analyzed. METHODS: A prospective, randomized study including patients with HD grades II and III was performed. Participants were randomly assigned (1:1) into SP or HAL-RAR, during a recruitment period between September 2019 and February 2020. Therapeutic success (Sodergren's and bleeding scores) was the primary outcome. Other outcomes evaluated included complications and implication in the professional life. Efficacy and safety outcomes were evaluated during the 8 weeks after surgery or the final SP session. RESULTS: Forty-six patients were allocated either to SP (n=22) or HAL-RAR (n=24). Most patients achieved therapeutic success (SP 100% vs. HAL-RAR 90.9%, p=0.131). Complete success was higher in the SP group (91.7% vs. 68.2%, p=0.045) and SP patients had less complications (25% vs. 68.2%, p=0.003). HAL-RAR had a greater negative impact on work activity of the patient. CONCLUSION: SP was more effective and safer than HAL-RAR. SP patients had less impact on their work activity. Clinical trials identifier NCT04675177.

Thrombocytopenia-Absent Radius Syndrome: Descriptions of Three New Cases and a Novel Splicing Variant in RBM8A That Expands the Spectrum of Null Alleles.

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by the bilateral absence of the radius and thrombocytopenia, and sometimes by other skeletal, gastrointestinal, cardiac, and renal abnormalities. The underlying genetic defect is usually the compound inheritance of a microdeletion in 1q21.1 (null allele) and a low-frequency, non-coding single nucleotide variant (SNV) in the RBM8A gene (hypomorphic allele). We report three new cases from two unrelated families. The two siblings presented the common genotype, namely the compound heterozygosity for a 1q21.1 microdeletion and the hypomorphic SNV c.-21G>A in RBM8A, whereas the third, unrelated patient presented a rare genotype comprised by two RBM8A variants: c.-21G>A (hypomorphic allele) and a novel pathogenic variant, c.343-2A>G (null allele). Of the eight documented RBM8A variants identified in TAR syndrome patients, four have hypomorphic expression and four behave as null alleles. The present report expands the RBM8A null allele spectrum and corroborates the particularities of RBM8A involvement in TAR syndrome pathogenesis.

Anxiety and Depression in Patients with Prostate Cancer, at Cancer Diagnosis and after a One-Year Follow-Up.

Prostate cancer (PCa) is the most prevalent among men, and psychological symptoms may affect many patients. This study aims to describe the prevalence of probable anxiety and depression before PCa treatments and after one year and to identify sociodemographic and clinical factors associated with these outcomes. Between February 2018 and March 2020, 292 patients recently diagnosed with PCa were recruited at the Instituto Português de Oncologia-Porto. The Hospital Anxiety and Depression Scale (HADS) was used to define probable anxiety and depression (cutoff = 11). The prevalence of probable anxiety remained stable from baseline to one year (7.8% vs. 8.5%, p = 0.866) while there was an increase in probable depression (3.1% vs. 6.8%, p = 0.012). After one year, probable depression persisted in 55.6% of patients with probable depression at baseline and 47.8% of those with probable anxiety at the first assessment had normal anxiety scores. At baseline, anxiety was more frequent among dwellers in rural areas (adjusted odds ratio-aOR, 95%CI: 2.80, 0.91-8.58) and less frequent in patients with body mass index 25-29.9 kg/m2 (aOR, 95%CI: 0.33, 0.12-0.91) compared to 18.5-24.9 Kg/m2, while those living alone had higher odds of depression (aOR, 95%CI: 6.35, 1.43-28.30). The frequency of anxiety and depression fluctuated during the course of treatment. Monitoring these symptoms would identify the most affected patients, contributing for a better use of mental health services.

Cost-Effectiveness of BRCA 1/2 Genetic Test and Preventive Strategies: Using Real-World Data From an Upper-Middle Income Country.

Although BRCA1/2 genetic testing in developed countries is part of the reality for high-risk patients for hereditary breast and ovarian cancer (HBOC), the same is not true for upper-middle-income countries. For that reason, this study aimed to evaluate whether the BRCA1/2 genetic test and preventive strategies for women at high risk for HBOC are cost-effective compared to not performing these strategies in an upper-middle-income country. Adopting a payer perspective, a Markov model with a time horizon of 70 years was built to delineate the health states for a cohort of healthy women aged 30 years that fulfilled the BRCA1/2 testing criteria according to the guidelines. Transition probabilities were calculated based on real-world data of women tested for BRCA1/2 germline mutations in a cancer reference hospital from 2011 to 2020. We analyzed 275 BRCA mutated index cases and 356 BRCA mutation carriers that were first- or second-degree relatives of the patients. Costs were based on the Brazilian public health system reimbursement values. Health state utilities were retrieved from literature. The BRCA1/2 genetic test and preventive strategies result in more quality-adjusted life years (QALYs) and costs with an incremental cost-effectiveness ratio of R$ 11,900.31 (U$ 5,504.31)/QALY. This result can represent a strong argument in favor of implementing genetic testing strategies for high-risk women even in countries with upper-middle income, considering not only the cancer prevention possibilities associated with the genetic testing but also its cost-effectiveness to the health system. These strategies are cost-effective, considering a willingness-to-pay threshold of R$ 25,000 (U$ 11,563.37)/QALY, indicating that the government should consider offering them for women at high risk for HBOC. The results were robust in deterministic and probabilistic sensitivity analyses.

Active Control System to Prevent Malfunctioning Caused by the Pressure Difference in Gasket Plate Heat Exchangers Applied in the Oil and Gas Industry.

In the oil and gas industry, heat exchangers are subject to loads that cause malfunctioning. These loads are divided into thermal and mechanical stresses; however, most efforts are focused on studying thermal stresses. The present work reduces mechanical stresses by mitigating pressure events in a gasket plate heat exchanger (GPHE). GPHE requires that the hot and cold stream branches have approximately the same pressure. Thus, the work focuses on controlling the pressure difference between the branches. A test bench was used to emulate, on a small scale, the typical pressure events of an oil production plant. A control valve was used in different positions to evaluate the controller. In the experiments, it was observed that the best option to control the pressure difference is to use a hydraulic pump and control valve in the flow of the controlled thermal fluid branch. The reduction in pressure events was approximately 50%. Actuator efforts are also reduced in this configuration.

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort.

Purpose: Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Methods and Materials: Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. Results: One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the "hero" model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. Conclusions: ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan.

Prevalence of Cognitive Impairment before Prostate Cancer Treatment.

Cognitive impairment is common among patients with different types of cancer, even before cancer treatment, but no data were reported among patients with prostate cancer (PCa), who may be at high risk due to advanced age. This study aims to estimate the prevalence of cognitive impairment before PCa treatment. Between February 2018 and April 2021, the NEON-PC cohort recruited 605 patients with PCa proposed for treatment at the Portuguese Institute of Oncology of Porto. The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. Participants with a MoCA < 1.5 standard deviations (SD) of age- and education-specific normative values were considered to have probable cognitive impairment (PCI) and were referred for a comprehensive neuropsychological assessment. Data from the population-based cohort EPIPorto (n = 351 men aged ≥40 years, evaluated in 2013−2015) were used for comparison. The prevalence of PCI was 17.4% in EPIPorto and 14.7% in NEON-PC (age- and education-adjusted odds ratio: 0.82, 95%CI: 0.58,1.18). Neuropsychological assessment was performed in 63 patients with PCa: 54.0% had cognitive impairment. These results suggest that the impact of PCa on cognitive performance could be negligible in the short term, contrary to what other studies have reported regarding other types of cancer.

The Prevalence of Polypharmacy and Potentially Inappropriate Medications and Its Relationship with Cognitive Status in Portuguese Institutionalized Older Adults: A Cross-Sectional Study.

The aim of this study was to evaluate the prevalence of polypharmacy and potentially inappropriate medications (PIMs) in a population of older adults living in nursing homes. Furthermore, we also intended to assess the possible association between polypharmacy, potentially inappropriate medications and cognitive impairment in institutionalized older adults. A cross-sectional study analyzed data from 193 nursing home residents in the district of Viseu, Portugal, between September 2018 and June 2019, with a mean age of 82.4 ± 6.2 years (ranging from 65 to 95 years old); 72.5% (n = 140) were female participants. Major polypharmacy was presented in 80.8% of the study population, who took 7.6 ± 3.3 drugs per day. Using the Beers Criteria, we found that 79.3% took PIMs. There was a positive association between polypharmacy and PIM (p < 0.001), showing that higher medicines intake increased the number of PIMs. Polypharmacy was not associated with the functionality of the older adults to perform activities of daily living, but was associated with cognitive impairment. The older adults with lower scores on the Mini Mental State Examination (MMSE) took more drugs (p = 0.039) and used more PIM (p < 0.001). Moreover, patients taking five or more prescription drugs per day (major polypharmacy) consuming any psychiatric, gastrointestinal or oral antidiabetic agents (regardless of whether they were considered potentially inappropriate or not) had higher odds of displaying cognitive impairment than those who did not (p < 0.05). Older adult residents of the studied nursing homes were potentially affected by polypharmacy and inappropriate polypharmacy. This observation reveals the need to adopt and implement strategies that make drug therapy more adequate and safer for older adults.

Changes in xylem morphology and activity of defense-related enzymes are associated with bean resistance during Fusarium oxysporum colonization.

Genetic resistance is the main strategy to control Fusarium wilt in common bean. Despite this, few studies have focused on defense mechanisms involved in bean resistance to Fusarium oxysporum f. sp. phaseoli (Fop). Thus, the present study aimed to investigate the changes in xylem morphology and involvement of phenylpropanoid compounds and their biosynthetic enzymes in bean resistance against Fop. Uirapuru and UFSC-01 genotypes characterized, respectively, as susceptible and resistant were used. In roots and hypocotyls, guaiacol peroxidase (GPX), phenylalanine ammonia-lyase (PAL), and polyphenol oxidase (PPO) activities were determined at 0, 1, 2, 3, 4, 5, and 6 days after inoculation (dai), and flavonoids, total phenolics, and lignin content were quantified at 0, 3, and 6 dai. Cross sections of taproots and hypocotyls were examined under epifluorescence (at 1, 3, and 6 dai) and transmission electron (at 6 dai) microscopic to analyze the morphology of xylem cell walls. Overall, there was an increase in the activity of all studied enzymes in resistant bean plants, mainly during advanced colonization stages. Modifications in xylem morphology were more intense in roots of resistant genotype resulting in an increase of occluded cells, organelles, and cell wall strengthening. This study provides evidence that bean resistance is associated with increased phenylpropanoid enzymatic activity and cell wall reinforcement of some xylem cells.

First report on the Annona exsucca DC. Essential oil and in silico identification of potential biological targets of its major compounds.

In the present study, the essential oil (EO) of Annona exsucca DC. or Rollinia exsucca was extracted by hydrodistillation, and the identification and quantification of volatile compounds were performed by GC-MS and GC-FID. A. exsucca leaves were collected from the Magalhães Barata, northeast of the State of Pará (Brazil) in March and September of 2019. Moreover, we used computational approaches to evaluate possible biological targets for the major compounds of the EO. In the sample obtained in March, 50 compounds were identified, with hydrocarbon sesquiterpenes being the predominant ones with the content of 80.52%. In the sample collected in September, 58 compounds were identified, and the chemical class of hydrocarbon monoterpenes and sesquiterpenes were the dominant ones with contents of 43.36 and 31.29%, respectively. Computational methods demonstrated that some major compounds have potential biological activity against some strains of pathogenic bacteria, as well as against molecular targets involved in cancer development.

Cost-effectiveness of stereotactic body radiotherapy versus conventional radiotherapy for the treatment of surgically ineligible stage I non-small cell lung cancer in the Brazilian public health system.

Background: The Brazilian public health system does not pay for the use of Stereotactic body radiotherapy (SBRT) due to its costs and the absence of cost-effectiveness analysis showing its benefit. The present study aims to evaluate whether the SBRT is a more cost-effective strategy than the conventional fractionated radiotherapy (CFRT) for surgically ineligible stage I non-small cell lung cancer (NSCLC) in the Brazilian public health system. Methods: Adopting the perspective of the Brazilian Unified Healthcare System (SUS) as the payer, a Markov model with a lifetime horizon was built to delineate the health states for a cohort of 75-years-old men with medically inoperable NSCLC after treatment with SBRT or CFRT. Transition probabilities and health states utilities were adapted from the literature. Costs were based on the public health system reimbursement values and simulated in the private sector. Findings: The SBRT strategy results in more quality-adjusted life-year (QALYs) and costs with an incremental cost-effectiveness ratio (ICER) of R$ 164.86 (U$ 65.16) per QALY and R$ 105 (U$ 41.50) per life-year gained (LYG). This strategy was cost-effective, considering a willingness-to-pay of R$ 25,000 (U$ 9,881.42) per QALY. The net monetary benefit (NMB) was approximately twice higher. The outcomes were confirmed with 92% of accuracy in the probabilistic sensitivity analysis. Interpretation: Using a threshold of R$25,000 per QALY, SBRT was more cost-effective than CFRT for NSCLC in a public health system of an upper-middle-income country. SBRT generates higher NMB than CFRT, which could open the opportunity to incorporate new technologies. Funding: Varian Medical Systems.