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Objetivo: Investigar os efeitos de ligação do 5-hidroximetilfurfural (5-HMF) e Voxelotor na Hemoglobina A (HbA), para avaliação da afinidade, cooperatividade heme-heme e efeito Bohr. Material e métodos: Utilizou-se hemolisado isolado de amostras de sangue periférico de 3 voluntários adultos saudáveis que assinaram o TCLE (CAAE: 62849022.5.0000.5404). A Hb foi purificada por cromatografia de exclusão molecular em colunas de Sephadex 25G (Sigma-Aldrich; Missouri, USA) em tampão Hepes 50 mM (Sigma-Aldrich; Missouri, USA) e por cromatografia de troca iônica (Amberlite MB3; Sigma-Aldrich; Missouri, USA). Obteve-se Curvas de Dissociação de Oxigênio (CDO) por espectrofotometria (DU800 Beckman Coulter-Fullerton, EUA) a 25oC, 70uM de Hb e relação estequiométrica Hb:composto de 1:1.5 (Voxelotor ou 5-HMF). Também realizou-se experimentos com Inositol Hexafosfato (IHP, Sigma-Aldrich) 1 mM como mimético do 2,3-BPG. A afinidade de oxigênio foi determinada com a obtenção de P50 (pressão parcial de O2 necessária para saturação de 50% da Hb total). Cooperatividade heme-heme foi calculada pela Constante de Hill (n), em que n = 1 indica interação não cooperativa e n = 2 indica interação heme-heme cooperativa. Os experimentos foram realizados nos pHs 6,5, 7,0 e 7,5 para avaliação de Efeito Bohr. Resultados: Voxelotor aumentou significativamente a afinidade pela Hb nos pHs 6,5 (p = 0.004) e 7,0 (p = 0.0104) em comparação a stripped HbA (controle) e em todos os pHs em comparação com 5-HMF (p = 0.0448, p = 0.0109 e p = 0.0047). Amostras com 5-HMF não tiveram alterações comparado com o controle. Na presença de IHP, houve diferença significativa de P50 nas amostras com Voxelotor em todos os pHs (6,5 p = 0.0038, 7,0 p = 0.043 e 7,5 p = 0.0007), demonstrando mudança significativa no alosterismo proteico e efeito Bohr positivo. Foi observada também diferença significativa entre 5-HMF e Voxelotor em pH 7,0 (p = 0.0275). Em relação à cooperatividade heme-heme, o Voxelotor apresentou valores de n abaixo de 1 para HbA stripped, indicando uma ligação não cooperativa, semelhantemente às mioglobinas. Diferenças significativas nos valores de n foram observadas entre Voxelotor e controle nos pHs 6.5 (p = 0.0114) e 7.0 (p = 0.0331), e entre Voxelotor e 5-HMF em todos os pHs (p = 0.0047, p = 0.026 e p = 0.0248, respectivamente). Com IHP, não foram encontradas diferenças significativas na cooperatividade heme-heme entre os grupos, e os valores de n foram aproximadamente 2, indicando que a ligação de Hb-O2 permaneceu cooperativa e sensível à ligação de fosfatos orgânicos, como o IHP. Discussão: Este trabalho sugere que o Voxelotor, atualmente utilizado no tratamento da anemia falciforme, possa aumentar a afinidade da HbA pelo O2 reduzindo drasticamente a cooperatividade heme-heme, mas permitindo que a mesma ainda se mostre sensível a variações de pH ou mesmo à presença de fosfatos orgânicos. Conclusão: Voxelotor aumentou significativamente a afinidade Hb-O2 em diferentes pHs, tanto em ambientes ácidos quanto alcalinos, modulando o alosterismo da Hb na presença de H+ e fosfatos. Estes achados mostram propriedades ainda não descritas do Voxelotor quanto a dinâmicas de ligação entre Hb e O2 e podem ser investigadas posteriormente como uma alternativa terapêutica em situações de baixa captação pulmonar de oxigênio e acidose.

Background: Although the oral health status has improved in developed countries in recent years, oral diseases are still unequally distributed across socio-economic groups. Research on the impact of socio-economic factors on oral health care among older adults in Europe, including Portugal, remains limited. The main aim of this study was to investigate the association between socio-economic factors and oral health indicators in Portuguese older adults., Methods: This retrospective cross-sectional study analyzed data from 915 participants (aged 65 years and older) from the third wave (2015-2016) of the Epidemiology of Chronic Diseases Cohort Study (EpiDoC), a population-based study. Socio-economic and demographic information, general health-related characteristics and oral health data (prosthetic need, oral hygiene frequency, and last dental procedure) were collected by questionnaire. Multivariate logistic and multinomial regression models analyzed the associations between socio-economic factors and oral health indicators., Results: Participants with lower education level, perceived lower income and a fewer number of private sector appointments were more likely to have poor oral health (need for prosthetic treatment, less frequent oral hygiene, and tooth extraction as last dental procedure). Other factors found to be associated with oral health were sex, age, geographical area, smoking habits, and body mass index., Conclusions: Socio-economic factors were associated with oral health in Portuguese older adults. These findings may contribute to future national public health strategies by expanding oral health services to ensure better access and coverage for at-risk groups., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the tenets of the Declaration of Helsinki, as revised in Fortaleza in 2013. The EpiDoC study was approved by the Ethics Committee of the NOVA Medical School and the Portuguese Data Protection Authority (Comissão Nacional de Proteção de Dados). Details of the ethical aspects of the EpiDoC study have been described in a previous report [20]. The secondary analysis of the present study was approved by the Ethics Committee of the NOVA Medical School (n.79/2020/CEFCM). All participants provided written informed consent for all phases of the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Fragility fractures are a major problem in our aging society leading to early death and loss of independence for activities of daily living. Physical activity in a long-term follow-up of Portuguese women over 50 years with a fragility fracture was associated with better physical function and quality of life., Purpose: To evaluate the long-term impact of physical activity on physical function and health-related quality of life (HRQoL) in women ≥ 50 years old who suffered a fragility fracture., Methods: We evaluated the association of physical activity with physical function and HRQoL in women ≥ 50 years old who self-reported at least one low-impact fracture ≥ 40 years old from the EpiDoC cohort, a population-based cohort. Self-reported data regarding sociodemographics, clinical, and lifestyle behaviors were collected through a semi-structured questionnaire at baseline during a face-to-face clinical interview. During a long-term follow-up, a phone interview was conducted to evaluate physical activity (using a non-validated scale developed for the EpiDoC study), physical function (Health Assessment Questionnaire), and HRQoL (European Quality of Life - 5 Dimension). Women were divided into three groups according to the frequency of physical activity (non-frequent = 0 times/week, frequent = 1-2 times/week, or very frequent =  ≥ 3 times/week). The association of physical activity frequency (non-frequent, frequent, and very frequent) with physical function and HRQoL over time was assessed through linear mixed models considering varying intercepts for each woman., Results: This study followed 323 post-fracture women, during a mean follow-up of 3.9 ± 3.5 years. Frequent (β =  - 0.1419 [- 0.2783, - 0.0064]) and very frequent (β =  - 0.1908 [- 0.2944, - 0.0881]) physical exercise were associated with improvements in physical function relative to non-frequent physical exercise adjusted for BMI, multimorbidity, hospitalizations, alcohol and smoking habits, and the number of fragility fractures at baseline. As for HRQoL, a positive association was found for exercise frequency, specifically frequent (β = 0.1305 [0.0646, 0.1958]) and very frequent (β = 0.1354 [0.0856, 0.1859]) suggesting improvements for HRQoL, in this follow-up period., Conclusions: These findings based on longitudinal data with long-term follow-up suggest that regular physical activity is associated with better function and HRQol among middle-aged and older post-fracture osteoporotic Portuguese women., Competing Interests: Declarations. Conflict of interest: David G. Lopes, Carolina Mazeda, Jaime Cunha Branco, and Helena Canhão declare that they have no conflict of interest. Ana Rodrigues reports grants from Amgen and Pfizer. Anabela Barcelos has received honoraria for presentations from Janssen and support for attending meetings and/or travel from Amgen, Janssen, and Novartis., (© 2024. The Author(s).)

Background: Digital patient-centered interventions may be important tools for improving and promoting social interaction, health, and well-being among older adults. In this regard, we developed a mobile app called DigiAdherence for an older adult population, which consisted of easy-to-access short videos and messages, to improve health-related knowledge among them and prevent common health conditions, such as falls, polypharmacy, treatment adherence, nutritional problems, and physical inactivity., Objective: This study aimed to assess the usability and utility of the DigiAdherence app among Portuguese older adults 65 years or older., Methods: In this pilot noncontrolled quasi-experimental study, older adults who were patients at the primary health care center in Portimão, Portugal, and owned a smartphone or tablet were recruited. Participants were assessed at baseline, given access to the DigiAdherence app for 1 month, and assessed again immediately after 30 days (first assessment) and 60 days after stopping the use of the app (second assessment). App usability and utility (primary outcomes) were analyzed in the first follow-up assessment using a structured questionnaire with 8 items. In the second follow-up assessment, our focus was on knowledge acquired through the app. Secondary outcomes such as treatment adherence and health-related quality of life were also assessed., Results: The study included 26 older adults. Most participants rated the different functionalities of the app positively and perceived the app as useful, attractive, and user-friendly (median score of 6 on a 7-point Likert scale). In addition, after follow-up, participants reported having a sense of security and greater knowledge in preventing falls (16/24, 67%) and managing therapies and polypharmacy (16/26, 62%)., Conclusions: The DigiAdherence mobile app was useful and highly accepted by older adults, who developed more confidence regarding health-related knowledge., International Registered Report Identifier (irrid): RR2-10.2196/29675., (©Marta Lemos, Ana Rita Henriques, David Gil Lopes, Nuno Mendonça, André Victorino, Andreia Costa, Miguel Arriaga, Maria João Gregório, Rute de Sousa, Helena Canhão, Ana M Rodrigues. Originally published in JMIR Formative Research (https://formative.jmir.org), 17.05.2024.)

Introduction: The population in Portugal is ageing due to increased life expectancy and reduced fertility rates. We aimed to estimate the health trajectories of Portuguese older adults (60 + years old) in a 10-year period and to assess associated sociodemographic, lifestyle factors and multimorbidity status., Methods: Using the population-based EpiDoC cohort, we estimated the trajectories of health-related quality of life and physical function of 4135 Portuguese older adults over 10 years using linear mixed models. Factors associated to health-related quality of life and physical function were assessed using linear mixed models and random intercept tobit regression, respectively., Results: The physical disability of participants increased by 0.263 (0.240, 0.286), and health-related quality of life declined by 0.074 (-0.084, -0.063), over 10 years. With advancing age, older adults reported a faster reduction in health-related quality of life and faster increase in physical disability. In general, women were in worse health than men at baseline, albeit with a similar rate of change throughout the follow-up. Higher education and regular exercise were associated with better health-related quality of life and physical function while multimorbidity and excess weight were associated with worse reporting of these outcomes., Conclusions: These findings, based on longitudinal data with 10 years of follow-up, are essential to effectively plan resource allocation, plan better healthcare and design informed public health policies in Portugal. This study characterizes ageing in Portugal showing increased physical disability and decreased health-related quality of life with advancing age older adults, helping to develop public health policies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To identify long-term trajectories of physical function and health-related quality of life (HRQoL) among people with hip and/or knee osteoarthritis (HKOA) and the sociodemographic, lifestyle, and clinical factors associated with different trajectories., Methods: Participants with HKOA from the EpiDoC study, a 10-year follow-up (2011-2021) population-based cohort, were considered. Sociodemographic, lifestyle, and clinical variables were collected at baseline in a structured interview and clinical appointment. Physical function and HRQoL were evaluated with the Health Assessment Questionnaire (HAQ) and EuroQoL, respectively, at baseline and the three follow-ups. Group-based trajectory modeling identified physical function and HRQoL trajectories. Multinomial logistic regression analyzed the associations between the covariates of interest and trajectory assignment (p < 0.05)., Results: We included 983 participants with HKOA. We identified three trajectories for each outcome: "consistently low disability" (32.0%), "slightly worsening moderate disability" (47.0%), and "consistently high disability" (21.0%) for physical function; "consistently high HRQoL" (18.3%), "consistently moderate HRQoL" (48.4%) and "consistently low HRQoL" (33.4%) for HRQoL. Age ≥ 75 years, female sex, multimorbidity, and high baseline clinical severity were associated with higher risk of assignment to poorer physical function and HRQoL trajectories. Participants with high education level and with regular physical activity had a lower risk of assignment to a poor trajectory. Unmanageable pain levels increased the risk of assignment to the "consistently moderate HRQoL" trajectory., Conclusion: Although the trajectories of physical function and HRQoL remained stable over 10 years, approximately 70% of people with HKOA maintained moderate or low physical function and HRQoL over this period. Modifiable risk factors like physical activity, multimorbidity and clinical severity were associated with poorer physical function and HRQoL trajectories. These risk factors may be considered in tailored healthcare interventions., (© 2023. The Author(s).)

Hip and knee osteoarthritis (HKOA) is a chronic disease characterized by joint pain that leads to reduced physical function and health-related quality of life (HRQoL). At present, no cure is available. Clinical trials indicate that people with HKOA benefit from physical activity in several health-related outcomes. However, few studies have evaluated the long-term positive effect of regular physical activity. This study analyzed participants with HKOA from a nationwide population-based cohort (EpiDoC Cohort) to assess the impact of physical activity on patients' physical function and HRQoL over a long-term follow-up. The regular weekly frequency of intentional physical activity was self-reported as non-frequent (0 times/week), frequent (1-2 times/week), or very frequent (≥ 3 times/week). This study followed 1086 participants over a mean period of 4.7 ± 3.4 years, during which 6.3% and 14.9% of participants reported frequent and very frequent physical activity, respectively. Using linear mixed models, we found that frequent (β =  - 0.101 [- 0.187, - 0.016]; β = 0.039 [- 0.002, 0.080]) and very frequent physical activity (β =  - 0.061 [- 0.118, - 0.004]; β = 0.057 [0.029, 0.084]) were associated with improved physical function and HRQoL over time, respectively, when compared with non-frequent exercise, adjusting for years to baseline, sex, age, years of education, body mass index, multimorbidity, hospitalizations, clinical severity, and unmanageable pain levels. These findings raise awareness of the importance of maintaining exercise/physical activity long term to optimize HRQoL and physical function. Further studies must address barriers and facilitators to improve the adoption of regular physical activity among citizens with HKOA., (© 2023. The Author(s).)

Background: Pain due to knee and / or hip osteoarthritis (HKOA) is the most common symptom for seeking healthcare. Pain interferes on daily activities, social and occupational participation in people with HKOA. The goal of this study is to estimate the prevalence of unmanageable pain levels (UPL) among people with HKOA), characterize this population and identify factors associated with UPL, and compare therapeutic strategies used by people with UPL versus manageable pain levels (MPL)., Methods: We analysed data from the EpiReumaPt study (n = 10,661), that included a representative sample of the Portuguese population. Among these, 1081 participants had a validated diagnosis of HKOA by a rheumatologist.. Sociodemographic, lifestyle and health-related data were collected in a structured interview. Pain intensity (NPRS) data were collected in a medical appointment. Painmedication (last month), physiotherapy and surgery were considered as therapies for pain management. UPL was defined as a mean pain intensity in the previous week of ≥5 points on 11-point numeric pain rating scale. The factors associated with UPL were analyzed with logistic regression (p < 0.05, 95%CI). The effect of unmanageable pain levels was assessed by the HOOS/KOOS activities of daily living and quality of life subscales. Symptoms of anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Analysis was completed with linear and logistic regression. All analysis were weighted., Results: The estimated prevalence of UPL among people with HKOA was 68.8%. UPL was associated with being female (odds ratio (OR) = 2.36, p < 0.001), being overweight (OR = 1.84, p = 0.035) or obese (OR = 2.26, p = 0.006), and having multimorbidity (OR = 2.08, p = 0.002). People with UPL reported worse performance in activities of daily living and lower quality of life (β = - 21.28, p < 0.001 and β = - 21.19, p < 0.001, respectively) than people with MPL. People with UPL consumed more NSAIDs (22.0%, p = 0.003), opioids (4.8%, p = 0.008), paracetamol (2.7%, p = 0.033), and overall analgesics (7.3%, p = 0.013) than people with MPL. A higher proportion of people with UPL underwent physiotherapy (17.5%, p = 0.002) than people with MPL., Conclusion: Two-thirds of people with HKOA in Portugal have poor management of their pain levels. Clinical and lifestyle factors, that are highly presented in individuals with HKOA, are associated with unmanageable pain. Our results highlighting the need for further research and implementation of effective interventions to improve pain, function and quality of life in people with HKOA., (© 2023. The Author(s).)

Introduction: Zoonoses represent 75% of emerging diseases. These diseases pose a permanent threat to human health and well-being and have the potential to become increasingly frequent due to habitat degradation; land-use changes; and increased global mobility of humans, animals, and animal products. The objective of this study was to investigate the impact ten zoonoses (brucellosis, cysticercosis, echinococcosis, leishmaniasis, leptospirosis, Lyme disease, rabies, toxoplasmosis, trichinellosis, and West Nile fever) had on human hospitalizations between 2002 and 2016 in Portuguese National Health Service hospitals., Material and Methods: A retrospective nationwide study was conducted using hospitalization records gathered by Administração Central do Sistema de Saúde from all Portuguese public hospitals., Results: Between 2002 and 2016, zoonoses caused 181,741 hospitalizations, a total number of hospitalization days of 2,033,125, and 10,611 deaths. The ten studied zoonoses caused 5,183 hospitalizations, 71,548 hospitalization days, and 176 deaths. All, except Lyme disease, showed a trend of decreasing numbers of hospitalizations., Discussion and Conclusion: The impact of each zoonosis in hospitalized patients regarding their age, sex, the severity of disease, and region can be attributed to the specific characteristics of each disease, regarding means of infection, pathogenicity, and geographic distribution. Hospitalizations caused by zoonoses have declined since the beginning of the century in Portugal. They still represent, however, relevant impacts on Public Health. The promotion of trans professional cooperation guided by One Health principles will further aid in the control of these important diseases., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel on behalf of NOVA National School of Public Health.)

Introduction: Multimorbidity is a worldwide health problem, especially in elderly patients who have a higher risk of fragility fracture. Currently, there is insufficient knowledge about the burden of multimorbidity in patients with previous fragility fracture. The aim of this study was to evaluate the association between multimorbidity and previous fragility fracture, and to assess the effect of fragility fracture and/or multimorbidity in the perception of quality-of-life and physical function, in women 50 years of age and older., Methods: Women aged ≥50 years from the EpiReumaPt study (2011-2013), a nationwide population-based study, were evaluated. Self-reported data regarding sociodemographics, health-related quality of life, physical functioning, fragility fracture, and multimorbidity were collected using a semi-structured questionnaire. Multimorbidity was defined as 2 or more chronic non-communicable diseases. Descriptive exploratory analysis of the data was performed using hypothesis testing. Multiple logistic regression modelling was used to assess the association between multimorbidity and fragility fractures, and linear regression was used for the quality-of-life and physical function outcomes., Results: The estimated prevalence of fragility fracture in women older than 50 years was 17.5%. A higher prevalence of multimorbidity (74.6%) was found in the group of women with previous fragility fracture than in those without previous fragility fracture. Multivariate logistic regression analysis revealed that women with multimorbidity had a higher odds of fragility fracture (adjusted odds ratio, 1.38; 95% confidence interval, 1.12-1.69), compared with women with 1 or no self-reported non-communicable chronic diseases. In women with previous fragility fracture, rheumatic diseases (62.7%) and hypertension (58.6%) were the most frequently self-reported non-communicable chronic diseases. The combination of fragility fracture and multimorbidity was associated with a lower quality of life and higher degree of disability., Conclusions: Women 50 years and older with multimorbidity had a significantly increased odds of fragility fracture. Fragility fracture combined with multimorbidity was negatively associated with quality of life and positively associated with disability. This study emphasizes the need to redesign health services to care for patients to prevent non-communicable chronic diseases and fragility fracture, particularly in women 50 years and older, in whom these diseases are likely to potentiate the risk of fragility fracture., (© 2021 Published by Elsevier Inc.)

Background: Immunological protection via breastfeeding is well known. The immunological profile of human milk changes during lactation. No clinical trials have been conducted in lactating women with the newest mRNA vaccines against SARS- CoV-2. A Few studies have shown the presence of antibodies in breastmilk after vaccination. The aim of this work is to study possible antibodies transfer via breastmilk and also the immunological characteristics of lactating women compared to non-lactating women, after using the BNT162b2 Pfizer vaccine., Methods: This is a prospective cohort study with a convenience homogenous sample of 24 healthcare workers (14 lactating and 10 non-lactating women) enrolled at the time of COVID-19 vaccination. Clinical data was registered in a questionnaire. Titers of SARS-CoV-2 spike IgG, IgA and IgM were quantified in post vaccination blood and human milk. Antibody quantification was performed by an in-house ELISA to SARS-CoV-2 trimeric spike protein., Results: All women showed immunity after vaccination with positive antibodies for IgM, IgA and IgG antibodies. The dominant serum antibody response was IgG. Modest levels of antibodies in breastmilk of lactating mothers were observed in this study, especially IgG in 42.9%. There was a moderate association between higher titers of IgG and a longer duration of breastfeeding (R= 0.55, p=0.041)., Conclusions: Evidence of antibody transfer in human milk after COVID-19 vaccination is scarce. The presence of antibodies in human milk is reported, but immunization through breastfeeding is still to be established., (© 2021. The Author(s).)

Background: In response to rapid global spread of the newly emerged coronavirus disease 2019 (COVID-19), universities transitioned to online learning and telework to decrease risks of inter-person contact. To help administrators respond to the COVID-19 pandemic and better understand its impacts, we surveyed SARS-CoV-2 seroprevalence among NOVA University employees and assessed community mental health. Methods: Data were collected from voluntary participants at six NOVA University locations, in the Lisbon metropolitan area, from June 15-30, 2020. All subjects provided written informed consent. Of 1,627 recruited participants (mean age 42.0 ± 12.3 years), 1,624 were tested. Prior to blood collection, participants completed a questionnaire that assessed: COVID-19 symptoms during the previous 14 days, chronic non-communicable diseases, chronic medication, anxiety, and depression symptoms. SARS-CoV-2 serology tests were then performed, and results communicated approximately 4 days after blood draw. Participants with positive serology tests were contacted to assess COVID-19 symptoms since February. Results: Estimated prevalence of SARS-CoV-2 IgG antibodies was 3.1% ( n = 50), of which 43.5% reported symptoms in the previous 4 months. The Medical School had the highest seroprevalence (6.2%). Participants reported having at least one chronic disease (63.7%), depression-like symptoms (2.1%), and anxiety symptoms (8.1%). Rates of depression and anxiety symptoms were significantly higher in women, with sleep hours and occasional alcohol consumption negatively associated with depression. Male gender, older age, and sleep hours negatively associated with anxiety symptoms. School of employment and presence of comorbidities positively associated with anxiety. Conclusion: By measuring seroprevalence of SARS-CoV-2 antibodies among NOVA employees and assessing subjects' mental health, we aim to help administrators at European public universities in urban areas, such as Lisbon, Portugal, better understand the needs of their communities. This study resulted in implementation of a stricter contingency plan in the Medical School, while other schools continued to follow Government mitigation guidelines. These findings may also guide the development of tailored strategies to ensure physical and mental health of the academic community during this pandemic crisis. We conclude that, together with COVID-19 contingency plans, psychological support services and facilities to help people effectively face pandemic-associated challenges and minimise anxiety and depression should be implemented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lopes, Henriques, Santos-Dias, Nunes-da-Silva, Gonçalves, de Sousa, Abdulghani, Eletério, Braga, Soares, Branco, Canhão and Rodrigues.)

Background: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. In Brazil, even though low-molecular-weight heparin (LMWH) is the gold standard of care for the management of cancer-associated thrombosis (CAT), its cost limits its use and therefore warfarin is commonly prescribed. Direct oral anticoagulants (DOACs), such as edoxaban, have been introduced as an alternative in this setting., Objective: The aim of this study was to compare the cost-effectiveness of edoxaban with LMWH (Model 1) and warfarin (Model 2) to support clinicians and hospitals when choosing an anticoagulant to manage CAT., Materials and Methods: Cost-effectiveness analyses were performed using Markov state-transition models over a timeframe of 5 years, in a hypothetical, 64 years-old patients cancer population with an index VTE event. Transition probabilities, costs, quality-adjusted life years (QALYs) and risk reductions were either derived from the literature, estimated or calculated. A willingness-to-pay limit of 3 Gross Domestic Product (GDP) per head was used. Deterministic and probabilistic sensitivity analyses were performed for robustness. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained., Results: Model 1 base case analysis demonstrated dominance of edoxaban compared to LMWH, with an ICER of $5204.46, representing cost saved per QALY lost. In Model 2, edoxaban was associated with a $736.90 cost increase vs. warfarin, with an ICER of $2541.03. Sensitivity analyses confirmed base-case results., Conclusion: Edoxaban represents a cost-saving alternative to LMWH for the management of CAT and is cost-effective vs. warfarin., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pharmaceuticals are widespread contaminants across the aquatic systems and despite the role that these compounds play in society today, little is known about their effects in aquatic organisms once they are released into the environment. This study aims to provide quantitative insight on the effects of antidepressants on the reproduction of fish and crustaceans with a multilevel meta-analysis. A systematic literature search identified 19 studies investigating effects of antidepressant exposure in fish or crustaceans' reproduction, according to specific selection criteria. Heterogeneity analysis was performed and the moderating effect of the range of exposure concentrations, exposure time, organism group and toxicant was tested. Additionally, publication bias was also addressed. The results showed that, overall, there is no significant association between antidepressant exposure and the reproduction of fish and crustaceans, however, moderator analysis revealed that the range of concentrations is a significant moderator for fish and crustacean fecundity, showing contrary results between the two groups. Antidepressant concentration had a small, yet positive effect on fish fecundity, meaning that increased concentrations resulted in increased fish fecundity, whilst a negative effect on crustaceans' fecundity was apparent with increasing concentrations. This difference could be related to data artifacts, or, more likely, evidencing a hormetic dose-response curve, with different ranges of exposure concentrations considered in studies on fish and crustaceans. Antidepressants have shown effects on reproductive outcomes in aquatic organisms, based on individual studies and narrative reviews. However, our results show that other factors can have an important role. Additionally, data available for a quantitative assessment is scarce, focusing mainly on a few freshwater species, low concentration ranges and one SSRI compound, fluoxetine. Thus, more research on the subject is needed since meta-analysis are only as statistically powerful as the number of, good quality, studies they include., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present study investigates the drug release-governing microstructural properties of melt spray congealed microspheres encapsulating the drug crystals in the matrix of glyceryl behenate and poloxamer (pore former). The solid-state, morphology, and micromeritics of the microspheres were characterized, before and after annealing, using calorimetry, X-ray scattering, porosimetry, scanning electron microscopy, and, NMR diffusometry. The in vitro drug release from and water uptake by the microspheres were obtained. The extent and the rate of drug release from the microspheres increased with a high poloxamer content and at higher annealing temperature and RH. All the drug release profiles were describable using the Higuchi release kinetics pointing towards the diffusion controlled release, both before and after annealing. The annealing process led to the polymorphic conversion of lipid and the increase in the pore size, predominantly at a higher temperature and humidity and for a high poloxamer content. The poloxamer domain increased from an initial 300 nm, up to 2000 nm upon annealing. The water diffusion rate inside the annealed microsphere was twice as fast as for unannealed counterparts. The findings relate the overall phase and pore structure change of the microsphere to the increased drug release induced by annealing. This work serves as a basis for the rational understanding of the modification of the in vitro performance by annealing, a widely used post-process for solid lipid products., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The major challenge of conventional lipid-based excipients (LBE) for drug delivery is their unstable solid state, affecting the stability of pharmaceutical product. Polyglycerol esters of fatty acids (PGFAs) are oligomeric hydroxyethers of glycerol fully or partially esterified with fatty acids. Tuning the number of polyglycerol moieties, fatty acids chain length and free hydroxyl groups per molecule results in diverse physicochemical properties, e.g. HLB, melting point, and wettability, which makes these molecules attractive candidates as novel LBE for different pharmaceutical applications. In this first part of our studies the solid state of PGFAs and the stability thereof were profiled on molecular, nano, and microstructural level and the resulting properties as LBE. DSC analysis confirmed the single phase system of PGFAs without phase separation. WAXS patterns revealed the absence of polymorphism and the direct crystallization into a stable α-form; without transition to more dense configurations. SAXS patterns exposed the lamellar arrangement. The lamellae stacks were characterized by the crystallite thickness and growth. The nano, microstructure and physicochemical properties of PGFAs remained stable during storage. The stable solid state and the broad functionality of PGFAs offer a novel approach to overcome the challenges faced by conventional LBE for advanced pharmaceutical applications. Examples for such applications are presented in the next parts of this study., Competing Interests: Declaration of Competing Interest The Austrian COMET Program, the Austrian Research Promotion Agency (FFG) and IOI Oleo GmbH Germany funded this research. The research is free of bias. The authors declares that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Posttraumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs. However, oral nonsteroidal anti-inflammatory drugs cause several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed at evaluating the efficacy and safety of loxoprofen patch (LX-P) in the treatment of patients with posttraumatic pain. This phase III, randomized, double-blind, noninferiority study enrolled Brazilian patients aged 18 to 65 years diagnosed with lower and upper limb posttraumatic injury who were experiencing moderate or severe pain. Patients were assigned to active LX-P or to loxoprofen tablet (LX-T), and pain intensity was measured based on a visual analog scale score variation after 7 days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. Visual analog scale score variation was compared using a 10% noninferiority margin. Two hundred forty-two patients were randomly assigned to LX-P (n = 123) or to LX-T (n = 119). The results showed a reduction in pain after 7 days of treatment: -49.96 (n = 118; SE 1.7) in the LX-P and -47.71 (n = 117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 to 1.47; P = 0.23). On the safety analysis, the LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary end point. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of posttraumatic injury pain.

This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an iterative calibration routine to describe the behavior of the powder in the roller compactor and improves the predictive quality of the mechanistic models at low and high-throughput. The model has been validated with an experimental design of experiments of two ibuprofen formulations. The predicted sweet spots in the operating space are in good agreement with the experimental results.

Hot-melt coating (HMC) as a solvent-free technology grants faster and more economic coating processes with reduced risk of dissolving the drug during the process. Moreover, traditional coating equipment can be modified to enable the HMC process. Despite the indubitable advantages and feasibility of the process, HMC is not well-known to pharmaceutical industry and its employment is still limited. The main aspect hindering the widespread application of this technique is the need of materials alternative to the conventional polymeric coatings. The current work reviews the published HMC formulations and describes the properties that have led to their selection. As these materials are mainly solid lipid excipients, attention should be paid to their crystallization and solid state behavior, and their impact on the performance of coated drug products, particularly on the stable drug release profile. Although different drug release profiles can be easily tailored, much development work is needed to respond to the unmet requirements of a stable formulation. Ensuring stable solid-state behavior and providing a mechanistic understanding of the macroscopic properties are essential steps towards fulfilling these requirements and establishing of HMC as advanced coating technology for manufacturing of pharmaceutical products., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Solvent-free hot-melt coating processing is a novel and cost-efficient approach to manufacturing taste-masked multiparticulate systems. However, most API powders are fine and cohesive and not processable by hot-melt coating. The aim of this study was to produce dense and abrasion-resistant granules with high drug content (>80%) via roller compaction for hot-melt coating process optimization. The selected API was ibuprofen sodium dihydrate, a salt of ibuprofen with improved bioavailability and poor intrinsic compactibility. The formulation and roller compaction process were developed for the production of granules with 94%w/w of API and low friability (∼30%), using sorbitol and isomalt as excipients. The strong bonding mechanism relied on powder jamming prior to the rollers and was investigated via scanning electron microscopy, differential scanning calorimetry and small and wide angle X-ray scattering. It was shown that sorbitol crystals are solubilized during roller compaction and recrystallize as sorbitol hydrate, acting as strong solid bridges. The robustness of the roller compaction process and the re-compaction of fines were investigated. A statistical design of experiments was conducted to evaluate the hot-melt coating process for taste masking of ibuprofen sodium granules. Taste masking required coating ratios higher than 40%w/w of granule batch, emphasizing the need for high-drug-content and abrasion-resistant granules., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hot-melt coating is of growing interest, because it does not require solvents, resulting in reduced process times and costs. However, excipients for this technology are mainly triacylglycerides (TAGs) or their derivatives, which exhibit polymorphism, surface disruption, and complex crystallite networks, affecting the release profile of produced microcapsules. In this work, anhydrous citric acid crystals were coated with molten tristearin using conventional inlet air temperatures (microcapsules A) and temperatures above the melting point of α-form (microcapsules B). Additionally, microcapsules A were tempered to achieve polymorphic stability (microcapsules AB). The product yield and coating efficacy were above 90% and 97%, respectively, demonstrating the feasibility and efficacy of the process. Small angle X-ray scattering analysis confirmed that the tristearin shell of microcapsules B is in the β-form with a larger average crystallite size than microcapsules A and AB. Scanning electron microscopy images revealed a nonbloomed surface of microcapsules B. We showed that blooming does not play a critical role in the drug release, but the apparent diffusion coefficient of drug is dramatically reduced by increasing TAGs crystallite size and resulting tortuosity. This work brings new insights on the micrometric properties of solid lipid dosage forms, being an important step to prevent the overuse of excipients with unknown toxicity., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Objective: To compare the efficacy of a cycle ergometer-based exercise program to a standard protocol on the increment of the maximum distance walked during the six-minute walk test in the postoperative rehabilitation of patients submitted to coronary artery bypass grafting., Methods: A controlled clinical trial pilot, blinded to the outcome, enrolled subjects who underwent coronary artery bypass grafting in a hospital from Southern Brazil. Subjects were designated for the standard physical rehabilitation protocol or to an alternative cycle ergometer-based protocol through simple random sampling. The primary outcome was the difference in the maximum distance walked in the six-minute walk test before and after the allocated intervention., Results: Twenty-four patients were included in the analysis, 10 in the standard protocol and 14 in the alternative protocol group. There was an increment in the maximum distance walked in both groups, and borderline superiority in the intervention group comparing to the control group (312.2 vs. 249.7; P=0.06)., Conclusion: There was an increase in the maximum distance walked in the alternative protocol compared to the standard protocol. Thus, it is postulated that the use of a cycle ergometer can be included in physical rehabilitation in the hospital phase of postoperative coronary artery bypass grafting. However, randomized studies with larger sample size should be conducted to assess the significance of these findings.

This study aimed to assess social and clinical factors associated with the fact that older adults (≥ 60 years) go out of their homes. The study interviewed 5,898 older adults identified through home visits, randomly selected in 59 cities in the State of Rio Grande do Sul, Brazil. Multivariate logistic regression was used to assess the association between the outcome and independent variables. Factors associated with going out were being men, younger and married, presence of arthrosis, ease in performing specific activities, and good self-rated health. Heart disease was a negative factor for going out. Given the importance of social activity for quality of life and the World Health Organization policy for active aging, it is extremely important to consider clinical conditions that allow the older adults to remain active in the community. Studies like this can help to adjust public policies for the elderly, especially acting on modifiable clinical and functional conditions.

This article seeks to investigate environmental aspects that may be associated with falls among elderly residents in the state of Rio Grande do Sul. It is a population-based, descriptive, cross-sectional study, with primary data collection taken from an epidemiological study entitled A Profile of the Elderly in the state of Rio Grande do Sul. The study was conducted between the years of 2010 and 2011 with 6751 elderly individuals in 59 cities in the state of Rio Grande do Sul. The association between falling and the independent variables was verified by univariate and multivariate analysis, to estimate chances of falling, adjusted for sex and age. The frequency of falls was 10.7%. Factors detected to be effective against falling: being male, having higher education, perception of insecurity, placing of seats in public places and participation in social and civic activities. The following were considered risk factors: old age, use of walking aids and participation in community activities. The results remained significant after adjustment for demographic factors. Falling is commonly associated with physical and behavioral aspects, though social and environmental factors also prove significant in this respect.