Unveiling the crucial role of betaine: modulation of GABA homeostasis via SLC6A1 transporter (GAT1).

Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling.In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Here we demonstrate that betaine at low concentration modulates the GABA uptake by GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. This modulation occurs through the temporal inhibition of the transporter, wherein prolonged occupancy by betaine impedes the swift transition of the transporter to the inward conformation. Importantly, the modulatory effect of betaine on GAT1 is reversible, as the blocking of GAT1 disappears with increased extracellular GABA. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine has a dual role in GAT1: at mM concentration acts as a slow substrate, and at µM as a temporal blocker of GABA, when it is below its K0.5. Given this unique modulatory characteristic and lack of any harmful side effects, betaine emerges as a promising neuromodulator of the inhibitory pathways improving GABA homeostasis via GAT1, thereby conferring neuroprotection against excitotoxicity.

Bioisosteric analogs of MDMA: Improving the pharmacological profile?

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re-emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5-HT2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N-demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

CDK4/6 inhibitors and endocrine therapy in the treatment of metastatic breast cancer: A real-world and propensity score-adjusted comparison.

INTRODUCTION/BACKGROUND: Hormone Receptor-positive (HR+) and Human Epidermal Growth Factor Receptor 2-negative (HER2-) breast cancer is the most common subtype, predominantly treated with endocrine therapy. The efficacy of CDK4/6 inhibitors combined with endocrine therapy in this context remains to be fully evaluated. MATERIALS (OR PATIENTS) AND METHODS: This study compared the effectiveness of CDK4/6 inhibitors (palbociclib and ribociclib) in combination with an aromatase inhibitor or fulvestrant against endocrine therapy alone in patients with HR+/HER2- advanced breast cancer. The main focus was on progression-free survival (PFS) and overall survival (OS). The study involved a population treated exclusively with endocrine therapy for bone involvement, examining median OS and PFS, and adjusting for variables like stage, visceral metastasis, age, and treatment line. RESULTS: The study found no significant OS difference between treatments with palbociclib, ribociclib, and endocrine therapy alone. However, ribociclib combined with letrozole significantly improved PFS over letrozole alone. Propensity score weighting indicated a potential 50 % reduction in death risk with ribociclib compared to palbociclib, though this was not confirmed by cox regression. CONCLUSION: CDK4/6 inhibitors, particularly ribociclib in combination with letrozole, show promise in improving outcomes for HR+/HER2- breast cancer patients. While palbociclib may not be superior to traditional endocrine therapy, the results underscore the need for further research. These findings could influence future treatment protocols, emphasizing the importance of personalized therapy in this patient group.

Bioisosteric analogs of MDMA with improved pharmacological profile.

3,4-Methylenedioxymethamphetamine (MDMA, ' ecstasy' ) is re-emerging in clinical settings as a candidate for the treatment of specific psychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubation with isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin and dopamine transporters (hSERT and hDAT, respectively) but decreased activity at 5-HT 2A/2B/2C receptors. Regarding their hepatic metabolism, they differed from MDMA, with N -demethylation being the only metabolic route shared, and without forming phase II metabolites. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA analogs might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT and hDAT, but displaying a reduced activity at 5-HT 2A/2B/2C receptors and reduced hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.

Treating and Managing Urinary Incontinence: Evolving and Potential Multicomponent Medical and Lifestyle Interventions.

Incontinence is defined by either ICS 2002 or IUGA/ICS 2010 as the involuntary loss of urine and includes urgency urinary incontinence (UUI), stress urinary incontinence (SUI) or mixed urinary incontinence (MUI). It has a high worldwide prevalence with an associated impact on quality of life. Despite existing management options for the management of urinary incontinence, patients continue to be troubled by symptoms or side effects of existing treatment. There is therefore a requirement for ongoing research into treatment options for the management of UUI and SUI, that are more effective and tolerable to patients. Advances in treatment of UUI include a more selective beta 3 agonist, Vibegron, which has less impact on cardiac function than Mirabegron. Hormonal treatment, including Ospemifene and Prasterone, may improve GSM and in turn symptoms of UUI. There are advances in the types of neuromodulators available, including those that are rechargeable at home and are MRI safe. Laser has shown promising initial results. There is developing interest in the microbiome, and how this may impact future treatment modalities. Advances in treatment of SUI include the use of mobile health applications to support delivery of pelvic floor muscle training. Litoxetine, a selective serotonin reuptake inhibitor, has shown promising results at phase III trials. Functional magnetic stimulation is being developed to improve contractility of pelvic floor muscles. We also discuss interventions that improve tissue elasticity and regeneration, such as platelet rich plasma, autologous stem cell transplantation, laser therapy and radiofrequency treatment, which show short term benefits.

Metabolic syndrome parameters and multiple sclerosis disease outcomes: A Portuguese cross-sectional study.

BACKGROUND: Metabolic syndrome and multiple sclerosis [MS] share the presence of chronic inflammation in their pathogenic mechanisms. This study aimed to estimate the prevalence of metabolic syndrome parameters in MS and their association with disease disability, cognitive function, and Neurofilament Light chain [NfL] levels. METHODS: Clinical, analytical, and magnetic resonance imaging data were obtained through medical records. Disease disability was measured by the Expanded Disability Status Scale [EDSS], the MS Severity Scale [MSSS] along with cognitive impairment by the Brief International Cognitive Assessment for MS [BICAMS] and Word List Generation test [WLG]. Metabolic syndrome parameters were evaluated by fasting blood glucose, triglycerides, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol, total cholesterol, blood pressure, and waist circumference [WC]. We also analysed serum leptin and ghrelin and cerebrospinal fluid NfL. RESULTS: Our sample included 51 people with MS, 34 (66.7%) females, mean age of 38.20±12.12 years and median disease duration of 3 years (P25=2.0, P75=5.0). Multivariate linear regression analysis confirmed that WC correlates with EDSS (ß=0.04, p=.001) and MSSS (ß=0.07, p=.002) as well as Brief Visuospatial Memory Test-Revised (ß=-0.29, p=.008), WLG (ß=-0.20, p=.039). NfL is also negatively associated with HDL-C (ß=-4.51, p=.038). CONCLUSIONS: Waist circumference is associated with disability and deficits in cognitive tests. A decrease in HDL-C is associated with an increase in NfL. This suggests metabolic syndrome might be an important factor in MS disease course.

Promoção da saúde dos adolescentes em tempo de pandemia COVID-19 desafios para o enfermeiro / Promoting adolescent health during the COVID-19 pandemic: challenges for nurses

A pandemia COVID-19 tem produzido impactos na saúde da população em geral e no desenvolvimento infantil e juvenil através da exposição ao vírus e consequente infeção, mas também através do confinamento social recomendado na tentativa de evitar a progressão da doença, de permitir cuidados médicos adequados, e de prevenir o colapso dos sistemas de saúde. Contudo estas medidas, para as crianças e para os adolescentes, têm criado potenciais perdas para o seu desenvolvimento físico e psicológico e para a sua saúde individual e coletiva. Neste contexto, investigar e compreender o impacto da pandemia COVID-19 na saúde e no desenvolvimento das crianças e dos adolescentes podem ajudar a orientar estratégias para prevenir os efeitos nocivos e a promover a sua saúde e bem-estar. Desta forma, delineei o meu percurso formativo, com vista ao desenvolvimento de competências de Enfermeiro Especialista em Enfermagem de Saúde Infantil e Pediátrica (EEESIP), no âmbito da promoção da saúde dos adolescentes em tempo de pandemia. Assim, considerando que a promoção da saúde é uma estratégia basilar nos cuidados aos adolescentes, enquanto intervenção do EEESIP, após a identificação das minhas necessidades de desenvolvimento de competências, através de um autodiagnóstico, foram definidos dois objetivos gerais a alcançar: desenvolver competências de EEESIP no cuidado à criança, ao adolescente e família, nos processos de saúde-doença, atendendo às suas etapas de desenvolvimento; e, desenvolver competências na prestação de cuidados de enfermagem especializados na área da promoção da saúde dos adolescentes, em tempo de pandemia COVID-19. E para tal, o percurso formativo centrou-se numa metodologia de análise crítica e reflexiva sobre as atividades e competências desenvolvidas, com base na filosofia dos cuidados centrados na família, e nos cuidados não traumáticos evidenciando a importância da parceria de cuidados de enfermagem em pediatria, sustentado no Modelo de Promoção da Saúde de Nola Pender.

The COVID-19 pandemic has had an impact on the health of the general population and on child and adolescents development through exposure to the virus and consequent infection, but also through the recommended social confinement in an attempt to prevent the progression of the disease, to allow adequate medical care, and to prevent the collapse of health systems. However, these measures, for children and adolescents, have created potential losses for their physical and psychological development and for their individual and collective health. In this context, investigating and understanding the impact of the COVID-19 pandemic on the health and development of children and adolescents can help guide strategies to prevent harmful effects and promote their health and well-being. In this way, i outlined my training path, with a view to the development of Pediatric Nurse specialist skills, in the context of promoting the health of adolescents in pandemic time. Thus, considering that health promotion is a basic strategy in the care of adolescents, as an intervention of the Pediatric Nurse Specialist, after the identification of my needs for development of competencies, through a self-diagnosis, two general objectives were defined to achieve: develop Pediatric Nurse Specialist competencies in the care of children, adolescents and families in health-disease processes, taking into account their stages of development; and, to develop competences in the provision of specialized nursing care in the area of adolescent health promotion, in a time of pandemic COVID-19. And for this, the formative path was focused on a methodology of critical and reflective analysis of the activities and competencies developed, based on the philosophy of family-centered care, and on non traumatic care, evidencing the importance of the partnership of nursing care in pediatrics, supported by the Health Promotion Model of Nola Pender.

Training Effects on the Stress Predictors for Young Lusitano Horses Used in Dressage.

The purpose of this study was to investigate stressful responses during a 6-week training protocol in young Lusitano horses used for dressage. The hypothesis was that the proposed training protocol would improve fitness and ensure the welfare of the animals by reducing stress predictors. Nine 4-year-old horses were evaluated before (M1) and six weeks after (M2) beginning a training protocol. The training program was performed six times per week and included 40−80 min of individually intensity-adjusted preparatory exercises for dressage. For both moments, the horses were examined before (T0) and after (T1) dressage simulation tests (DST), and at 30 (T2) and 240 min (T3) during the recovery period. Blood samples were taken to determine the horses' cortisol levels, total WBC, and neutrophil and lymphocyte counts. All variables were analyzed by one-way ANOVA and Tukey tests, with p ≤ 0.05. After training, there was a significant reduction in cortisol (p = 0.0133), HR (p = 0.0283), total WBC (p < 0.0001), and neutrophil (p < 0.0001) and lymphocyte (p = 0.0341) counts. Other findings included an increase in HRV parameters related to a cardiac vagal modulation. In conclusion, the chosen training protocol led to better fitness as the horses worked more intensively with lower cardiovascular requirements, and they showed blunted cortisol responses at M2. Such data can be used to evaluate performance, but also to predict the welfare of athletic horses.

Capacitação do cuidador informal da pessoa dependente no domicílio, no autocuidado transferir-se / Empowering the informal caregiver of the dependent person at home in self-care transferring

O avanço dos conhecimentos na área da saúde ao longo dos tempos contribuiu para o aumento da esperança média de vida, segundo Ribeiro (2013), o aumento da população idosa, acompanhado do desenvolvimento e agravamento de doenças crónicas, apresentam- se como determinantes para o aumento do número de pessoas com elevado grau de dependência e, portanto, dependentes de terceiros no seu contexto familiar e meio habitual de vida. A inevitável associação destes dois fatores, implica a crescente necessidade de cuidados deste tipo de população, o que consequentemente potencia a necessidade da existência de cuidadores informais, cujo papel na maioria das situações é assumido pelo familiar cuidador (MARTINS et al, 2014). Neste sentido surgiu a necessidade de investimento na área dos cuidados no domicílio, uma vez que o seu objetivo consiste em proporcionar a mais elevada qualidade de vida possível ao doente/família/cuidador informal, nada se afigura mais importante que a capacitação do C.I. em aspetos tão simples como o autocuidado, mas ao mesmo tempo tão exigentes fisicamente como o autocuidado transferir-se, a prevenção das complicações inerentes á imobilidade da pessoa dependente, bem como a prevenção das lesões músculo- esqueléticas do cuidador, sendo cruciais para um cuidado de boa qualidade. Neste sentido, e inserido no desenvolvimento do estágio de Natureza Profissional, surgiu a presente pesquisa que se tratou de um estudo sobre a capacitação do Cuidador informal da pessoa dependente no domicílio no autocuidado transferir-se, cujo objetivo geral é Capacitar o Cuidador Informal para cuidar da pessoa dependente no âmbito do autocuidado transferir-se. E como objetivos específicos foram definidos os seguintes: • Identificar que conhecimentos os cuidadores informais de pessoas dependentes no domicílio possuem sobre complicações da imobilidade; • Conhecer quais as dificuldades dos cuidadores informais no que concerne aos posicionamentos /mobilizações; • Identificar as fragilidades e as necessidades de formação dos cuidadores informais; • Realização de ações de formação, no domicílio, formais e informais de acordo com as fragilidades formativas dos cuidadores informais;Compreender as razões que levam os cuidadores informais á não adesão dos levantes dos seus dependentes. Os métodos utilizados para a recolha de dados foram, a observação direta em campo de estágio, realização de entrevista aos cuidadores de pessoas dependentes no domicílio. Este trabalho teve como finalidade contribuir para a prevenção das complicações inerentes à imobilidades das pessoas dependentes e contribuir para a prevenção das lesões músculo-esqueléticas do cuidador de pessoas dependentes. Com este presente estudo, foi possível mostrar que a maioria dos C.I.´s, são mulheres, filhas dos dependentes e a vivenciar uma situação de desemprego. Não tiveram formação para a realização desta tarefa de cuidar e muitas desenvolveram esta capacidade vendo fazer a outros, ou empiricamente. A maioria das cuidadoras não se sentem capazes de mobilizar o seu dependente sozinhas e por isso mesmo adotam posições viciosas para o fazer, desenvolvendo LME. O método utilizado nesta pesquisa foi a investigação-ação na qual o investigador foi corrigindo/agindo sobre o C.I. durante a sua pesquisa capacitando o C.I. no autocuidado transferir-se. Tratou-se de uma investigação qualitativa, na qual o investigador após reunir os dados sobre a realidade dos C.I.´s e identificado necessidades dos mesmos, desenvolveu uma ação de formação de modo a capacitar o Cuidador Informal, deixando material de apoio como manual do Cuidador, panfletos e material multimédia (vídeo) material de apoio técnico, para esse efeito. Por fim , constatou-se que pelas lacunas existentes ao nível desta problemática, faz todo o sentido, a criação de programas de intervenção de suporte à prevenção das complicações da imobilidade, o desenvolvimento de estudos que gerem modelos de intervenção e que visem promover o autocuidado transferir-se e a capacitação do C.I., bem como o apoio e remuneração dos C.I.´s, pois estes vêm esta sua tarefa como uma imposição social, castrando todo o seu desenvolvimento financeiro e social, tornado pesaroso o cuidar dos seus dependentes.

The advancement of knowledge in the area of health over time has contributed to the increase in average life expectancy, according to Ribeiro (2013), the increase in the elderly population, accompanied by the development and worsening of chronic diseases, present themselves as determinants for the increase in the number of people with a high degree of dependence and, therefore, dependent on third parties in their family context and usual way of life. The inevitable association of these two factors implies the growing need for care in this type of population, which consequently enhances the need for informal caregivers, whose role in most situations is assumed by the family caregiver (MARTINS et al, 2014). In this sense, the need for investment in the area of home care arose, since its objective is to provide the highest possible quality of life to the patient/family/informal caregiver, nothing seems more important than the training of the C.I. in aspects as simple as self-care, but at the same time as physically demanding as self-care transferring oneself, the prevention of complications inherent to the immobility of the dependent person, as well as the prevention of musculoskeletal injuries of the caregiver, being crucial for a care of good quality. In this sense, and inserted in the development of the Professional Nature stage, the present research emerged, which was a study on the training of the informal caregiver of the dependent person at home in the self-care transference, whose general objective is to train the Informal Caregiver to care of the dependent person within the scope of self-care to transfer. And as specific objectives, the following were defined: • Identify what knowledge informal caregivers of dependent people at home have about immobility complications; • Knowing the difficulties of informal caregivers regarding placements/mobilizations; • Identify weaknesses and training needs of informal caregivers; • Carrying out formal and informal training actions at home, according to the training weaknesses of informal caregivers; • Understand the reasons that lead informal caregivers to non-adherence to the uprisings of their dependents. The methods used for data collection were direct observation in the internship field, interviews with caregivers of dependent people at home. This study aimed to contribute to the prevention of complications inherent to the immobility of dependent people and to contribute to the prevention of musculoskeletal injuries in caregivers of dependent people. With this present study, it was possible to show that most C.I.'s are women, daughters of dependents and experiencing a situation of unemployment. They were not trained to perform this task of caring and many developed this ability by watching others do it, or empirically. Most caregivers do not feel capable of mobilizing their dependent on their own and therefore adopt vicious positions to do so, developing SCI. The method used in this research was the action investigation in which the researcher corrected/acted on the C.I. during its research enabling the C.I. in self-care transfer. It was a qualitative investigation, in which the researcher, after gathering data on the reality of the C.I.'s and identifying their needs, developed a training action in order to train the Informal Caregiver, leaving support material such as the Caregiver's manual, pamphlets and multimedia material (video) technical support material for this purpose. Finally, it was found that due to the existing gaps in terms of this problem, it makes perfect sense to create intervention programs to support the prevention of immobility complications, the development of studies that generate intervention models and that aim to promote self-care transfer and the training of the C.I., as well as the support and remuneration of the C.I.'s, as they see their task as a social imposition, castrating all their financial and social development, making caring for their dependents regretful.

Assessment of indoor radon concentration and time-series analysis of gamma dose rate in three thermal spas from Portugal.

This work is a follow-up study on the exposure to indoor radon levels in Portuguese thermal spas. The previous research involved 16 thermal spas, where radon measurements in air and thermal mineral water were performed twice a year, from 2012 to 2016. These studies revealed concerning radon concentrations both in air and water. Therefore, a follow-up study on long-term radon measurements was conducted to estimate the year-round average radon exposure. The closer the long-term measurement is to 365 days, the more representative it will be of annual average radon levels. Continuous measurements over 1 year for the indoor radon levels are now presented for three of the 16 previously studied thermal spas, together with a time-series analysis of the gamma dose rates registered within the facilities of these thermal spas (TS). An attempt to identify possible patterns in the variation of gamma dose rates was made. Hourly gamma dose rates were modelled and forecasted using the Box-Jenkins seasonal time series models (SARIMA). The results showed that between December 2018 and November 2019, the indoor radon concentration varied from 202 to 1941 Bq/m3 (TS1), from 52 to 191 Bq/m3 (TS2), and from 937 to 1750 Bq/m3 (TS3). Approximately 60% of the obtained values for radon concentration in the indoor air exceed the reference level of 300 Bq/m3. Gamma dose rates were continuously measured with GAMMA SCOUT® detectors for hourly readings (µSv/h) between 83 and 229 days. On average, the results are similar in all considered locations and range between 0.169 and 0.264 µSv/h, although variations are different in winter and summer. The calculated effective doses ranged between 3.49 and 18.65 mSv/year (TS1), between 1.37 and 2.53 mSv/year (TS2), and between 13.89 and 22.97 mSv/year (TS3). For occupational exposure purposes, workers would be classified as category A in nine locations (out of 20), as the exposure is liable to exceed an effective dose of 6 mSv/year. For the time-series analysis, the obtained models captured the dynamics of the time series data and produced short-term forecasts. Their accuracies have been quantified by minimizing the root mean square error, the mean absolute error due to the actual forecast, and the mean absolute scaled error. The current results corroborate the conclusions of previous research and give continuous data on occupational exposure to radon for three Portuguese thermal spas. For TS1 and TS3, the indoor radon levels are much higher than the reference level. Under this circumstance, mitigation measures must be implemented to reduce the radon levels accordingly with the Euratom Directive 2013/59 and the Decree-Law No. 108/2018. In general, the gamma dose rates were below 1 µSv/h and, therefore, the contribution to the annual effective dose is not significant. Nevertheless, the variation of the gamma dose rates showed a coherent behavior with the radon progeny build up in closed spaces, as when the considered facilities were closed for certain periods. The time series analysis made it possible to fit some models to the gamma dose rate variation, and although the produced models cannot forecast exact gamma dose rates, they can provide valuable information to build sound planning and decision-making strategies in occupational exposure.

Bioengineered Hierarchical Bonelike Compartmentalized Microconstructs Using Nanogrooved Microdiscs.

Fabrication of vascularized large-scale constructs for regenerative medicine remains elusive since most strategies rely solely on cell self-organization or overly control cell positioning, failing to address nutrient diffusion limitations. We propose a modular and hierarchical tissue-engineering strategy to produce bonelike tissues carrying signals to promote prevascularization. In these 3D systems, disc-shaped microcarriers featuring nanogrooved topographical cues guide cell behavior by harnessing mechanotransduction mechanisms. A sequential seeding strategy of adipose-derived stromal cells and endothelial cells is implemented within compartmentalized, liquefied-core macrocapsules in a self-organizing and dynamic system. Importantly, our system autonomously promotes osteogenesis and construct's mineralization while promoting a favorable environment for prevascular-like endothelial organization. Given its modular and self-organizing nature, our strategy may be applied for the fabrication of larger constructs with a highly controlled starting point to be used for local regeneration upon implantation or as drug-screening platforms.

Freestanding Magnetic Microtissues for Tissue Engineering Applications.

A long-sought goal in tissue engineering (TE) is the development of tissues able to recapitulate the complex architecture of the native counterpart. Microtissues, by resembling the functional units of living structures, can be used to recreate tissues' architecture. Howbeit, microfabrication methodologies fail to reproduce cell-based tissues with uniform shape. At the macroscale, complex tissues are already produced by magnetic-TE using solely magnetized cells as building materials. The enhanced extracellular matrix (ECM) deposition guaranties the conservation of tissues' architecture, leading to a successful cellular engraftment. Following the same rational, now the combination of a versatile microfabrication-platform is proposed with magnetic-TE to generate robust micro-tissues with complex architecture for TE purposes. Small tissue units with circle, square, and fiber-like shapes are designed with high fidelity acting as building blocks for engineering complex tissues. Notably, freestanding microtissues maintain their geometry after 7 days post-culturing, overcoming the challenges of microtissues fabrication. Lastly, the ability of microtissues in invading distinct tissue models while releasing trophic factors is substantiated in methacryloyl laminarin (LAM) and platelet lysates (PLMA) hydrogels. By simply using cells as building units and such microfabrication-platform, the fabrication of complex multiscale and multifunctional tissues with clinical relevance is envisaged, including for therapies or disease models.

Metabolic syndrome is associated with prostate enlargement: a systematic review, meta-analysis, and meta-regression on patients with lower urinary tract symptom factors.

BACKGROUND: Metabolic syndrome (MetS) is defined by at least three of the following five criteria: blood pressure ⩾130/85 mmHg, fasting blood glucose ⩾5.6 mmol/l, triglycerides concentration ⩾1.7 mmol/l, waist circumference ⩾102 cm (for men), and high-density lipoprotein cholesterol concentration <1.03 mmol/l (for men). MetS has been associated with worse lower urinary tract symptoms (LUTS) and higher International Prostate Symptom questionnaire scores. MATERIALS AND METHODS: MEDLINE, Cochrane, ClinicalTrials.gov, and SCOPUS were critically appraised for all peer-reviewed manuscripts that suitably fulfilled our protocol's inclusion criteria established a priori. Meta-analytical and meta-regression calculations were performed in R using the Sidik-Jonkman and Hartung-Knapp random effects model and predefined covariates. RESULTS: A total of 70 studies (n = 90,206) were included in qualitative synthesis. From these, 60 studies focused on MetS and LUTS: 44 reported positive correlations, 5 reported negative correlations, 11 reported no association, and 10 studies focused on MetS and total prostate volume (TPV). MetS positively correlated with moderate LUTS [odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.35-1.80], severe LUTS (OR = 2.35, 95% CI = 1.82-3.03), overactive bladder (OAB; OR = 3.2, 95% CI = 1.6-5.8), and nocturia severity (OR = 2.509, 95% CI = 1.571-4.007) at multivariate analysis. A total of 30 studies (n = 22,206) were included in meta-analysis; MetS was significantly associated with higher TPV (mean differences = 4.4450 ml, 95% CI = 2.0177-6.8723), but no significant predictive factors for effect sizes were discovered. CONCLUSION: Our meta-analysis demonstrates a significant association between the aggravating effects of MetS, which commonly coexists with obesity and benign prostate enlargement.

Structure-Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes.

Several new synthetic cathinones, which mimic the effect of classical psychostimulants such as cocaine or MDMA, have appeared in the global illicit drug market in the last decades. In fact, the illicit drug market is continually evolving by constantly adding small modifications to the common chemical structure of synthetic cathinones. Thus, the aim of this study was to investigate the in vitro and in vivo structure-activity relationship (SAR) of six novel synthetic cathinones currently popular as recreational drugs, pentedrone, pentylone, N-ethyl-pentedrone (NEPD), N-ethyl-pentylone (NEP), 4-methyl-pentedrone (4-MPD), and 4-methyl-ethylaminopentedrone (4-MeAP), which structurally differ in the absence or presence of different aromatic substituents and in their amino terminal group. Human embryonic kidney (HEK293) cells expressing the human isoforms of SERT and DAT were used for the uptake inhibition and release assays. Moreover, Swiss CD-1 mice were used to investigate the psychostimulant effect, rewarding properties (3, 10, and 30 mg/kg, i.p.), and the induction of immediate-early genes (IEGs), such as Arc and c-fos in the dorsal striatum (DS) and ventral striatum (VS) as well as bdnf in the medial prefrontal cortex (mPFC), of the test compounds. Our results demonstrated that all tested synthetic cathinones are potent dopamine (DA) uptake inhibitors, especially the N-ethyl analogs, while the ring-substituted cathinones tested showed higher potency as SERT inhibitors than their no ring-substituted analogs. Moreover, unlike NEP, the remaining test compounds showed clear "hybrid" properties, acting as DAT blockers but SERT substrates. Regarding the locomotion, NEP and NEPD were more efficacious (10 mg/kg) than their N-methyl analogs, which correlates with their higher potency inhibiting the DAT and an overexpression of Arc levels in the DS and VS. Furthermore, all compounds tested induced an increase in c-fos expression in the DS, except for 4-MPD, the least effective compound in inducing hyperlocomotion. Moreover, NEP induced an up-regulation of bdnf in the mPFC that correlates with its 5-HTergic properties. Finally, the present study demonstrated for the first time that NEP, 4-MPD, and 4-MeAP induce reward in mice. Altogether, this study provides valuable information about the mechanism of action and psychostimulant and rewarding properties as well as changes in the expression of IEGs related to addiction induced by novel second-generation synthetic cathinones.

Healthcare professional's choice for surgical management of stress urinary incontinence in a U.K. tertiary hospital.

OBJECTIVE: In July 2018, NHS England, introduced a pause on vaginal mesh, including the mid-urethral sling (MUS) for treatment of stress urinary incontinence (SUI). NICE guidelines recommend MUS as one of the surgical options for SUI. The aim of our study was to investigate healthcare professionals choices for surgical treatment of SUI, if conservative measures failed. STUDY DESIGN: The urogynaecology department at our tertiary level hospital devised a questionnaire using SurveyMonkey. This was distributed via email to 1058 healthcare professionals of different medical backgrounds. The surgical options were based on the NICE guideline and its patient decision making aid. We also used surgical information from the British society of Urogynaecology (BSUG) and British association of urological surgeons (BAUS). RESULTS: We received 214 responses of which 204 were complete. Twenty six percent of replies were from obstetricians and gynaecologists, 36 % had over 20 years experience and 79 % were female. Forty four percent had no previous knowledge of surgical options. Mid-urethral sling was the most popular choice based on description, success and specific complications. Urethral bulking agent was the only option that increased in popularity after describing complications. Twenty two percent would avoid surgery due to the risk of complications. CONCLUSION: This is the first study evaluating healthcare professionals surgical choice for SUI. Despite negative media publicity and NHS pause on MUS, it was still the most popular choice before and after informing of specific complications. The urethral bulking agent was the only surgical treatment, which increased in popularity after considering complications.

Weight loss with bariatric surgery or behaviour modification and the impact on female obesity-related urine incontinence: A comprehensive systematic review and meta-analysis.

Women with obesity are at risk of pelvic floor dysfunction with a 3-fold increased incidence of urge urinary incontinence (UUI) and double the risk of stress urinary incontinence (SUI). The National Institute for Health and Care Excellence (NICE) and European Association of Urology (EAU) recommend that women with a body mass index ≥30 kg/m2 should consider weight loss prior to consideration for incontinence surgery. This systematic review and meta-analysis will assess this recommendation to aid in the counselling of women with obesity-related urinary incontinence (UI). Medical Literature Analysis and Retrieval System online (MEDLINE), EMBASE, Cochrane, ClinicalTrials.gov, and SCOPUS were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori and presented original, empirical data relevant to weight loss intervention in the management of urinary incontinence. Thirty-three studies and their outcomes were meta-analysed. Weight loss interventions were associated in a decreased prevalence in UI (OR 0.222, 95% CI [0.147, 0.336]), SUI (OR 0.354, 95% CI [0.256, 0.489]), UUI (OR 0.437, 95% CI [0.295, 0.649]) and improved quality of life (PFDI-20, SMD -0.774 (95% CI [-1.236, -0.312]). This systematic review and meta-analysis provide evidence that weight loss interventions are effective in reducing the prevalence of obesity-related UI symptoms in women. Bariatric surgery in particular shows greater sustained weight loss and improvements in UI prevalence. Further large scale, randomized control trials assessing the effect of bariatric surgery on women with obesity-related UI are needed to confirm this study's findings.

Modern management of genitourinary syndrome of menopause.

The genitourinary syndrome of menopause (GSM) is the accepted term used to describe the broad spectrum of genitourinary tract symptoms and signs caused by the loss of endogenous sex steroids that occurs at the time of and after the menopause. Global improvements in healthcare have resulted in an ageing population. Today, women are spending 40% of their lives in the postmenopausal state, and with 50-70% of postmenopausal women reporting symptomatic GSM, safe and efficacious treatments are needed for this troublesome condition. This article reviews current evidence for non-pharmacological and pharmacological treatments with a focus on novel and minimally invasive procedures such as energy-based devices (CO2 laser, YAG laser), hyaluronic acid, dehydroepiandrosterone, and selective oestrogen receptor modulators.

Defining nocturnal polyuria in women.

AIMS: Nocturnal polyuria (NP) is defined by the International Continence Society (ICS) as "excessive production of urine during the main sleep period" and is one of the main causes of nocturia. The ICS recognized that "excessive" is not clearly defined and that this needs to be highlighted in both clinical and research settings. The aim of this study was to identify different definitions of NP and apply them to a population of women attending the Urogynaecology clinic. METHODS: This was a retrospective study of complete bladder diaries collected from women attending a tertiary Urogynaecology Unit. Six different definitions were identified and were divided into "absolute," "relative," and "functional definitions." Prevalence data were calculated and values generated for sensitivity, specificity, positive and negative predictive values when related to women voiding ≥ 2 times per night. RESULTS: Complete bladder diaries were obtained from 1398 women, over 6 years, with a mean age of 57 years. Prevalence varied across the definitions from 21.5% (absolute definition) to 77% (relative definition). Sensitivity ranged from 43% (absolute) to 87% (relative). The definitions that showed the highest combined sensitivity and specificity were the functional definitions. CONCLUSION: From this study it is clear that more work needs to be done to arrive at a consensus for defining NP to enable accurate diagnosis and development of treatment pathways. We propose that a relative definition may provide a more clinically relevant method of defining NP.

Recent advances in managing overactive bladder.

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. In this review, we focus on recent advances in the management of OAB. We examine the evidence on the effect of anticholinergic load on OAB patients. Advances in medical treatment include a new beta-3 agonist, vibegron, which is thought to have fewer drug interactions than mirabegron. Treatment of genitourinary syndrome of the menopause with oestrogens and ospemifene have also shown promise for OAB. Botulinum toxin has been shown to be an effective treatment option. We discuss the new implantable neuromodulators that are on the market as well as selective bladder denervation and laser technology.

Recent advances in urodynamics in women.

Urodynamics is the study of the storage and evacuation of urine from the urinary tract. The aim is to reproduce the patient's symptoms and provide a pathophysiological explanation for them by identifying all factors that contribute to the lower urinary tract dysfunction, including those that are asymptomatic. Urodynamics consists of various tests, each of which is designed to assess a different aspect of lower urinary tract function. There is a lack of evidence regarding when urodynamics should be used in the non-neurogenic bladder. Some small randomised controlled trials suggest that urodynamics does not alter the outcome of surgery for stress urinary incontinence when compared with office evaluation alone. However, this is widely felt to be inaccurate and many health-care professionals still advocate the use of urodynamics prior to any invasive treatment, especially surgery on the lower urinary tract. There have been few technological advances in urodynamics in recent years. Air-charged rather than fluid-filled catheters were thought to help reduce artefact, but the evidence is unclear, and there is doubt over their accuracy. Ambulatory urodynamics is carried out over a longer period of time, enabling physiological bladder filling, but it remains invasive and artificial. To attempt to replicate symptoms more accurately, there have been efforts to develop wireless devices to measure detrusor pressure directly. These may be promising but are far from suitable in humans at present. Urodynamics continues to provide useful information for assessing lower urinary tract function, but further large studies are required to assess its value and develop innovations to improve the accuracy of the tests and acceptability to patients.