Free energy profile of the substrate-induced occlusion of the human serotonin transporter.

The serotonin transporter (SERT) is a member of the Solute Carrier 6 (SLC6) family and is responsible for maintaining the appropriate level of serotonin in the brain. Dysfunction of SERT has been linked to several neuropsychiatric disorders, including depression, anxiety and obsessive-compulsive disorder. Therefore, an in-depth understanding of the mechanism on an atomistic level, coupled with a quantification of transporter dynamics and the associated free energies is required. Here, we constructed Markov state models (MSMs) from extensive unbiased molecular dynamics simulations to quantify the free energy profile of serotonin (5HT) triggered SERT occlusion and explored the driving forces of the mechanism of occlusion. Our results reveal that SERT occludes via multiple intermediate conformations and show that the motion of occlusion is energetically downhill for the 5HT-bound transporter. Force distribution analyses show that the interactions of 5HT with the bundle domain are crucial. During occlusion, attractive forces steadily increase and pull on the bundle domain, which leads to SERT occlusion. Some interactions become repulsive upon full occlusion, suggesting that SERT creates pressure on 5HT to promote its movement towards the cytosol.

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.

Research evidence communication for policy-makers: a rapid scoping review on frameworks, guidance and tools, and barriers and facilitators.

BACKGROUND: Communication is a multifaceted process, ranging from linear, one-way approaches, such as transmitting a simple message, to continuous exchanges and feedback loops among stakeholders. In particular the COVID-19 pandemic underscored the critical need for timely, effective and credible evidence communication to increase awareness, levels of trust, and evidence uptake in policy and practice. However, whether to improve policy responses in crises or address more commonplace societal challenges, comprehensive guidance on evidence communication to decision-makers in health policies and systems remains limited. Our objective was to identify and systematize the global evidence on frameworks, guidance and tools supporting effective communication of research evidence to facilitate knowledge translation and evidence-informed policy-making processes, while also addressing barriers and facilitators. METHODS: We conducted a rapid scoping review following the Joanna Briggs Manual. Literature searches were performed across eight indexed databases and two sources of grey literature, without language or time restrictions. The methodological quality of included studies was assessed, and a narrative-interpretative synthesis was applied to present the findings. RESULTS: We identified 16 documents presenting either complete frameworks or framework components, including guidance and tools, aimed at supporting evidence communication for policy development. These frameworks outlined strategies, theoretical models, barriers and facilitators, as well as insights into policy-makers' perspectives, communication needs, and preferences. Three primary evidence communication strategies, comprising eleven sub-strategies, emerged: "Health information packaging", "Targeting and tailoring messages to the audience", and "Combined communication strategies". Based on the documented barriers and facilitators at micro, meso and macro levels, critical factors for successful communication of evidence to policy-makers were identified. CONCLUSIONS: Effective communication is indispensable for facilitating knowledge translation and evidence-informed policy-making. Nonetheless gaps persist in frameworks designed to enhance research communication to policy-makers, particularly regarding the effectiveness of multiple communication strategies. To advance in this field, the development of comprehensive frameworks incorporating implementation strategies is warranted. Additionally, barriers and facilitators to implementing effective communication must be recognized and addressed taking diverse contexts into consideration. Registration https://zenodo.org/record/5578550.

Renal biomarkers, clinical parameters, and renal Doppler velocimetry in bitches with cystic endometrial hyperplasia-pyometra complex.

Cystic endometrial hyperplasia (CEH)-pyometra complex is the most common uterine infection in adult and elderly bitches and can cause renal dysfunction. The aim of this study was to measure and compare urinary creatinine, urea, symmetric dimethylarginine (SDMA), urinary protein-creatinine ratio (UPC), measurement of systolic blood pressure (SBP), and Doppler velocimetry of renal arteries in patients with CEH-pyometra complex before and after an average of 6 months of treatment, evaluating the possibility of the changes persisting. The evaluation was conducted at two moments: M1 (at the diagnosis of CEH-pyometra, n = 36) and M2 (after an average of six months of treatment, n = 16). For the control group, eight bitches with no changes in blood tests or history of conditions underwent Doppler ultrasound evaluation of the renal arteries. At both M1 and M2, we measured creatinine, urea, and serum SDMA, UPC, SBP, and Doppler ultrasound of the renal arteries. Patients were evaluated according to the following groups: azotemic (AZO) and non-azotemic (NAZO), and open and closed cervix pyometra. The parameters were compared between animals present in both moments presented as M1R (bitches that were in M1 and M2) and M2. Statistical significance was considered when p < .05. The medians found for creatinine in M1 were as follows: 1.15 mg/dL, being 1.8 mg/dL for AZO (12/36) and 0.95 mg/dL for NAZO (24/36); and in M2: 0.85 mg/dL (16/16), being 1.15 mg/dL for AZO (4/16) and 0.8 mg/dL for NAZO (12/36). For urea, in M1 it was 36 mg/dL (32/36), with AZO being 103 mg/dL (11/32) and 33 mg/dL in NAZO (21/32); and in M2 32 mg/dL (16/ 16), being 29 mg/dL for AZO (4/36), and 31 mg/dL for NAZO (3/15). The median SDMA measured in M1R was 17 µg/dL (15/16), with AZO being 31 µg/dL (3/15), and NAZO being 16.5 µg/dL (12/15); and in M2, SDMA was 12 µg/dL (16/16), with AZO being 12.5 µg/dL (4/16), and NAZO being 12 µg/dL (12/16). The median UPC measured in M1 was 1.15 (10/36), with AZO being 0.25 (1/10), and NAZO being 1.38 (9/10); and in M2, it was 0.2 (13/16), being 0.1 in AZO (4/13), and 0.2 (9/16) in NAZO. For SBP, in M1, it was 118 mmHg (30/36), with AZO being 102 mmHg (10/30) and 133 mmHg in NAZO (20/30); and in M2 142.5 mmHg (12/16), being 155 mmHg for AZO (4/12), and 140 mg/dL for NAZO (8/12). When comparing animals with open and closed cervixes, a difference was found between SDMA measurements (p = .001). There was a distinction between PI and RI of the left and right kidneys consecutively (p = .007; p = .033; p = .019; p = .041). Correlations found in M1: SDMA × PI RIM DIR (r = 0.873; p = .002), SDMA × PSV RIM ESQ (r = 0.840; p = .004), SDMA × EDV RIM ESQ (r = 0.675; p = .046). With this study, we conclude a return to normality of renal biomarkers and clinical parameters after six months. Yet, there is a persistence of Doppler velocimetric measurements between the two moments. Thus, this parameter is not suitable for identifying and classifying chronic kidney injury in bitches with pyometra.

Characteristics and Risk Factors of Central Nervous System Infection in Children With Febrile Seizures.

OBJECTIVE: The aim of the present study is to evaluate the necessity of performing lumbar puncture in patients experiencing febrile seizures, considering the epidemiology specific to Brazil. METHODS: A retrospective cross-sectional study was performed from January 2017 to December 2021. RESULTS: A total of 469 children with seizure and fever were analyzed. The identified event was the first in 65.9% (n = 309). A total of 54.2% (n = 254) of patients had a simple febrile seizure. Infectious focus, excluding previous central nervous system (CNS) infection, was identified in 35.6% (n = 167) patients. Meningitis was identified in 7.7% (n = 36) patients, all of them were viral. Patients with CNS infection had a higher frequency of symptoms such as nausea and vomiting, drowsiness, headache, and higher level of leukocytosis. A longer duration of fever was found to be more strongly associated with CNS infection. CONCLUSIONS: When considering the use of lumbar puncture in febrile seizure, it is important to conduct a comprehensive evaluation that considers multiple factors, including clinical signs, symptoms, and the overall clinical context. Meningeal signs may be less prominent, and other symptoms such as lethargy, irritability, and vomiting may serve as more reliable indicators. Although clinical examination suggestive of meningitis remains an important factor, the recurrence of febrile seizures and a longer length of fever can provide additional insights and aid in decision-making regarding lumbar puncture.

[Evidence for Health Promotion in Brazil: report on a rapid response serviceEvidencia para la promoción de la salud en Brasil: informe sobre un servicio de respuesta rápida]. / Evidências para a Promoção da Saúde no Brasil: relato de um serviço de resposta rápida.

Objective: Present the experience of a rapid response service to support decision-making in health systems. Methodology: Description of the processes and results of a service that produces rapid reviews and evidence maps to support decision-making under the National Health Promotion Policy, as well as the authors' perception of the work process. Results: The rapid response service started in 2020. By December 2023, 54 rapid reviews and five evidence maps had been produced, covering nine health promotion topics. These products were developed in 14 stages by a team made up of a coordinator, supervisors, proofreaders, and a librarian. The development of rapid responses involved a knowledge translation process, with continuous interactions between the requesting teams and production teams. Establishing effective communication was a critical factor in delivering products on time and in line with the needs of decision-makers and their supporters. Conclusion: Rapid response services can help improve the use of evidence for decision-making in health policies and health systems.

Objetivo: Presentación de la experiencia de un servicio de respuesta rápida para brindar apoyo a la toma de decisiones en materia de salud. Método: Se describen los procesos y resultados de un servicio de elaboración de revisiones rápidas y mapas de evidencia para brindar apoyo a la toma de decisiones en el marco de la Política Nacional de Promoción de la Salud, así como la percepción de los autores sobre el proceso de trabajo. Resultados: El servicio de respuesta rápida se inició en el 2020. Hasta diciembre del 2023, se habían elaborado 54 revisiones rápidas y cinco mapas de evidencia, que abarcaban nueve temas de promoción de la salud. Estos productos fueron elaborados en 14 etapas por un equipo formado por un coordinador, varios supervisores y revisores y un bibliotecario. La elaboración de respuestas rápidas fue un proceso de traducción del conocimiento e implicó una interacción continua entre los equipos solicitantes y el equipo de elaboración. El establecimiento de una comunicación eficaz fue un factor decisivo para entregar los productos a tiempo y en consonancia con las necesidades de los responsables de la toma de decisiones y su personal de apoyo. Conclusión: Los servicios de respuesta rápida pueden ayudar a mejorar el uso de evidencia en la toma de decisiones relacionadas con las políticas y los sistemas de salud.

A New Real-Time Simple Method to Measure the Endogenous Nitrate Reductase Activity (Nar) in Paracoccus denitrificans and Other Denitrifying Bacteria.

The transmembrane nitrate reductase (Nar) is the first enzyme in the dissimilatory alternate anaerobic nitrate respiratory chain in denitrifying bacteria. To date, there has been no real-time method to determine its specific activity embedded in its native membrane; here, we describe such a new method, which is useful with the inside-out membranes of Paracoccus denitrificans and other denitrifying bacteria. This new method takes advantage of the native coupling of the endogenous NADH dehydrogenase or Complex I with the reduction of nitrate by Nar through the quinone pool of the inner membranes of P. denitrificans. This is achieved under previously reached anaerobic conditions. Inner controls confirming the specific Nar activity determined by this new method were made by the total inhibition of the Nar enzyme by sodium azide and cyanide, well-known Nar inhibitors. The estimation of the Michaelis-Menten affinity of Nar for NO3- using this so-called Nar-JJ assay gave a Km of 70.4 µM, similar to previously determined values. This new Nar-JJ assay is a suitable, low-cost, and reproducible method to determine in real-time the endogenous Nar activity not only in P. denitrificans, but in other denitrifying bacteria such as Brucella canis, and potentially in other entero-pathogenic bacteria.

World trends in publication for maxillofacial and dental trauma in the elderly.

Aging may increase the risk of maxillofacial and dentoalveolar trauma (MDT). This review assessed global trends in scientific publications on MDT in the elderly. Six databases were searched. Studies about MDT in the elderly (≥60 years old) were included in two text mining stages (S1 and S2). In S1, all studies with elderly subjects were included, while in S2 only studies in which the elderly were assessed in a separate set of data or in a subanalysis by age groups were included. In S1, relevant data were mined using VantagePoint™ software. In S2, data were descriptively analyzed. There were 2265 studies at S1 and 110 at S2. The publication dates spanned from 1963 to 2023. In S1, the most cited keywords and terms were aged (n = 1872), male (n = 1839), female (n = 1777), "mandible fracture" (n = 460), "orbit fracture" (n = 362), and "maxilla fracture" (n = 118). Thirty authors published 10 or more articles with visible collaboration networks. There was a progressive increase in publications, especially in Europe (n = 150). In S2, most studies were case reports/case series (n = 62). The primary etiology was accidental falls (n = 84), the most affected region was the middle third of the face (n = 65), and dental trauma was rarely reported (n = 15). Cone Beam computed tomography was the most used diagnostic tool (n = 67). Of the 81 articles that addressed therapy, 52 opted for surgical treatment. Although there has been an increase in the number of articles on MDT over the years, studies with the elderly population as a specific study group are still needed. Accidental falls were the most reported etiology, while the middle third of the face and the mandible were the anatomic region and bone most affected, respectively. The high number of case reports indicates the need for improvement in the available scientific evidence about MDT in the elderly.

Survey of Rickettsia spp. in ticks (Acari: Ixodidae) infesting opossums (Didelphis albiventris) and capybaras (Hydrochoerus hydrochaeris) from an urban park in southeastern Brazil.

Ticks are hematophagous arthropods and, during feeding, may transmit pathogens to vertebrate hosts, including humans. This study aimed to investigate the presence of Rickettsia spp. in ticks collected between 2010 and 2013 from free-ranging capybaras (Hydrochoerus hydrochaeris) and opossums (Didelphis albiventris) that inhabit Sabiá Park in Uberlândia, Brazil. Overall, 1,860 ticks were collected: 1,272 (68.4%) from capybaras (487 of the species Amblyomma sculptum, 475 adults and 12 nymphs; 778 Amblyomma dubitatum, 727 adults and 51 nymphs; and seven larva clusters of the genus Amblyomma); and 588 (31.6%) from opossums (21 A. sculptum, one adult and 20 nymphs; 79 A. dubitatum, all nymphs; 15 Ixodes loricatus, 12 adults and three nymphs; 457 Amblyomma sp. larva clusters; 15 Ixodes sp. larva clusters; and one Argasidae larva cluster). Out of 201 DNA samples tested for the presence of Rickettsia spp. DNA using polymerase chain reaction (PCR) 12 showed amplification of a gtlA gene segment that was specific to Rickettsia bellii, a bacterium non-pathogenic to humans. As there has been a report showing serological evidence of infections caused by Rickettsia species of the spotted fever group (SFG) in capybaras and opossums in the park, including Rickettsia rickettsii, the etiological agent of Brazilian spotted fever, and considering the presence of A. sculptum ticks, which are aggressive to humans, as well as these vertebrate hosts, which are amplifiers of R. rickettsii, it is important to monitor the presence of SFG rickettsiae in the Sabiá Park, which is visited daily by thousands of people.

Effect of Prenatal Care on Perinatal Outcomes of Pregnant Women with Diabetes Mellitus: A Systematic Review.

Objective: to evaluate the effect of prenatal care (PC) on perinatal outcomes of pregnant women with diabetes mellitus (DM). Methods: systematic review developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines and conducted through the population, intervention, control, and outcomes (PICO) strategy. Clinical trials and observational studies were selected, with adult pregnant women, single-fetus pregnancy, diagnosis of DM, or gestational DM and who had received PC and/or nutritional therapy (NT). The search was carried out in PubMed, Scopus, and BIREME databases. The quality of the studies was evaluated using the tools of the National Heart, Lung and Blood Institute-National Institutes of Health (NHLBI-NIH). Results: We identified 5972 records, of which 15 (n=47 420 pregnant women) met the eligibility criteria. The most recurrent outcomes were glycemic control (14 studies; n=9096 participants), hypertensive disorders of pregnancy (2; n=39 282), prematurity (6; n=40 163), large for gestational age newborns (4; n=1556), fetal macrosomia (birth weight >4kg) (6; n=2980) and intensive care unit admission (4; n=2022). Conclusions: The findings suggest that PC interferes with the perinatal outcome, being able to reduce the risks of complications associated with this comorbidity through early intervention, especially when the NT is an integral part of this assistance.

Black soldier fly (Hermetia illucens) larvae meal improves quail growth performance.

The aim of the present study was to determine the nutritional value of black soldier fly (BSF) larvae meal for quail (experiment I) and the dose-response effects of BSF levels on growth performance, relative organ weight, and body composition of growing quails (experiment II). In experiment I, 100 35-day-old quail were distributed in a completely randomized design, with two treatments (reference and test diet) and 10 replicates. The experimental period consisted of 5 days of adaptation, followed by 5 days of total excreta collection. The experimental feed consisted of a reference diet and a test diet formulated with 850 g/kg reference diet and 150 g/kg BSF. In experiment II, 1000 1-day-old quail were distributed in a completely randomized design, with five dietary levels of BSF (0, 25, 50, 75, and 100 g/kg). At 42 days of age, birds were slaughtered, and the relative organ weight and body composition were determined. Apparent metabolizable energy values corrected for nitrogen retention of BSF meal were 13.8 MJ/kg. Across the starter (1-14 days) and overall period (1-42 days), increasing BSF levels had a quadratic effect on body weight and body weight gain. Feed conversion ratio was quadratically affected during the starter phase and linearly reduced over the overall period. Additionally, the BSF levels linearly decreased the small intestine's relative weight at 42 days and had a quadratic effect on the rate of protein deposition. We concluded that the inclusion of 100 g/kg BSF meal improves feed conversion ratio for growing quail.

Injectable progesterone in 13-month-old prepubertal Nellore heifers: effects on in vitro embryo production and pregnancy rate.

The aim of this study was to evaluate the effect of injectable progesterone administration before ovum pick-up (OPU) on in vitro embryo production (IVEP) and pregnancy rate in prepubertal Nellore heifers. Twenty-three Nellore females, 13.04 ± 0.8 months of age, were randomly assigned to two groups: control group (no progesterone application) and progesterone group (intramuscular administration of 1 mL [150 mg/mL] progesterone 7 days before OPU). The second OPU was performed after 28 days (crossover between groups). After OPU, oocytes were selected for IVEP and a sample was fixed in 4% paraformaldehyde. Viable oocytes were subjected to immunofluorescence staining for IGFBP2 and caspase-3. For each oocyte, one image was generated per channel (A555 and A488 filters) and analyzed with the ImageJ program for the quantification of fluorescence intensity (in pixels). The produced embryos were transferred to multiparous Nellore cows and pregnancy was diagnosed by ultrasound 30 days after transfer. Data were analyzed using the MIXED and GLIMMIX procedure of SAS®. Treatment with injectable progesterone had no effect on the number or size of the antral follicles of heifers. No differences between the control and progesterone groups were observed for total number of aspirated oocytes (P = 0.78), viable oocytes (P = 0.80), cleavage rate (P = 0.60), or blastocyst rate (P = 0.56). There were no differences in pixel intensity between the two groups, nor in the levels of IGFBP2 or caspase-3. However, a difference was observed in the pregnancy rate of embryos produced from heifers of the progesterone group (42.1%; 32/76) when compared to the rate of embryos produced from control heifers (28.4%; 23/81) (P = 0.02). The use of injectable progesterone before OPU in prepubertal Nellore heifers does not improve IVEP but increases the pregnancy rate after transfer.

A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia.

To the best of our knowledge, this is the first case to address episodic ataxia (EA) as a possible phenotypic feature of HECW2-related disorder. This single case study describes a 26-year-old female born at term with mild intellectual disability, neonatal hypotonia, and a history of febrile seizures who presented with paroxysmal events since the age of 2. These episodes include frequent falls due to imbalance, dilated pupils, vertigo, diaphoresis, nausea, vomiting, and nystagmus. Brain imaging was normal. A prolonged electroencephalogram (EEG) revealed interictal epileptiform discharges but failed to capture her clinical events. For several years, she was treated for presumed focal seizures with preserved awareness and trialed on adequate dosing of several antiepileptic medications without improvement. After 25 years, given the more prolonged nature of her episodes and the mild interictal cerebellar signs, empiric treatment with acetazolamide was initiated for a presumed diagnosis of EA. Acetazolamide treatment led to a dramatic reduction in event frequency and severity. The initial EA genetic panel was negative. Clinical exome sequence analysis revealed a novel pathogenic de novo missense variant in the HECW2 gene [c.3829 T > C;(p.Tyr1277His)], located in the HECT domain. HECW2 variants are associated with neurodevelopmental delay, hypotonia, and epilepsy. This study expands the genetic and clinical spectrum of HECW2-related disorder and adds EA to the phenotypic spectrum in affected individuals.

The efficacy of an inactivated avian influenza H5N1 vaccine against an African strain of HPAI H5N8 (clade 2.3.4.4 B).

Highly pathogenic avian influenza (HPAI) viruses from the Goose/Guangdong/96-lineage emerged in Southeast Asia and subsequently spread to the Middle East, Africa and Europe, infecting a range of birds and mammals (including humans). This lineage of H5 viruses can efficiently establish itself in wild birds after circulating among gallinaceous poultry, facilitating reassortment with low pathogenic avian influenza (LPAI) virus strains, enhancing dispersal over long distances and contributing to endemicity. The detection of HPAI H5N8 virus (clade 2.3.4.4B) in 2017 in the Mpumalanga Province of South Africa marked the beginning of an epidemic that devastated the South African poultry industry. Vaccines were tested to assess protection against the circulating field strain. This article describes the performance of a reverse genetics inactivated H5N1 vaccine from Zoetis (RG-H5N1), with 96.1% identity to the circulating HPAI H5N8 virus. Two locally formulated benchmarks, one containing an H5N8 antigen homologous to the field strain (Benchmark-H5N8), the other containing a heterologous (87.6% identity to field virus) LPAI H5N1 antigen (Benchmark-H5N1), were included for comparison. Efficacy was assessed in specific pathogen-free (SPF) chickens using a prime-boost approach (injections at days 21 and 45), followed by a challenge with a South African HPAI H5N8 isolate (70 days of age). The Zoetis RG-H5N1 vaccine and Benchmark-H5N8 outperformed the Benchmark-H5N1 in terms of humoral response against the H5N8 antigen and reduction of shedding. The Zoetis RG-H5N1 vaccine protected 100% of the chickens against clinical disease and death. This study confirmed that antigenically matched inactivated vaccines could induce robust protection and markedly reduce viral shedding.RESEARCH HIGHLIGHTSConditionally licensed vaccine protected against HPAI H5N8 (clade 2.3.4.4B).Complete protection against clinical disease and mortality.Drastic reduction of viral shedding after challenge.

Grape juice reduces the effects of amyloid ß aggregation phenotype and extends the longevity in Caenorhabditis elegans.

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of aggregated amyloid-ß (Aß) peptides. Several natural compounds have been proposed against this disease and grape products are among these. However, little is known about grape juice potential. Transgenic Caenorhabditis elegans (C. elegans) strains that express human Aß have been used as an in vivo model for AD. METHODS: In this study, we have exposed CL2006 worms to nine different juices obtained from different cultivars. RESULTS: Cora, Bordo, Isabel, Isabel Precoce, BRS-Magna, BRS-Rubea and BRS-Violeta juices improved the behavioral phenotype (paralysis) that is caused by Aß aggregation in the transgenic animals at the concentrations tested and no toxic effects were found. Some juices were also able to increase the worm's lifespan. We could not attribute lifespan increase and paralysis reduction with any specific compound found in the phytochemical analysis. DISCUSSION: Our data indicate that the rich constitution of the juices is responsible for attenuating the phenotype caused by Aß aggregation in C. elegans.

Is Mobility Sufficient to Understand Community Participation of Adolescents and Young Adults With Cerebral Palsy? The Mediating and Moderating Roles of Contextual Factors.

OBJECTIVE: To explore whether self-determination and family socioeconomic status (SES) mediate and/or moderate the relationship between mobility and community participation of adolescents and young adults with cerebral palsy (CP). DESIGN: Survey. SETTING: Online platform. PARTICIPANTS: Of 55 eligible adolescents/young adults with CP, 50 agreed to participate and 2 were excluded. The final convenience sample included 48 individuals (N=48), aged 15-32 years, levels I-IV of the Gross Motor Function Classification System and I-II of the Communication Function Classification System. MAIN OUTCOME MEASURES: The Temple University Community Participation Measure documented the amount, breadth, and insufficiency/sufficiency ratios of participation across 26 community settings. The ARC Self-determination Scale and the Mobility Scale of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) measured individuals' self-determination (ie, autonomy, psychological empowerment, self-realization) and mobility skills, respectively. The Brazilian Economic Classification Criteria-2021 assessed family SES. RESULTS: Analyses of mediating/moderating effects revealed that the influence of individuals' mobility skills on their breadth of community participation was mediated by autonomy. Family SES moderated the indirect effect of mobility on community participation breadth through autonomy. When the model was adjusted for participants' age, individuals with higher SES reported greater breadth in community participation than those from moderate and lower SES for all mobility levels. However, the magnitude of the differences among individuals of different SES levels diminished as mobility increased. CONCLUSIONS: The mobility skills of youths with CP influence their community participation through autonomy. To foster greater engagement of these individuals in the community, rehabilitation professionals should focus not only on improvement of mobility skills but also on the promotion of self-determined behaviors, especially autonomy.

Development and validation of LC-MS/MS methods for the simultaneous quantification of sofosbuvir and its major metabolite (GS-331007) in blood plasma and cerebrospinal and seminal fluid: Application to a pilot clinical trial with a focus on Zika.

Zika still poses a threat to global health owing to its association with serious neurological conditions and the absence of a vaccine and treatment. Sofosbuvir, an anti-hepatitis C drug, has shown anti-Zika effects in animal and cell models. Thus, this study aimed to develop and validate novel LC-MS/MS methods for the quantification of sofosbuvir and its major metabolite (GS-331007) in human plasma and cerebrospinal (CSF) and seminal fluid (SF), and apply the methods to a pilot clinical trial. The samples were prepared by liquid-liquid extraction and separated using isocratic mode on Gemini C18 columns. Analytical detection was performed using a triple quadrupole mass spectrometer equipped with an electrospray ionization source. The validated ranges for sofosbuvir were 0.5-2,000 ng/mL (plasma) and 0.5-100 ng/mL (CSF and SF), while for the metabolite they were 2.0-2,000 ng/mL (plasma), 5.0-200 ng/mL (CSF) and 10-1,500 ng/mL (SF). The intra-day and inter-day accuracies (90.8-113.8%) and precisions (1.4-14.8%) were within the acceptance range. The developed methods fulfilled all validation parameters concerning selectivity, matrix effect, carryover, linearity, dilution integrity, precision, accuracy and stability, confirming the suitability of the method for the analysis of clinical samples.

Comparison of two pharmacological semen collection times with α2-adrenergic agonist in domestic cats.

The use of α2-adrenergic agonists in association with urethral catheterization has been used as a technique for pharmacological semen collection in cats. The mechanism of action of this drug is the stimulation of adrenoreceptors in the vas deferens, which results in ejaculation. While medetomidine is the α2-agonist most commonly used in studies, ejaculation with the use of dexmedetomidine associated with ketamine has been effective, but with variable results. Therefore, further studies regarding the methodology of use are required to obtain better seminal quality. This study aimed to compare two pharmacological semen collection times after the association of dexmedetomidine (30 µg/kg, IM; Dormitor®, Zoetis), ketamine (5 mg/kg, IM; ketamine, Vetnil) and urethral catheterization using a tomcat probe (0.8 mm × 1.00 mm × 11 cm). The collections were divided into two experimental groups: G10 (N = 8; urethral catheterization after 10 min of anaesthesia) and G15 (N = 8; urethral catheterization after 15 min of anaesthesia). The ejaculates were evaluated for ejaculate volume, sperm concentration, morphology and kinetics using the CASA system. To compare the groups, the t-test and the Mann-Whitney U-test were used with a significance level of 5%. It was identified that ejaculate volume (G10: 22.62 ± 2.13 vs. G15: 26.81 ± 1.55; p < .001) and sperm concentration (G10: 48.10 × 106 ± 17.84 vs. G15: 90.18 × 106 ± 19.35; p < .001) was higher in G15 than in G10 and had a lower percentage of minor defects than G10 (G10: 3.12 ± 2.41 vs. G15: 1.00 ± 1.19; p = .043). Regarding the kinetic parameters, the results of G15 were better for total motility-TM (G10: 67.00 ± 10.33 vs. G15: 81.87 ± 7.99; p = .006) and faster cells-RAPID: (G10: 55.00 ± 16.63 vs. G15: 74.25 ± 11.94; p = .019); whereas a higher proportion of cells with slow speed-SLOW were seen in G10 (G10: 31.00 ± 12.07 vs. 17.12 ± 7.53; p = .015). Based on these findings, we suggest that collection via urethral catheterization should be performed 15 min after the application of ketamine-associated dexmedetomidine to obtain a better-quality ejaculate.

[Adherence, barriers, and facilitators for the treatment of systemic arterial hypertension: rapid review of evidenceAdhesión, obstáculos y elementos facilitadores en relación con el tratamiento de la hipertensión: revisión rápida de la evidencia]. / Adesão, barreiras e facilitadores no tratamento de hipertensão arterial: revisão rápida de evidências.

Objective: To identify strategies to increase adherence to systemic arterial hypertension (SAH) treatment and describe the barriers and facilitators for implementing these strategies in primary health care (PHC). Method: A rapid evidence review was performed. We included systematic reviews with or without meta-analyses, published in English, Spanish or Portuguese, covering adults (age 18 to ≤ 60 years) with SAH followed in the PHC. Searches were performed in nine databases in December 2020 and updated in April 2022. The systematic reviews were assessed for methodological quality using the AMSTAR 2 tool. Results: Fourteen systematic reviews on treatment adherence strategies and three on barriers and facilitators for implementation were included. Regarding methodological quality, one systematic review was classified as moderate, four as low, and the others as critically low. Four strategies were identified as options for health policies: actions performed by pharmacists; actions performed by non-pharmaceutical health professionals; self-monitoring, use of mobile apps, and text messages; and subsidies for the purchase of medicines. Low digital literacy, limited access to the internet, work process and incipient training were barriers for professionals. The users' educational and health literacy levels, accessibility to health services and good relationships with professionals were facilitators. Conclusions: Positive effects of strategies related to pharmaceutical care, self-monitoring, and the use of cell phone applications and text messages were identified to increase adherence to the treatment of SAH in the context of PHC. However, for implementation purposes, it is necessary to consider barriers and facilitators, in addition to the methodological limitations of the analyzed systematic reviews.

Objetivo: Buscar estrategias para aumentar la adhesión al tratamiento de la hipertensión arterial sistémica y describir las barreras y los elementos facilitadores para la implementación de esas estrategias en el ámbito de la atención primaria de salud. Métodos: Se realizó una revisión rápida de la evidencia. Se incluyeron revisiones sistemáticas, con o sin metaanálisis, publicadas en español, inglés o portugués, en las cuales se evaluaban a personas adultas (de 18 a ≤ 60 años) con hipertensión arterial sistémica observadas en el ámbito de la atención primaria de salud. Las búsquedas se realizaron en nueve bases de datos en diciembre del 2020 y se actualizaron en abril del 2022. Se evaluó la calidad metodológica de las revisiones sistemáticas incluidas con la herramienta AMSTAR 2. Resultados: Se incluyeron 14 revisiones sistemáticas sobre estrategias de adhesión al tratamiento y tres sobre obstáculos y elementos facilitadores para la implementación. La calidad metodológica fue moderada en una revisión sistemática, baja en cuatro y críticamente baja en las demás. Se identificaron cuatro estrategias como opciones para las políticas de salud: medidas tomadas por farmacéuticos; medidas tomadas por profesionales no farmacéuticos; autocontrol, uso de aplicaciones para teléfonos celulares y mensajes de texto; y oferta de subvenciones para la compra de medicamentos. La escasa alfabetización digital, el acceso limitado a internet y los procesos de trabajo y formación incipiente fueron obstáculos para los profesionales. Los elementos facilitadores fueron el nivel de educación y de conocimientos de los usuarios en materia de salud, la accesibilidad a los servicios de salud y las buenas relaciones con los profesionales. Conclusiones: Se observaron efectos positivos de las estrategias relacionadas con la atención farmacéutica, el autocontrol y el uso de aplicaciones de telefonía celular y mensajería de texto para aumentar la adhesión al tratamiento de la hipertensión arterial sistémica en el ámbito de la atención primaria de salud. Sin embargo, para fines de implementación, es necesario considerar los obstáculos y los elementos facilitadores, además de las limitaciones metodológicas de las revisiones sistemáticas analizadas.

[Telehealth, food consumption, and eating behavior in adults: a rapid review of systematic reviewsTelesalud, consumo de alimentos y comportamiento alimentario de la población adulta: examen rápido de revisiones sistemáticas]. / Telessaúde no consumo e comportamento alimentar em adultos: uma revisão rápida de revisões sistemáticas.

Objective: To synthesize the evidence about the effects of telehealth interventions provided through smart-phone apps and text messages on the behavior of adults regarding healthy food consumption. Method: A rapid systematic review of the literature was performed through searches in nine electronic databases to identify systematic reviews published in English, Portuguese, and Spanish that evaluated telehealth strategies compared to face-to-face interventions to improve dietary intake in the adult population (18 to 59 years old). Searches were performed in November 2020 and updated in April 2022. The included systematic reviews were assessed for methodological quality using the AMSTAR 2 tool. Results: Five systematic reviews were included. Methodological quality was moderate in one review and critically low in four. There was a dearth of studies comparing the use of telehealth strategies with face-to-face interventions for the promotion of healthy eating in adults. The most consistent results refer to an increase in the consumption of fruits and vegetables with the use of an app or text messages, in addition to improvement in the dietary habits of people with diabetes or glucose intolerance with the use of text messages. Conclusion: Positive effects were observed on healthy eating outcomes for most interventions using mobile apps or text messages; however, the findings refer to a few clinical trials with small samples that were analyzed in the systematic reviews covered in the present rapid review, most of which had low methodological quality. Thus, the current knowledge gap warrants the performance of further methodologically robust studies.

Objetivo: Sintetizar la evidencia sobre los efectos de las intervenciones de telesalud ofrecidas por medio de aplicaciones de telefonía móvil y mensajes de texto en el comportamiento de la población adulta relacionado con una alimentación saludable. Métodos: Se realizó un examen rápido mediante búsquedas en nueve bases bibliográficas electrónicas para localizar revisiones sistemáticas publicadas en español, inglés y portugués en las que se evaluaran estrategias de telesalud en comparación con atención presencial para mejorar la alimentación de la población adulta (de 18 a 59 años). Las búsquedas se realizaron en noviembre del 2020 y se actualizaron en abril del 2022. La calidad metodológica de las revisiones sistemáticas incluidas se evaluó con la herramienta AMSTAR 2. Resultados: Se incluyeron cinco revisiones sistemáticas, una con un grado de confianza moderado y las otras con un grado de confianza sumamente bajo. Se comprobó una falta de estudios en los que se compararan el uso de estrategias de telesalud con la atención presencial para promover la alimentación saludable de la población adulta. Los resultados más coherentes se refieren al aumento del consumo de frutas y verduras con el uso de aplicaciones móviles o de mensajes de texto, así como a la mejora del patrón alimentario de las personas con diabetes o con intolerancia a la glucosa con el uso de mensajes de texto. Conclusión: La mayoría de los análisis de las intervenciones en las que se emplearon aplicaciones de telefonía móvil o mensajes de texto mostraron efectos positivos en los resultados relativos a una alimentación saludable. Sin embargo, estos hallazgos se refieren a unos pocos ensayos clínicos con pequeñas muestras de participantes incluidos en las revisiones sistemáticas del presente examen rápido, en su mayoría de baja calidad metodológica. En conclusión, existe una laguna en los conocimientos y es importante realizar estudios con una metodología más sólida.