Water restriction alters seed bank traits and ecology in Atlantic Forest seasonal forests under climate change.

The soil seed bank (SSB) is one of the key mechanisms that ensure the perpetuity of forests, but how will it behave in the scenarios projected for the future climate? Faced with this main question, still little explored in seasonal tropical forests, this study evaluated the germination, ecological attributes, and functional traits of the SSB in a seasonal forest in the Atlantic Forest. Forty-eight composite samples of the SSB were collected from 12 plots, distributed across four treatments, each with 12 replicates. The samples were placed in two climate-controlled greenhouses, establishing two environments of controlled climatic conditions, both with two levels of water, as follows: Cur: current scenario without water restriction; Cur_WR: current scenario with water restriction; RCP8.5: future scenario without water restriction; RCP8.5_WR: future scenario with water restriction. The germinants were identified, and their ecological attributes and functional traits were obtained. Leaf area and biomass production, differences in abundance, richness, and diversity were evaluated, along with analysis of variance to assess the interaction between water levels and scenarios. All ecological attributes and functional traits evaluated drastically decreased in the future projection with water restriction, with this restriction being the main component influencing this response. The increased temperature in the future scenario significantly raised water consumption compared to the current scenario. However, persistent water restrictions in the future could undermine the resilience of seasonal forests, hindering seed germination in the soil. Richness and abundance were also adversely affected by water scarcity in the future scenario, revealing a low tolerance to the projected prolonged drought. These changes found in the results could alter the overall structure of seasonal forests in the future, as well as result in the loss of the regeneration potential of the SSB due to decreased seed viability and increased seedling mortality.

Resumo O banco de sementes do solo (SSB) é um dos principais mecanismos que garantem a perpetuidade das florestas, mas como ele se comportará nos cenários projetados para o clima futuro? Diante dessa questão principal, ainda pouco explorada em florestas tropicais sazonais, este estudo avaliou a germinação, atributos ecológicos e traços funcionais do SSB em uma floresta sazonal na Mata Atlântica. Quarenta e oito amostras compostas do SSB foram coletadas de 12 parcelas, distribuídas em quatro tratamentos, cada uma com 12 réplicas. As amostras foram colocadas em duas estufas com controle climático, estabelecendo dois ambientes de condições climáticas controladas, ambos com dois níveis de água, conforme segue: Cur: cenário atual sem restrição hídrica; Cur_WR: cenário atual com restrição hídrica; RCP8.5: cenário futuro sem restrição hídrica; RCP8.5_WR: cenário futuro com restrição hídrica. Os germinantes foram identificados e seus atributos ecológicos e traços funcionais foram obtidos. Área foliar e produção de biomassa, diferenças na abundância, riqueza e diversidade foram avaliadas, juntamente com análise de variância para avaliar a interação entre níveis de água e cenários. Todos os atributos ecológicos e traços funcionais avaliados diminuíram drasticamente na projeção futura com restrição hídrica, sendo essa restrição o principal componente influenciando essa resposta. O aumento da temperatura no cenário futuro elevou significativamente o consumo de água em comparação com o cenário atual. No entanto, a restrição hídrica persistente no futuro pode comprometer a resiliência das florestas sazonais, dificultando a germinação de sementes no solo. Riqueza e abundância também foram adversamente afetadas pela escassez de água no cenário futuro, revelando uma baixa tolerância à seca prolongada projetada. Essas mudanças encontradas nos resultados podem alterar a estrutura geral das florestas sazonais no futuro, além de resultar na perda do potencial de regeneração do SSB devido à diminuição da viabilidade das sementes e ao aumento da mortalidade das plântulas.

3-methoxycatechol causes vasodilation likely via KV channels: ex vivo, in silico docking and in vivo study.

Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from ∼10 to 24 µM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.

How is feedback perceived by Brazilian students and faculty from a nursing school?

AIM: This study aims to explore the perceptions of feedback among undergraduate students and faculty members at a Brazilian private nursing school. BACKGROUND: Feedback plays a crucial role in the socioemotional development of learners, with its interpretation varying across different sociocultural contexts. Student evaluations frequently express dissatisfaction regarding both the quality and quantity of feedback received. Conversely, delivering feedback poses a challenge for faculty, requiring the establishment of an empathetic connection that fosters trust and credibility. Brazil, being a developing country characterized by social disparities and economic challenges, presents a unique backdrop for examining feedback dynamics. DESIGN: Qualitative research, employing Inductive Content Analysis, was used to understand feedback perceptions in Brazilian nursing education. Symbolic interactionism was adopted as methodological framework and guided data interpretation. METHODS: We carried out five virtual focus groups composed of a group of teachers (n=5) and four of students (n=34). Semi-structured interviews guided data collection. The recorded sessions were subsequently analyzed to identify key themes and codes. Symbolic interactionism was employed as a framework to derive meaning from qualitative data. RESULTS: Content analysis generated two categories that reveal the perception of teachers and students in the feedback process. The first, called "Feedback in Education: Sociocultural Influences for Students and Teachers", expresses the beliefs and interpretations of students and teachers within the shared feedback environment. The second called "Challenging resonance, transformative construction: Navigating the dualities of feedback for teachers and students", which elucidated how relational dynamics shape behaviors and attitudes, promoting the development of social skills and learning. Faculty's previous feedback experiences significantly influence their self-perception and behavior with students. As a result of the resonance of these past interactions, we recognize that the teaching self also plays a crucial role in the quality and perception of feedback. Furthermore, students construct social reality with similar beliefs and values, they believe in the learning potential generated by feedback. Our findings also corroborate that perceptions of feedback are deeply influenced by the sociocultural context and the narratives corroborate previous findings indicating that, in Brazil, honest feedback can be implicitly perceived as criticism rather than an opportunity for growth. CONCLUSIONS: Faculty members often draw on their past experiences when providing feedback, highlighting the adaptive nature of feedback interactions. Additionally, the feedback process is consistently influenced by the commitment to maintaining positive relationships with students. Students recognize the constructive dimension of feedback as a valuable tool for learning and personal growth.

Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults.

Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.

Behavioral therapy in migraine: Expanding the therapeutic arsenal.

BACKGROUND AND PURPOSE: The US Headache Consortium developed evidence-based guidelines for the treatment of migraine and found grade A evidence in support of behavior therapy (BT). Understanding the mechanisms of BT may improve the management of migraine and reduce its burden. METHODS: We performed a narrative review to define the current evidence of BT and determine its usefulness in migraine management. RESULTS: The information was obtained from 116 publications, with 56 of them retrieved through direct searches in PubMed (2011-2020) and the remainder selected by the authors to complete the content. BT might reduce migraine impact by decreasing the sympathetic nervous system's response to stress and increasing pain tolerance. Acting in headache-related surroundings can be improved, together with headache duration and self-efficacy. Applications such as mobile health and electronic health applications can help to carry out healthier lifestyle patterns. Regarding medication overuse, BT seems to be a good choice, with similar results to pharmacological prophylaxis. Advantages of using BT are the lack of adverse effects and the unrestricted use in children, where BT is postulated to be even more effective than the standardized pharmacopeia. CONCLUSIONS: BT is an interesting tool that can be used as an add-on therapy in migraine. Through BT, the autonomy and empowerment of migraine patients is enhanced. BT may not cure migraine, but it could help to reduce pain severity perception, disability, and migraine impact, adding an emotive and cognitive approach to the perceptive role of pharmacopeia. Thus, a better approach in migraine, implementing specific therapeutic management, can improve migraine control.

Association of handgrip strength with nutritional status and clinical outcomes in hospitalized pediatric patients.

BACKGROUND & AIMS: Malnutrition in children and adolescents is prevalent at hospital admission and the incidence increases with length of stay. Malnourished patients have loss of muscle mass and strength, compromising their functionality. Handgrip strength (HGS) is a nutritional marker understudied in pediatrics although it is capable of detecting nutritional deprivation before changes in body composition are observed. Therefore, this study aimed to evaluate the association between reduced HGS at hospital admission, compromised nutritional status and worse clinical outcomes of pediatric patients. METHODS: Cohort study conducted with patients aged 6-18 years admitted to a pediatric ward. Nutritional status was assessed in the first 48 h of hospital admission using the z-score of height for age (H/A) and body mass index for age (BMI/A), percentile of mid-arm muscle circumference for age (MAMC/A) and the pediatric global subjective nutritional assessment (SGNA). HGS was measured using a digital dynamometer and considered reduced when the maximum value of three measurements was below the 5th percentile for sex and age. The clinical outcomes analyzed were length of hospital stay and frequency of readmission within 3 months after hospital discharge. RESULTS: A total of 135 patients were evaluated (median age 10.9 years, 55.6% male) and 17.8% had reduced HGS. Patients with reduced HGS had lower H/A z-score (-0.50 vs 0.22, p = 0.012) and a higher frequency of reduced MAMC when compared to those with normal HGS (8% vs 13%, p = 0.007). Reduced HGS was not associated with malnutrition (OR = 0.63; 95%CI 0.23-1.77), prolonged hospital stay (OR = 1.89; 95%CI 0.72-4.92) or readmission to hospital 3 months after hospital discharge (OR = 1.82; 95%CI 0.67-4.93), in a model adjusted for the clinical condition. CONCLUSION: Reduced HGS was not a predictor of malnutrition and clinical outcomes. However, it was associated with lower H/A Z-score and MAMC/A percentile values and can be used as a complementary measure in the nutritional status assessment of hospitalized pediatric patients.

A water-soluble preparation for intravenous administration of isorhamnetin and its pharmacokinetics in rats.

Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 µg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2ß: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.

Cardiac-Specific Deletion of Scn8a Mitigates Dravet Syndrome-Associated Sudden Death in Adults.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. OBJECTIVES: In this study, the authors sought to provide evidence implicating remodeling of Na+ - and Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. METHODS: The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. RESULTS: DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death. CONCLUSIONS: These data demonstrate that NaV 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca2+ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.

Large-Vessel Vasculitis and Q Fever Correlation.

Q fever is a zoonotic infection caused by the pathogen Coxiella burnetii, and patients can present with a wide spectrum of clinical manifestations, depending on whether it is an acute or a chronic infection. We present the case of a 61-year-old male with fatigue, posterior thoracalgia, intermittent fever, night sweats and weight loss for a month. After an extensive workup, he was diagnosed with acute Q fever with large-vessel vasculitis. The FDG-PET/CT scan suggested an active vasculitis specifically in the thoracic aorta, proximal abdominal aorta, subclavian and carotid vessels, suggesting an immunologic response to acute Q fever infection, barely reported worldwide. LEARNING POINTS: Large-vessel vasculitis is a possible immunologic response to acute Q fever infection.There are few data about the management and treatment of patients with Q fever related large-vessel vasculitis.

Parents' hope in perinatal and neonatal palliative care: a scoping review.

BACKGROUND: The diagnosis of a life-limiting condition of a child in the perinatal or neonatal period is a threat to parental hopes. Hope is an interactional and multidimensional construct, and in palliative care, it is a determinant of quality of life, survival, acceptance and peaceful death. OBJECTIVE: To map scientific evidence on parents' hope in perinatal and neonatal palliative care contexts. METHOD: a scoping review theoretically grounded on Dufault and Martocchio's Framework, following the Joanna Briggs Institute methodological recommendations. Searches were performed until May 2023 in the MEDLINE, CINAHL and PsycINFO databases. The searches returned 1341 studies. RESULTS: Eligible papers included 27 studies, most of which were carried out in the United States under a phenomenological or literature review approach. The centrality of women's perspectives in the context of pregnancy and perinatal palliative care was identified. The parental hope experience is articulated in dealing with the uncertainty of information and diagnosis, an approach to which interaction with health professionals is a determinant and potentially distressful element. Hope was identified as one of the determinants of coping and, consequently, linked to autonomy and parenthood. Cognitive and affiliative dimensions were the hope dimensions that predominated in the results, which corresponded to the parents' ability to formulate realistic goals and meaningful interpersonal relationships, respectively. CONCLUSION: Hope is a force capable of guiding parents along the path of uncertainties experienced through the diagnosis of a condition that compromises their child's life. Health professionals can manage the family's hope by establishing sensitive therapeutic relationships that focus on the dimension of hope. The need for advanced research and intervention in parental and family hope are some of the points made in this study. PROTOCOL REGISTRATION: https://osf.io/u9xr5/ .

Proposed mechanisms of action of herbal drugs and their biologically active constituents in the treatment of coughs: an overview.

Various medicinal plants find their use in cough treatment, based on traditions and long-term experience. Pharmacological principles of their action, however, are much less known. Herbal drugs usually contain a mixture of potentially active compounds, which can manifest diverse effects. Expectorant or antitussive effects, which can be accompanied by others, such as anti-inflammatory or antibacterial, are probably the most important in the treatment of coughs. The aim of this review is to summarize the current state of knowledge of the effects of medicinal plants or their constituents on cough, based on reliable pharmacological studies. First, a comprehensive description of each effect is provided in order to explain the possible mechanism of action in detail. Next, the results related to individual plants and substances are summarized and critically discussed based on pharmacological in vivo and in vitro investigation.

Characterization of three adults and an adolescent with Osteogenesis Imperfecta type VI and a novel founder SERPINF1 variant.

Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived factor (PEDF). We report on four patients (three adults and one adolescent) with a severe deforming form of OI. All patients presented no abnormalities at birth, frequent long bone and vertebrae fractures (mainly during childhood), marked short stature, severe bone deformities, chronic mild to moderate pain, and severe limitation of mobility, with three being completely wheelchair bound. Blue sclera and dentinogenesis imperfecta were absent, although some patients presented tooth, ophthalmological, and/or cardiac features. Radiographic findings included, among others, thin diaphysis and popcorn calcifications, both of which are non-specific to this type of OI. The novel homozygous variants c.816_819del (p.Met272Ilefs*8) and c.283+2T > G in SERPINF1 were identified in three and one patient, respectively. The three patients carrying the frameshift variant were born in nearby regions suggesting a founder effect. Describing the long-term outcomes of four patients with OI type VI, this cohort adds relevant data on the clinical features and prognosis of this type of OI.

Searching for human connection to transcend symbolisms in pediatric palliative care.

OBJECTIVES: to present a theoretical model for the interactional context of health professionals and families of children and adolescents under palliative care. METHODS: qualitative study based on the theoretical frameworks of Grounded Theory and Symbolic Interactionism. Ten palliative care professionals took part in this study through semi-structured interviews employing snowball technique from 2020 to 2021. RESULTS: the comparative data analysis resulted in the theoretical model "Searching for human connection to transcend symbolisms in pediatric palliative care". It reveals symbolic elements that substantiate the construction of a collaborative context integrating two phenomena: "Overcoming boundaries and intertwining paths" and "Embracing suffering to weave meaningful experiences". Symbolisms in palliative care guide the behavior of families and professionals, which makes them the key factor to be managed. FINAL CONSIDERATIONS: symbolisms and suffering continually integrate the interactional experience of professionals. Empathy and compassion are fundamental elements to enable their connection with families.

Outcomes of a QST Protocol in Healthy Subjects and Chronic Pain Patients: A Controlled Clinical Trial.

Chronic pain is an important cause of disability with a high burden to society. Quantitative sensory testing (QST) is a noninvasive multimodal method used to discriminate the function of nerve fibers. The aim of this study is to propose a new, reproducible, and less time-consuming thermal QST protocol to help characterize and monitor pain. Additionally, this study also compared QST outcomes between healthy and chronic pain subjects. Forty healthy young/adult medical students and fifty adult/elderly chronic pain patients were evaluated in individual sessions including pain history, followed by QST assessments divided into three proposed tests: pain threshold, suprathreshold, and tonic pain. In the chronic pain group, a significantly higher pain threshold (hypoesthesia) and a higher pain sensibility (hyperalgesia) were demonstrated at threshold temperature when compared to healthy participants. The sensitivity to the suprathreshold and tonic stimulus did not prove to be significantly different between both groups. The main results demonstrated that the heat threshold QST tests can be helpful in evaluating hypoesthesia and that the sensitivity threshold temperature test can demonstrate hyperalgesia in individuals with chronic pain. In conclusion, this study demonstrates the importance of using tools such as QST as a complement to detect changes in several pain dimensions.

Comprehensive review of safety in Experimental Human Pneumococcal Challenge.

INTRODUCTION: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies. METHODS: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation. RESULTS: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety. DISCUSSION: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated. CONCLUSION: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.

Postoperative transfusion hemoglobin threshold and functional recovery after high-risk oncologic surgery: A randomized controlled pilot study.

BACKGROUND: Robust evidence to inform best transfusion management after major oncologic surgery, where postoperative recovery might impact treatment regimens for cancer, is lacking. We conducted a study to validate the feasibility of a larger trial comparing liberal versus restrictive red blood cells (RBC) transfusion strategies after major oncologic surgery. STUDY DESIGN AND METHODS: This was a two-center, randomized, controlled, study of patients admitted to the intensive care unit after major oncologic surgery. Patients whose hemoglobin level dropped below 9.5 g/dL, were randomly assigned to immediately receive a 1-unit RBC transfusion (liberal) or delayed until the hemoglobin level dropped below 7.5 g/dL (restrictive). The primary outcome was the median hemoglobin level between randomization to day 30 post-surgery. Disability-free survival was evaluated by the WHODAS 2.0 questionnaire. RESULTS: 30 patients were randomized (15 patients/group) in 15 months with a mean recruitment rate of 1.8 patients per month. The median hemoglobin level was significantly higher in the liberal group than in the restrictive group: 10.1 g/dL (IQR 9.6-10.5) versus 8.8 g/dL (IQR 8.3-9.4), p < .001, and RBC transfusion rates were 100% versus 66.7%, p = .04. The disability-free survival was similar between groups: 26.7% versus 20%, p = 1. DISCUSSION: Our results support the feasibility of a phase 3 randomized controlled trial comparing the impact of liberal versus restrictive transfusion strategies on the functional recovery of critically ill patients following major oncologic surgery.

ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome.

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

The effects of bisphenols on the cardiovascular system ex vivo and in vivo.

The human population is regularly exposed to bisphenols. The first compound of this class, bisphenol A, is burdened by numerous reports of its potential toxicity and has been hence replaced by its analogues, so-called next generation bisphenols. Their widespread use has made them pervasive throughout the environment. These endocrine disrupting chemicals can affect the cardiovascular system, and hence the aim of this study was to test 14 bisphenols (A, AF, AP, B, BP, C, E, F, G, M, P, PH, S and Z), and compare their effects in vitro (human and rat cell lines), ex vivo (isolated rat aorta) and in vivo (Wistar Han rats, acutely or chronically exposed to low environmental and high toxic doses). The majority of the tested bisphenols relaxed rat aorta, but their potency varied markedly. The most potent compound, bisphenol AF, had an EC50 of 57 µM. The mechanism of action was likely based on the inhibition of calcium influx via L-type calcium channels. The cytotoxicity of bisphenols towards 4 human and rat cell lines (H9c2, A-10, MCF7/S0.5 and MCF7/182R-6) showed variable potencies ranging from units of micromolar to millimolar concentrations. Based on these data, an effect on arterial blood pressure and possible cardiotoxicity was expected. Contrarily, the in vivo acute effects of three doses (0.005, 0.05 and 2.5 mg/kg) of bisphenol AF and 3 other analogues (A, S and F) on the cardiovascular system were rather biologically negligible. The most potent bisphenol, AF, was also administered chronically at a dose of 2.5 mg/kg for 4 weeks to rats, but had no impact on arterial blood pressure. Our results showed that bisphenols can relax vascular smooth muscles, but the effective concentrations are too high to produce clear cardiovascular effects in relation to common biological exposure as was confirmed with the most potent bisphenol AF.