Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study).

BACKGROUND: Encorafenib plus binimetinib (EB) is a standard of care treatment for advanced BRAFV600-mutant melanoma. We assessed efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response. METHODS: E-BRAIN/GEM1802 was a prospective, multicenter, single arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression.Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%. RESULTS: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After two months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial PFS and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grade 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%). CONCLUSION: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response.

Biodiversity of Trichoderma species of healthy and Fusarium wilt-infected banana rhizosphere soils in Tenerife (Canary Islands, Spain).

Banana (Musa acuminata) is the most important crop in the Canary Islands (38.9% of the total cultivated area). The main pathogen affecting this crop is the soil fungal Fusarium oxysporum f. sp. cubense subtropical race 4 (Foc-STR4), for which there is no effective control method under field conditions. Therefore, the use of native biological control agents may be an effective and sustainable alternative. This study aims to: (i) investigate the diversity and distribution of Trichoderma species in the rhizosphere of different banana agroecosystems affected by Foc-STR4 in Tenerife (the island with the greatest bioclimatic diversity and cultivated area), (ii) develop and preserve a culture collection of native Trichoderma species, and (iii) evaluate the influence of soil chemical properties on the Trichoderma community. A total of 131 Trichoderma isolates were obtained from 84 soil samples collected from 14 farms located in different agroecosystems on the northern (cooler and wetter) and southern (warmer and drier) slopes of Tenerife. Ten Trichoderma species, including T. afroharzianum, T. asperellum, T. atrobrunneum, T. gamsii, T. guizhouense, T. hamatum, T. harzianum, T. hirsutum, T. longibrachiatum, and T. virens, and two putative novel species, named T. aff. harzianum and T. aff. hortense, were identified based on the tef1-α sequences. Trichoderma virens (35.89% relative abundance) and T. aff. harzianum (27.48%) were the most abundant and dominant species on both slopes, while other species were observed only on one slope (north or south). Biodiversity indices (Margalef, Shannon, Simpson, and Pielou) showed that species diversity and evenness were highest in the healthy soils of the northern slope. The Spearman analysis showed significant correlations between Trichoderma species and soil chemistry parameters (mainly with phosphorus and soil pH). To the best of our knowledge, six species are reported for the first time in the Canary Islands (T. afroharzianum, T. asperellum, T. atrobrunneum, T. guizhouense, T. hamatum, T. hirsutum) and in the rhizosphere of banana soils (T. afroharzianum, T. atrobrunneum, T. gamsii, T. guizhouense, T. hirsutum, T. virens). This study provides essential information on the diversity/distribution of native Trichoderma species for the benefit of future applications in the control of Foc-STR4.

Nurse-Led Approaches to Lowering Alcohol Use among Adolescents: Study Findings.

This study delves into how motivational sessions and brief interventions impact students' alcohol consumption, highlighting the vital role of nurses in fostering positive behavioural changes. The study aims to discern the effects of these interventions, starting with a pre-and post-intervention setup involving 62 students from a private school in northern Portugal. The intervention comprised a session delivered by school and mental health nurses, utilizing the motivational intervention and FRAMES method and a poster offering feedback on alcohol consumption scores. The results indicated that females tended to drink for fewer days and engage in less binge drinking than males. Furthermore, the intervention hinted at a reduction in the number of heavy drinking days. This study underscores the importance of including healthcare professionals, particularly nurses, in delivering brief interventions within school settings. The findings carry weight for crafting evidence-based interventions to cultivate healthier adolescent behaviours and enhance overall well-being.

Intraobserver reliability and validity of a single ultrasonic measurement of the lateral condyle-capsule distance in the temporomandibular joint.

PURPOSE: The purpose of the study was to examine the reliability and validity of a single lateral condyle-capsule distance (LCCD) measurement while saving on economic costs and clinical resources. METHODS: A longitudinal test-retest design was used to assess the reliability and validity of single-examiner measures over 72 TMJ sonographic analyses. Intraclass correlation coefficients (ICC) and a Bland-Altman plot were used to study reliability and validity, comparing the first measurement of the LCCD to the mean of 3 measurements taken one week later by the same examiner. RESULTS: ICC show intraobserver reliability of 0.981, 95% confidence intervals (CI) of 0.969 to 0.988. The mean difference between the ultrasound measurements is 0.019 mm (95% CI 0.0005-0.0383) with a standard deviation of 0.080 mm, demonstrating robust validity. The 95% Limits of Agreement (LoA) are - 0.138 for the lower limit and 0.177 for the upper. Mean relative error is 0.009 mm. CONCLUSION: Intraobserver reliability of a trained examiner is very high in the single measurement of the LCCD and validity is significant compared to more complex methods. The risk of bias is low since the mean of three LCCD measurements is calculated as opposed to recording only one single measurement.

First-trimester ventriculomegaly in fetuses with callosal agenesis: Cause or association?

The sonographic findings in four fetuses presenting with ventriculomegaly at first-trimester ultrasound that were subsequently diagnosed as having agenesis of the corpus callosum (ACC) are described. The diagnosis of early ventriculomegaly was suspected subjectively by identification of increased cerebrospinal fluid within the lateral ventricles and confirmed by measuring choroid plexus-to-lateral ventricle length and area ratios. Subsequent scans revealed complete ACC in two cases and partial ACC in the other two. This report adds to the increasing evidence suggesting that first-trimester ventriculomegaly is a strong sonographic marker of underlying brain anomalies, including less evident malformations such as ACC. Detailed second-trimester fetal neurosonography in those women continuing their pregnancies should be performed.

Yeast as a tool for membrane protein production and structure determination.

Membrane proteins are challenging targets to functionally and structurally characterize. An enduring bottleneck in their study is the reliable production of sufficient yields of stable protein. Here, we evaluate all eukaryotic membrane protein production experiments that have supported the deposition of a high-resolution structure. We focused on the most common yeast host systems, Saccharomyces cerevisiae and Pichia pastoris. The first high-resolution structure of a membrane protein produced in yeast was described in 1999 and today there are 186 structures of α-helical membrane proteins, representing 101 unique proteins from 37 families. Homologous and heterologous production are equally common in S. cerevisiae, while heterologous production dominates in P. pastoris, especially of human proteins, which represent about one-third of the total. Investigating protein engineering approaches (78 proteins from seven families) demonstrated that the majority contained a polyhistidine tag for purification, typically at the C-terminus of the protein. Codon optimization and truncation of hydrophilic extensions were also common approaches to improve yields. We conclude that yeast remains a useful production host for the study of α-helical membrane proteins.

[Allan-Herndon-Dudley syndrome: a diagnosis to rule out in any male infant with undiagnosed hypotonia]. / Síndrome de Allan-Herndon-Dudley: un diagnóstico a descartar ante todo lactante varón con hipotonía sin causa determinada.

Allan-Herndon-Dudley syndrome is a rare X-linked genetic disorder, caused by a deficiency of the monocarboxylate transporter 8 (MCT8), a specific transporter of thyroid hormones, with functions mainly at the brain level. The syndrome produces an early onset of severe neurological disorder, in which hypotonia predominates. OBJECTIVE: To present a rare case with an unexpected diagnosis, highlighting the usefulness of requesting a complete thyroid profile in every hypotonic male infant without a specific cause. CLINICAL CASE: A 10-month-old male infant with severe axial and peripheral hypotonia, global weakness with little spontaneous mobility, without head support or stable sitting. Complete metabolic and peripheral neurophysiological studies were performed. Genetic studies for spinal muscular atrophy, Prader Willi syndrome, and myotonic dystrophy were also performed. The trio exome analysis detected a probably pathogenic variant c.359C>T;p.(Ser120Phe), hemizygous in exon 1 of the SLC16A2 gene, inherited from the mother. Thyroid abnormalities as increased free triiodothyronine (T3) and thyroid-stimulating hormone (TSH), and delayed myelination were ob served. CONCLUSIONS: MCT8 deficiency should be considered in the case of the male infant with unex plained hypotonia and weakness without a determined cause. The diagnosis is guided by a thyroid profile including free T3 hormone, because it presents a characteristic thyroid profile with decreased free thyroxine (T4), increased free T3, and normal or slightly elevated TSH levels. In this case, the implementation of the trio exome analysis allows establishing an early certain diagnosis.

Prenatal diagnosis of Greig Cephalopolysyndactyly Syndrome. When to suspect it.

Greig Cephalopolysyndactyly Syndrome (GCPS) is a very rare multiple congenital anomaly with an estimated incidence of 1-9:1,000,000 in newborns with principal findings of macrocephaly, ocular hypertelorism, and polysyndactyly (preaxial or mixed preaxial and postaxial). Very few cases of prenatal diagnoses have been reported. The postnatal diagnosis is based on clinical findings and family background. GLI3, the only gene associated with this anomaly, is altered in more than 75% of cases. Deletions over 1 Mb and involving other genes yield severe clinical cases, which are known collectively as Greig Cephalopolysyndactyly-contiguous gene Syndrome. We report a case in which, despite early polydactyly findings on week 16, the diagnosis was established during the third trimester of pregnancy due to the late presentation of other anomalies corresponding to this syndrome.

Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia.

OBJECTIVES: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. METHODS: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. RESULTS: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. CONCLUSIONS: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.

Linfangiectasia intestinal en un paciente afectado de síndrome de Sanfilippo B / Intestinal lymphangiectasia in a patient with Sanfilippo B syndrome

La mucopolisacaridosis tipo III B es una enfermedad de depósito lisosomal causada por la deficiencia de la enzima N-acetil-alfa-d-glucosaminidasa, implicada en el catabolismo del heparán sulfato, que produce su acúmulo en diversos tejidos. Se presenta a un paciente de 8 años, afectado de mucopolisacaridosis tipo III B, con historia de diarrea crónica y hallazgos endoscópicos e histológicos compatibles con linfangiectasia intestinal. Tras tratamiento dietético con restricción de ácidos grasos de cadena larga y rica en triglicéridos de cadena media, presentó mejoría clínica, mantenida hasta la actualidad.La patogenia de la diarrea crónica en pacientes con mucopolisacaridosis tipo III B es aún desconocida. Debe investigarse la presencia de linfangiectasia intestinal en estos pacientes e iniciar, en caso de confirmarse, un tratamiento dietético adecuado para mejorar así su calidad de vida.

Mucopolysaccharidosis type IIIB is a lysosomal storage disease caused by a deficiency of the N-acetyl-alpha-d-glucosaminidase enzyme involved in the catabolism of heparan sulfate, causing its accumulation in various tissues. We present an 8-year-old patient with mucopolysaccharidosis type IIIB, with a history of chronic diarrhea and endoscopic and histological findings compatible with intestinal lymphangiectasia. After a dietary treatment with a low-fat diet supplemented with medium-chain triglyceride, our patient presents clinical improvement until today. The pathogenesis of chronic diarrhea in patients with mucopolysaccharidosis type IIIB is still unknown. The presence of intestinal lymphangiectasia in these patients should be investigated, and appropriate dietary treatment should be initiated, if confirmed, to improve their quality of life.

[Intestinal lymphangiectasia in a patient with Sanfilippo B syndrome]. / Linfangiectasia intestinal en un paciente afectado de síndrome de Sanfilippo B.

Mucopolysaccharidosis type IIIB is a lysosomal storage disease caused by a deficiency of the N-acetyl-alpha-d-glucosaminidase enzyme involved in the catabolism of heparan sulfate, causing its accumulation in various tissues. We present an 8-year-old patient with mucopolysaccharidosis type IIIB, with a history of chronic diarrhea and endoscopic and histological findings compatible with intestinal lymphangiectasia. After a dietary treatment with a low-fat diet supplemented with mediumchain triglyceride, our patient presents clinical improvement until today. The pathogenesis of chronic diarrhea in patients with mucopolysaccharidosis type IIIB is still unknown. The Linfangiectasia intestinal en un paciente afectado de síndrome de Sanfilippo B Intestinal lymphangiectasia in a patient with Sanfilippo B syndrome presence of intestinal lymphangiectasia in these patients should be investigated, and appropriate dietary treatment should be initiated, if confirmed, to improve their quality of life.

La mucopolisacaridosis tipo III B es una enfermedad de depósito lisosomal causada por la deficiencia de la enzima N-acetil-alfad- glucosaminidasa, implicada en el catabolismo del heparán sulfato, que produce su acúmulo en diversos tejidos. Se presenta a un paciente de 8 años, afectado de mucopolisacaridosis tipo III B, con historia de diarrea crónica y hallazgos endoscópicos e histológicos compatibles con linfangiectasia intestinal. Tras tratamiento dietético con restricción de ácidos grasos de cadena larga y rica en triglicéridos de cadena media, presentó mejoría clínica, mantenida hasta la actualidad. La patogenia de la diarrea crónica en pacientes con mucopolisacaridosis tipo III B es aún desconocida. Debe investigarse la presencia de linfangiectasia intestinal en estos pacientes e iniciar, en caso de confirmarse, un tratamiento dietético adecuado para mejorar así su calidad de vida.

Feasibility and Accuracy of Early Fetal Echocardiography Performed at 13+0-13+6 Weeks in a Population with Low and High Body Mass Index: a Prospective Study.

PURPOSE: The earlier the detection and diagnosis of congenital heart diseases (CHD), the greater the clinical benefit; however, early fetal cardiac examination can be a challenge. The aim of our study is to demonstrate that the fetal cardiac examination at 13+0-13+6 weeks can be as adequately assessed as the examination performed at 16 weeks in patients with low and high body mass index (BMI). METHODS: The study was a prospective observational cohort study. One hundred pregnant women at low risk of congenital heart anomalies were divided into two groups: 49 women with low BMI (<25) and 51 women with high BMI (≥ 25). A complete fetal cardiac scan was performed on each patient at 13+0-13+6 weeks, via the transvaginal and transabdominal approaches, and at 16 weeks by the transabdominal approach. RESULTS: The examination at 13+0-13+6 weeks was adequately assessed in at least one of the two routes in 97 patients, as opposed to 87 patients at 16 weeks. A significantly higher adequate assessment rate was obtained at 13+0-13+6 weeks than at 16 weeks (p=0.017). The transvaginal approach showed the best resolution of the three examinations in 42% of women with BMI ≥35. No CHD were overlooked. CONCLUSIONS: Early fetal echocardiography is feasible and accurate at 13+0-13+6 weeks. Within patients with high BMI, early fetal echocardiography may be performed two weeks in advance, since it allows visualization of the fetal heart through the transvaginal route with a higher resolution in a large number of women, which is not feasible at 16 weeks.

Association between temporomandibular disorders with clinical and sociodemographic features: An observational study.

BACKGROUND: Temporomandibular disorders (TMD) are the most common orofacial impairment, but the relevance of certain clinical features in TMD is not clear. OBJECTIVE: The main objective of this study was to analyse if temporomandibular disorders (TMD) are associated with sociodemographic (eg age, height, weight, body mass index and gender), psychological (eg anxiety and depression) and clinical features (eg use of dental splints, orthodontics, retainers, bruxism, sleep disturbance, familiar prior history of TMD and dental occlusion). METHODS: An observational study was conducted to calculate the correlation of TMD, as assessed with DC/TMD criteria, with sociodemographic, psychological and clinical features on 59 voluntary subjects with TMD (n = 45) and without TMD (n = 14). Sex, height, weight, body mass index, age, use of dental splint, orthodontics, retainers, parafunctional disorders, sleep disturbance, familiar history of TMD, bruxism, anxiety, stress and dental occlusion class data were included in a multivariable correlation analysis to determine which variables are associated with TMD and bruxism. RESULTS: TMD was found to be correlated with none of the features assessed (P > .05), but a negative correlation with the use of dental splint (P < .05). Dental occlusion class showed no statistically significant correlation with any assessed feature (P > .05). CONCLUSION: The etiology of TMD is not clear and considering certain clinical features including dental occlusion are not justified in the evidence-based TMD practice for making irreversible occlusal treatment decisions.

Deficiencia de lipasa ácida lisosomal: una causa poco reconocida de dislipemia y disfunción hepática / Lysosomal acid lipase deficiency: A rarely recognised cause of dyslipidaemia and liver dysfunction

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First-trimester cystic posterior fossa: reference ranges, associated findings, and pregnancy outcomes.

OBJECTIVE: To report reference ranges for fetal cerebral posterior fossa measurements and to describe the sonographic findings, karyotype results, and pregnancy outcomes in fetuses presenting with cystic posterior fossa (CPF) in the first trimester of pregnancy. METHODS: Two groups of patients undergoing first-trimester sonographic screening at 11-13 weeks' gestation were studied. The first (control group) consisted of 253 consecutive fetuses with normal posterior fossa, in which the brainstem (BS), fourth ventricle, cisterna magna, and BS-occipital bone (BS-OB) diameter were prospectively measured and the BS/BS-OB diameter ratio was calculated. The second (study group) consisted of 14 fetuses in which a CPF was detected. Information on sonographic findings, prenatal karyotype results, and pregnancy outcomes was obtained by reviewing ultrasound reports and medical records. The results from the two groups were then compared. RESULTS: In the control group, the size of all posterior fossa structures increased and the BS/BS-OB diameter ratio slightly decreased as the pregnancy progressed. In the study group, the BS diameter did not differ significantly from the measurements obtained in the control group. However, the BS-OB diameter and the fourth ventricle were significantly larger (p < .05 and p < .001, respectively) in the study group than in the control group. Additionally, the cisterna magna was not identified in 13 of the 14 fetuses (93%) in the study group, in comparison to zero out of the 253 fetuses in the control group (p < .001). Finally, the BS/BS-OB diameter ratio was significantly smaller in the study group when compared with the control group (p < .05). Regarding pregnancy outcomes, 12 of the 14 (86%) affected pregnancies underwent elective termination (n = 11) or ended in an early intrauterine demise (n = 1) due to the associated chromosomal abnormalities or structural defects. The two fetuses with isolated CPF had a normal second-trimester scan and resulted in the delivery of healthy newborn infants. CONCLUSIONS: The detection of a CPF in the first trimester is associated with a high rate of chromosomal and structural defects. By using normative data, early sonographic screening and detection of mildly and moderately abnormal cases is possible. Fetuses with isolated CPF require further study with a detailed second-trimester scan. This is essential in order to differentiate cases with poor and good perinatal outcomes. Finally, our data also demonstrate that the main sonographic tool when screening for CPF in the first trimester is the assessment of the fourth ventricle, which is significantly larger in abnormal cases as the result of the wide communication between the fourth ventricle and the cisterna magna.

Remodeling of the Microvasculature: May the Blood Flow Be With You.

The vasculature ensures optimal delivery of nutrients and oxygen throughout the body, and to achieve this function it must continually adapt to varying tissue demands. Newly formed vascular plexuses during development are immature and require dynamic remodeling to generate well-patterned functional networks. This is achieved by remodeling of the capillaries preserving those which are functional and eliminating other ones. A balanced and dynamically regulated capillary remodeling will therefore ensure optimal distribution of blood and nutrients to the tissues. This is particularly important in pathological contexts in which deficient or excessive vascular remodeling may worsen tissue perfusion and hamper tissue repair. Blood flow is a major determinant of microvascular reshaping since capillaries are pruned when relatively less perfused and they split when exposed to high flow in order to shape the microvascular network for optimal tissue perfusion and oxygenation. The molecular machinery underlying blood flow sensing by endothelial cells is being deciphered, but much less is known about how this translates into endothelial cell responses as alignment, polarization and directed migration to drive capillary remodeling, particularly in vivo. Part of this knowledge is theoretical from computational models since blood flow hemodynamics are not easily recapitulated by in vitro or ex vivo approaches. Moreover, these events are difficult to visualize in vivo due to their infrequency and briefness. Studies had been limited to postnatal mouse retina and vascular beds in zebrafish but new tools as advanced microscopy and image analysis are strengthening our understanding of capillary remodeling. In this review we introduce the concept of remodeling of the microvasculature and its relevance in physiology and pathology. We summarize the current knowledge on the mechanisms contributing to capillary regression and to capillary splitting highlighting the key role of blood flow to orchestrate these processes. Finally, we comment the potential and possibilities that microfluidics offers to this field. Since capillary remodeling mechanisms are often reactivated in prevalent pathologies as cancer and cardiovascular disease, all this knowledge could be eventually used to improve the functionality of capillary networks in diseased tissues and promote their repair.