ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review.

Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also described in patients with a primary intraosseous vascular malformation (PIVM; OMIM #606893). These patients presented gingival bleeding and cherubism phenotype. Herein, a patient with gingival hypertrophy, neurodevelopmental delay, and cherubism phenotype with a novel homozygous predicted loss-of-function (LOF) variant in the ELMO2 gene and family recurrence was reported. A surgical approach to treat gingival bleeding and mandible vascular malformation was also described. Furthermore, this study includes a comprehensive literature review of molecular data regarding the ELMO2 gene. All the variants, except one described in the ELMO2, were predicted as LOF, including our patient's variant. There is an overlapping between PIVM, also caused by LOF biallelic variants in the ELMO2 gene, and Ramon syndrome, which can suggest that they are not different entities. However, due to a limited number of cases described with molecular evaluation, it is hard to establish a genotype-phenotype correlation. Our study supports that LOF pathogenic biallelic variants in the ELMO2 gene cause a phenotype that has cherubism and gingival hypertrophy as main characteristics.

Role of induced nitric oxide synthases in orofacial nociception/discomfort after dental tooth bleaching with hydrogen peroxide.

OBJECTIVE: To evaluate the role of induced nitric oxide synthase (iNOS) in nociception/orofacial discomfort in rats submitted to tooth whitening with hydrogen peroxide (H2O2). DESIGN: Wistar rats were divided into three groups (n = 24/group): a sham group not submitted to whitening treatment, a saline group submitted to whitening treatment, and a test group submitted to whitening treatment and blockade of iNOS with aminoguanidine 50 mg/kg/day. After 24 and 48 h, and 7 days, the animals were euthanized to collect trigeminal ganglia and maxillae to histomorphometric analysis (size of neuronal bodies and percentage of pulp area filled by vessels) and behavior/nociception (Grimace scales, scratching and biting counting, weight loss and nociception assay). ANOVA-1- or - 2-way tests were used (p < 0.05, GraphPadPrism 5.0). RESULTS: The aminoguanidine-treated group showed a reduction in nociceptive threshold in the masseteric region (p < 0.001), Grimace scale scores (p < 0.001), number of scratching (p = 0.011) and body mass loss (p = 0.007). After 24 and 48 h of tooth bleaching, the saline group showed a significant increase in the mean area of the blood vessels (p = 0.020) and iNOS immunostaining in odontoblasts (p = 0.002) and non-odontoblasts cells (p = 0.025). Aminoguanidine reversed both increases. Tooth bleaching reduced the mean area of neuronal bodies, and aminoguanidine significantly reversed it (p = 0.019), but an increase in GFAP immunostaining in neuronal bodies did not reduce after seven-days or after aminoguanidine treatment (p = 0.003). CONCLUSION: iNOS blockage by aminoguanidine plays an important role in nociception and orofacial discomfort by control of inflammation in dental pulp after tooth bleaching with hydrogen peroxide (H2O2) 35%.

Melanoma prevention using an augmented reality-based serious game.

OBJECTIVES: The purpose of this study was to field-test a recently developed AR-based serious game designed to promote SSE self-efficacy, called Spot. METHODS: Thirty participants played the game and answered 3 questionnaires: a baseline questionnaire, a second questionnaire immediately after playing the game, and a third questionnaire 1 week later (follow-up). RESULTS: The majority of participants considered that the objective quality of the game was high, and considered that the game could have a real impact in SSE promotion. Participants showed statistically significant increases in SSE self-efficacy and intention at follow-up. Of the 24 participants that had never performed a SSE or had done one more than 3 months ago, 12 (50.0%) reported doing a SSE at follow-up. CONCLUSIONS: This study provides supporting evidence to the use of serious games in combination with AR to educate and motivate users to perform SSE. Spot seems to be an inconspicuous but effective strategy to promote SSE, a cancer prevention behavior, among healthy individuals. PRACTICE IMPLICATIONS: Patient education is essential to tackle skin cancer, particularly melanoma. Serious games, such as Spot, have the ability to effectively educate and motivate patients to perform a cancer prevention behavior.

Microsurgical Clipping of Unruptured Anterior Circulation Aneurysms-A Global Multicenter Investigation of Perioperative Outcomes.

BACKGROUND AND OBJECTIVES: Microsurgical aneurysm repair by clipping continues to be highly important despite increasing endovascular treatment options, especially because of inferior occlusion rates. This study aimed to present current global microsurgical treatment practices and to identify risk factors for complications and neurological deterioration after clipping of unruptured anterior circulation aneurysms. METHODS: Fifteen centers from 4 continents participated in this retrospective cohort study. Consecutive patients who underwent elective microsurgical clipping of untreated unruptured intracranial aneurysm between January 2016 and December 2020 were included. Posterior circulation aneurysms were excluded. Outcome parameters were postsurgical complications and neurological deterioration (defined as decline on the modified Rankin Scale) at discharge and during follow-up. Multivariate regression analyses were performed adjusting for all described patient characteristics. RESULTS: Among a total of 2192 patients with anterior circulation aneurysm, complete occlusion of the treated aneurysm was achieved in 2089 (95.3%) patients at discharge. The occlusion rate remained stable (94.7%) during follow-up. Regression analysis identified hypertension (P < .02), aneurysm diameter (P < .001), neck diameter (P < .05), calcification (P < .01), and morphology (P = .002) as preexisting risk factors for postsurgical complications and neurological deterioration at discharge. Furthermore, intraoperative aneurysm rupture (odds ratio 2.863 [CI 1.606-5.104]; P < .01) and simultaneous clipping of more than 1 aneurysm (odds ratio 1.738 [CI 1.186-2.545]; P < .01) were shown to be associated with an increased risk of postsurgical complications. Yet, none of the surgical-related parameters had an impact on neurological deterioration. Analyzing volume-outcome relationship revealed comparable complication rates (P = .61) among all 15 participating centers. CONCLUSION: Our international, multicenter analysis presents current microsurgical treatment practices in patients with anterior circulation aneurysms and identifies preexisting and surgery-related risk factors for postoperative complications and neurological deterioration. These findings may assist in decision-making for the optimal therapeutic regimen of unruptured anterior circulation aneurysms.

Global Outcomes for Microsurgical Clipping of Unruptured Intracranial Aneurysms: A Benchmark Analysis of 2245 Cases.

BACKGROUND AND OBJECTIVES: Benchmarks represent the best possible outcome and help to improve outcomes for surgical procedures. However, global thresholds mirroring an optimal and reachable outcome for microsurgical clipping of unruptured intracranial aneurysms (UIA) are not available. This study aimed to define standardized outcome benchmarks in patients who underwent clipping of UIA. METHODS: A total of 2245 microsurgically treated UIA from 15 centers were analyzed. Patients were categorized into low- ("benchmark") and high-risk ("nonbenchmark") patients based on known factors affecting outcome. The benchmark was defined as the 75th percentile of all centers' median scores for a given outcome. Benchmark outcomes included intraoperative (eg, duration of surgery, blood transfusion), postoperative (eg, reoperation, neurological status), and aneurysm-related factors (eg, aneurysm occlusion). Benchmark cutoffs for aneurysms of the anterior communicating/anterior cerebral artery, middle cerebral artery, and posterior communicating artery were determined separately. RESULTS: Of the 2245 cases, 852 (37.9%) patients formed the benchmark cohort. Most operations were performed for middle cerebral artery aneurysms (53.6%), followed by anterior communicating and anterior cerebral artery aneurysms (25.2%). Based on the results of the benchmark cohort, the following benchmark cutoffs were established: favorable neurological outcome (modified Rankin scale ≤2) ≥95.9%, postoperative complication rate ≤20.7%, length of postoperative stay ≤7.7 days, asymptomatic stroke ≤3.6%, surgical site infection ≤2.7%, cerebral vasospasm ≤2.5%, new motor deficit ≤5.9%, aneurysm closure rate ≥97.1%, and at 1-year follow-up: aneurysm closure rate ≥98.0%. At 24 months, benchmark patients had a better score on the modified Rankin scale than nonbenchmark patients. CONCLUSION: This study presents internationally applicable benchmarks for clinically relevant outcomes after microsurgical clipping of UIA. These benchmark cutoffs can serve as reference values for other centers, patient registries, and for comparing the benefit of other interventions or novel surgical techniques.

Role of temporary arterial occlusion in subarachnoid hemorrhage outcomes: a prospective cohort study.

PURPOSE: Temporary arterial occlusion (TAO) is a widespread practice in the surgical treatment of intracranial aneurysms. This study aimed to investigate TAO's role during ruptured aneurysm clipping as an independent prognostic factor on short- and long-term outcomes. METHODS: This prospective cohort included 180 patients with ruptured intracranial aneurysms and an indication of microsurgical treatment. Patients who died in the first 12 hours after admission were excluded. RESULTS: TAO was associated with intraoperative rupture (IOR) (odds ratio - OR = 10.54; 95% confidence interval - 95%CI 4.72-23.55; p < 0.001) and surgical complications (OR = 2.14; 95%CI 1.11-4.07; p = 0.01). The group with TAO and IOR had no significant difference in clinical (p = 0.06) and surgical (p = 0.94) complications compared to the group that had TAO, but no IOR. Among the 111 patients followed six months after treatment, IOR, number of occlusions, and total time of occlusion were not associated with Glasgow Outcome Scale (GOS) in the follow-up (respectively, p = 0.18, p = 0.30, and p = 0.73). Among patients who underwent TAO, IOR was also not associated with GOS in the follow-up (p = 0.29). CONCLUSIONS: TAO was associated with IOR and surgical complications, being the latter independent of IOR occurrence. In long-term analysis, neither TAO nor IOR were associated with poor clinical outcomes.

Prospective Analysis of Cerebral Edema Admission and Clinical Outcome in Ruptured Intracranial Aneurysm.

AIM: To evaluate the association between global cerebral edema (GCE) after subarachnoid hemorrhage (SAH) and its impact on functional outcome evaluated by the modified Rankin scale (mRS). MATERIAL AND METHODS: This is a prospective cohort study with patients who were admitted to the hospital due to SAH. During the period from January 2018 to November 2019, 107 patients with intracranial aneurysms were enrolled. Using univariate and multivariate analysis, we sought to identify predictors and evaluated the impact of GCE on outcome after 6 months using the mRS. RESULTS: GCE was present in 54 (50.5%) patients, of which 27 (25.2%) were mild, 20 (18.7%) moderate and 7 (6.5%) were severe. Univariate analysis identified high Hunt-Hess and Glasgow coma scale on clinical admission as predictors factors of GCE (p < 0.05), and higher modified Fisher scale as a radiological predictor of Glasgow coma scale (p < 0.05). Thirty-three (30.8%) patients were deceased at 6 months. Death or severe disability were predicted by higher age, poor clinical scale on admission and severe GCE (p < 0.05). CONCLUSION: GCE on admission is independently associated with poor clinical outcomes at discharge, and six months after SAH. Given its strong association with poor clinical grade on admission, GCE should be considered a straightforward and radiological important marker of early brain injury, with ominous implications.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and prognosis after aneurysmal subarachnoid hemorrhage: a cohort study.

BACKGROUND: Subarachnoid hemorrhage (SAH) prognosis remains poor. Vasospasm mechanism might be associated with inflammation. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied as inflammation markers and prognostic predictors. OBJECTIVE: We aimed to investigate NLR and PLR in admission as predictors of angiographic vasospasm and functional outcome at 6 months. METHODS: This cohort study included consecutive aneurysmal SAH patients admitted to a tertiary center. Complete blood count was recorded at admission before treatment. White blood cell count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR were collected as independent variables. Vasospasm occurrence-modified Rankin scale (mRS), Glasgow outcome scale (GOS), and Hunt-Hess score at admission and at 6 months were recorded as dependent variables. Multivariable logistic regression models were used to adjust for potential confounding and to assess the independent prognostic value of NLR and PLR at admission. RESULTS: A total of 74.1% of the patients were female, with mean age of 55.6 ± 12.4 years. At admission, the median Hunt-Hess score was 2 (interquartile range [IQR] 1), and the median mFisher was 3 (IQR 1). Microsurgical clipping was the treatment for 66.2% of the patients. Angiographic vasospasm incidence was 16.5%. At 6 months, the median GOS was 4 (IQR 0.75), and the median mRS was 3 (IQR 1.5). Twenty-one patients (15.1%) died. Neutrophil-to-lymphocyte ratio and PLR levels did not differ between favorable and unfavorable (mRS > 2 or GOS < 4) functional outcomes. No variables were significantly associated with angiographic vasospasm. CONCLUSION: Admission NLR and PLR presented no value for prediction of functional outcome or angiographic vasospasm risk. Further research is needed in this field.

ANTECEDENTES: O prognóstico da hemorragia subaracnoidea (HSA) permanece ruim. Vasoespasmo pode estar associado à inflamação. Razões neutrófilo-linfócito (NLR) e plaqueta-linfócito (PLR) têm sido estudadas como marcadores de inflamação e prognóstico. OBJETIVO: Investigar NLR e PLR na admissão como preditores de vasoespasmo angiográfico e desfecho aos 6 meses. MéTODOS: Este estudo de coorte incluiu pacientes consecutivos com HSA aneurismática de um centro terciário. Contagem de leucócitos, neutrófilos, linfócitos e plaquetas, proporção de neutrófilos para linfócitos e de plaquetas para linfócitos foram coletados como variáveis independentes. Ocorrência de vasoespasmo, escala de Rankin modificada, escala de desfecho de Glasgow e o escore de Hunt-Hess na admissão e 6 meses após a mesma foram registradas como variáveis dependentes. Modelos de regressão logística multivariável foram usados para ajustar potenciais fatores de confusão e avaliar valor prognóstico independente de NLR e PLR. RESULTADOS: Um total de 74,1% pacientes eram do sexo feminino, com idade média de 55,6 ± 12,4 anos. Na admissão, a pontuação média de Hunt-Hess foi de 2 (IQR 1) e a mediana de mFisher foi de 3 (IQR 1). Clipagem microcirúrgica foi o tratamento escolhido para 66,2% dos pacientes. A incidência de vasoespasmo angiográfico foi de 16,5%. Aos 6 meses, a escala de desfecho de Glasgow mediana era 4 (IQR 0,75) e a escala de Rankin modificada mediana era 3 (IQR 1,5). Vinte e um pacientes (15,1%) morreram. Os níveis de NLR e PLR não diferiram entre resultados funcionais favoráveis e desfavoráveis (mRS > 2 ou GOS < 4). Nenhuma variável foi significativamente associada ao vasoespasmo angiográfico. CONCLUSãO: Razão neutrófilo-linfócito e a PLR não apresentaram valor preditivo de desfecho funcional ou risco de vasoespasmo angiográfico. Mais pesquisas são necessárias neste campo.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and prognosis after aneurysmal subarachnoid hemorrhage: a cohort study / Razão neutrófilos-linfócitos e razão plaquetas-linfócitos e o prognóstico de hemorragia subaracnóidea aneurismática: um estudo de coorte

Abstract Background Subarachnoid hemorrhage (SAH) prognosis remains poor. Vasospasm mechanism might be associated with inflammation. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied as inflammation markers and prognostic predictors. Objective We aimed to investigate NLR and PLR in admission as predictors of angiographic vasospasm and functional outcome at 6 months. Methods This cohort study included consecutive aneurysmal SAH patients admitted to a tertiary center. Complete blood count was recorded at admission before treatment. White blood cell count, neutrophil count, lymphocyte count, platelet count, NLR, and PLR were collected as independent variables. Vasospasm occurrence-modified Rankin scale (mRS), Glasgow outcome scale (GOS), and Hunt-Hess score at admission and at 6 months were recorded as dependent variables. Multivariable logistic regression models were used to adjust for potential confounding and to assess the independent prognostic value of NLR and PLR at admission. Results A total of 74.1% of the patients were female, with mean age of 55.6 ± 12.4 years. At admission, the median Hunt-Hess score was 2 (interquartile range [IQR] 1), and the median mFisher was 3 (IQR 1). Microsurgical clipping was the treatment for 66.2% of the patients. Angiographic vasospasm incidence was 16.5%. At 6 months, the median GOS was 4 (IQR 0.75), and the median mRS was 3 (IQR 1.5). Twenty-one patients (15.1%) died. Neutrophil-to-lymphocyte ratio and PLR levels did not differ between favorable and unfavorable (mRS > 2 or GOS < 4) functional outcomes. No variables were significantly associated with angiographic vasospasm. Conclusion Admission NLR and PLR presented no value for prediction of functional outcome or angiographic vasospasm risk. Further research is needed in this field.

Resumo Antecedentes O prognóstico da hemorragia subaracnoidea (HSA) permanece ruim. Vasoespasmo pode estar associado à inflamação. Razões neutrófilo-linfócito (NLR) e plaqueta-linfócito (PLR) têm sido estudadas como marcadores de inflamação e prognóstico. Objetivo Investigar NLR e PLR na admissão como preditores de vasoespasmo angiográfico e desfecho aos 6 meses. Métodos Este estudo de coorte incluiu pacientes consecutivos com HSA aneurismática de um centro terciário. Contagem de leucócitos, neutrófilos, linfócitos e plaquetas, proporção de neutrófilos para linfócitos e de plaquetas para linfócitos foram coletados como variáveis independentes. Ocorrência de vasoespasmo, escala de Rankin modificada, escala de desfecho de Glasgow e o escore de Hunt-Hess na admissão e 6 meses após a mesma foram registradas como variáveis dependentes. Modelos de regressão logística multivariável foram usados para ajustar potenciais fatores de confusão e avaliar valor prognóstico independente de NLR e PLR. Resultados Um total de 74,1% pacientes eram do sexo feminino, com idade média de 55,6 ± 12,4 anos. Na admissão, a pontuação média de Hunt-Hess foi de 2 (IQR 1) e a mediana de mFisher foi de 3 (IQR 1). Clipagem microcirúrgica foi o tratamento escolhido para 66,2% dos pacientes. A incidência de vasoespasmo angiográfico foi de 16,5%. Aos 6 meses, a escala de desfecho de Glasgow mediana era 4 (IQR 0,75) e a escala de Rankin modificada mediana era 3 (IQR 1,5). Vinte e um pacientes (15,1%) morreram. Os níveis de NLR e PLR não diferiram entre resultados funcionais favoráveis e desfavoráveis (mRS > 2 ou GOS < 4). Nenhuma variável foi significativamente associada ao vasoespasmo angiográfico. Conclusão Razão neutrófilo-linfócito e a PLR não apresentaram valor preditivo de desfecho funcional ou risco de vasoespasmo angiográfico. Mais pesquisas são necessárias neste campo.

Clinical-Epidemiological Characteristics and IFITM-3 (rs12252) Variant Involvement in HIV-1 Mother-to-Children Transmission Susceptibility in a Brazilian Population.

Mother-to-children transmission (MTCT) is the main infection route for HIV-1 in children, and may occur during pregnancy, delivery, and/or postpartum. It is a multifactorial phenomenon, where genetic variants play an important role. This study aims at analyzing the influence of clinical epidemiological characteristics and a variant (rs12252) in interferon-induced transmembrane protein 3 (IFITM-3), a gene encoding an important viral restriction factor, on the susceptibility to HIV-1 mother-to-children transmission (MTCT). A case-control study was performed on 209 HIV-1-infected mothers and their exposed infected (87) and uninfected (122) children from Pernambuco, Brazil. Clinical-epidemiological characteristics are significantly associated with MTCT susceptibility. Transmitter mothers have a significantly lower age at delivery, late diagnosis, deficiency in ART use (pregnancy and delivery), and detectable viral load in the third trimester of pregnancy compared with non-transmitter mothers. Infected children show late diagnosis, vaginal delivery frequency, and tend to breastfeed, differing significantly from uninfected children. The IFITM-3 rs12252-C allele and TC/CC genotypes (dominant model) are significantly more frequent among infected than uninfected children, but the statistical significance does not remain when adjusted for clinical factors. No significant differences are observed between transmitter and non-transmitter mothers in relation to the IFITM-3 variant.

Sarcopenia as a Predictor of the Functional Outcome in Patients with Intracranial Aneurysms.

INTRODUCTION: Radiological indicators in head computed tomography (CT) scan have emerged as tools to evaluate sarcopenia using the sectional area and thickness of the temporal muscle. They can be obtained by standardized measurements in preoperative image assessment of patients with brain aneurysms. We aimed to evaluate the association between functional outcomes after interventions for intracranial aneurysms (IAs) and temporal muscle thickness (TMT) and area (TMA), as surrogates of sarcopenia. METHODS: This is a prospective observational cohort study in patients who underwent microsurgery or embolization for ruptured or unruptured IA between January 2018 and December 2019, with a 6-month follow-up. Preoperative CT scans were analyzed to measure TMT and TMA. The functional outcome was assessed by the modified Rankin Scale (mRS). The main outcome was the relationship between sarcopenia and the postoperative functional outcome. RESULTS: A total of 361 patients were included, of whom 199 (55.1%) had ruptured and 162 (44.9%) had unruptured lesions. Larger TMA significantly predicted better functional outcomes at discharge. TMT was associated with functional outcomes at both discharge and 6 months, adjusted for rupture and hypertension. Maximizing the sum sensitivity-specificity, an optimal TMT cutoff of 6.25 mm can predict unfavorable outcomes. Maximizing the positive predictive value × negative predictive value of a product, the cutpoint was 3.55 mm. CONCLUSIONS: Sarcopenia, represented by TMT and TMA, is associated with poorer functional results at discharge and 6-month follow-up in IA surgery. TMT below 6.25 mm was associated with unfavorable functional outcomes. These easily obtainable measurements may improve the decision-making process for patients with IAs.

Role of temporary arterial occlusion in subarachnoid hemorrhage outcomes: a prospective cohort study

Purpose: Temporary arterial occlusion (TAO) is a widespread practice in the surgical treatment of intracranial aneurysms. This study aimed to investigate TAO's role during ruptured aneurysm clipping as an independent prognostic factor on short- and long-term outcomes. Methods: This prospective cohort included 180 patients with ruptured intracranial aneurysms and an indication of microsurgical treatment. Patients who died in the first 12 hours after admission were excluded. Results: TAO was associated with intraoperative rupture (IOR) (odds ratio ­ OR = 10.54; 95% confidence interval ­ 95%CI 4.72­23.55; p < 0.001) and surgical complications (OR = 2.14; 95%CI 1.11­4.07; p = 0.01). The group with TAO and IOR had no significant difference in clinical (p = 0.06) and surgical (p = 0.94) complications compared to the group that had TAO, but no IOR. Among the 111 patients followed six months after treatment, IOR, number of occlusions, and total time of occlusion were not associated with Glasgow Outcome Scale (GOS) in the follow-up (respectively, p = 0.18, p = 0.30, and p = 0.73). Among patients who underwent TAO, IOR was also not associated with GOS in the follow-up (p = 0.29). Conclusions: TAO was associated with IOR and surgical complications, being the latter independent of IOR occurrence. In long-term analysis, neither TAO nor IOR were associated with poor clinical outcomes.

Microsurgery versus embolization: different risk factors for short- and longterm outcomes of patients with ruptured aneurysms.

PURPOSE: To evaluate the risk factors for poor outcomes after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Patients with ≥ 18-years of age and aSAH were included, while patients who died within 12 h of admission or lost follow-up were excluded. All participants underwent standardized clinical and radiological assessment on admission and were reassessed at discharge and at 6-months follow-up using the Glasgow Outcome Scale (GOS). RESULTS: Death at discharge was associated with female gender, anterior communication artery (ACoA) aneurysm location and presence of atherosclerotic plaque in the surgical group, and with age in the endovascular group. Both groups had clinical condition on follow-up associated with mFisher score on admission and hypertension. GOS on follow-up was also associated with presence of atherosclerotic plaque and multiple aneurysms in surgical group, and with age in endovascular group. CONCLUSIONS: Subjects treated surgically are prone to unfavorable outcomes if atherosclerotic plaques and multiple aneurysms are present. In patients with endovascular treatment, age was the main predictor of clinical outcome.

A Pilot Study Testing the Effectiveness of a Mindfulness-Based Program for Portuguese School Children.

Objectives: Research into the effectiveness of mindfulness-based programs (MBPs) in school settings has grown substantially. However, studies in the field are still scarce, present methodological limitations, and fail to examine how children's characteristics influence MBPs' effects. The twofold aim of this study was to analyze the effectiveness of an MBP on children's attention and emotional regulation, writing performance, and school grades, and to evaluate the moderating role of baseline scores, age, gender, and socioeconomic status. Methods: Fifty-seven third graders received the MBP (n = 28) or a health-based program (n = 29), which is the active control group, for 8 weeks. In each week, both programs were composed of two 30-min sessions delivered by psychologists and three 5-min sessions delivered by teachers. Before and after the implementation of the programs, we assessed teacher-rated children's attention and emotional regulation, performance-based attention networks (alerting, orienting, and conflict monitoring), writing performance (handwriting fluency, spelling, and text quality), and school grades in Portuguese, Mathematics, and Social Studies. Results: Compared to the control group, after the program, the mindfulness group displayed higher teacher-rated attention and emotional regulation, as well as better Portuguese, Mathematics, and Social Studies grades. Emotional regulation and alerting baseline scores as well as age were found to moderate the MBP's effects. Conclusions: These findings provide preliminary evidence on the effectiveness of a MBP on children's behavior and school grades. This means that students may benefit from the integration of mindfulness practices into the educational setting as a complement to the school curriculum.

Transcriptome Meta-Analysis Confirms the Hidradenitis Suppurativa Pathogenic Triad: Upregulated Inflammation, Altered Epithelial Organization, and Dysregulated Metabolic Signaling.

Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers.

Proximal tubular dysfunction related to tenofovir in people living with HIV/AIDS: a pharmacogenetic study.

OBJECTIVES: The purpose of this case-control study was to verify the association between single nucleotide polymorphisms (SNPs) in genes encoding drug transporters related to tenofovir disoproxil fumarate (TDF) and proximal renal tubular dysfunction (PRTD), and the association between PRTD and clinical characteristics. METHODS: The 'cases' met the diagnostic criteria for PRTD, determined by the presence of two or more of the following abnormalities: non-diabetic glycosuria, metabolic acidosis, increased uric acid and phosphorus excretion, decreased tubular phosphorus reabsorption and ß2-microglobulinuria. We analyzed eight SNPs in ABCC2, ABCC4, ABCC10 and SLC28A2 genes. Genotyping was performed using real-time PCR. RESULTS: Of the 204 people living with HIV, 38 (18.6%) met the criteria for diagnosis of PRTD and 131 were male (64.2%), with a mean age of 49 years and a history of previous antiretroviral therapy for an average of 5 years. In the multivariate analysis, older individuals, TDF use, protease inhibitor, antihypertensives and anticonvulsants were associated with a risk of developing PRTD. Increased excretion of ß2microglobulin was associated with the A/G genotype of rsCC8187710 from ABCC2 ( P = 0.003) and the following genotypes of ABCC4 SNPs: A/G from rs1059751 ( P = 0.023), G/G from rs1059751 ( P = 0.030) and C/C of rs3742106 ( P = 0.041). The increase in the fraction of excreted phosphorus was associated with the C/T genotype of SNCC rsP40037 from ABCC2 ( P = 0.0041). CONCLUSIONS: The results indicate an important relationship between SNPs associated with these markers and changes in proximal renal tubule function, and thus support their use as biomarkers for the early detection of PRTD risk.

Gain-of-function STAT1 mutation and visceral leishmaniasis.

Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Celecoxib in the treatment of orofacial pain and discomfort in rats subjected to a dental occlusal interference model.

PURPOSE: To evaluate the effect of a selective cyclooxygenase 2 (COX-2) inhibitor on trigeminal ganglion changes and orofacial discomfort/nociception in rats submitted to an experimental model of dental occlusal interference (DOI). METHODS: Female Wistar rats (180-200 g) were divided into five groups: a sham group (without DOI) (n=15); and four experimental groups with DOI treated daily with 0.1 mL/kg saline (DOI+SAL), 8, 16, or 32 mg/kg celecoxib (DOI+cel -8, -16, -32) (n=30/group). The animals were euthanized after one, three, and seven days. The bilateral trigeminal ganglia were analyzed histomorphometrically (neuron cell body area) and immunohistochemically (COX-2, nuclear factor-kappa B [NFkB], and peroxisome proliferator-activated receptor-y [PPARy]). A bilateral nociception assay of the masseter muscle was performed. The number of bites/scratches, weight, and grimace scale scores were determined daily. One-way/two-way analysis of variance (ANOVA)/Bonferroni post hoc tests were used (P < .05, GraphPad Prism 5.0). RESULTS: DOI+SAL showed a reduction in neuron cell body area bilaterally, whereas DOI+cel-32 exhibited a significative increase in neuron cell body area compared with DOI+SAL group (P < 0.05). The ipsilateral (P=0.007 and P=0.039) and contralateral (P < 0.001 and P=0.005) overexpression of COX-2 and NFkB and downregulation of PPARy (P=0.016 and P < 0.001) occurred in DOI+SAL, but DOI+cel-32 reverted this alteration. DOI+SAL showed increase in isplateral (P < 0.001) and contralateral (P < 0.001) nociception, an increased number of bites (P=0.010), scratches (P < 0.001), and grimace scores (P=0.032). In the group of DOI+cel-32, these parameters were reduced. CONCLUSIONS: Celecoxib attenuated DOI-induced transitory nociception/orofacial discomfort resulting from trigeminal COX-2 overexpression.

Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil.

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI). METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing. RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01). CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.