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LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049&#95;2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Dietary alternatives using insect-based products as an alternative for farm animal nutrition have been the object of study due to the high nutritional value of these feeds and the costs related to both their production and consequently their commercialization. Thus, the use of flies, especially larvae, has a high content of proteins and lipids (fat), as well as minerals and essential nutrients for development and growth, directly impacting the production of these animals, whether meat or milk. Therefore, the objective of this study was to compile data from the literature on the nutritional value of adults and larvae of Black soldier ( Hermetia illucens ) and housefly ( Musca domestica ) as a dietary alternative for animal feed. The Prisma checklist was used. After reviewing the data found in the literature, following the systematic review, it was noted that studies emerge that larvae of black soldier flies and domestic flies of the order Diptera obtain essential sources in the nutrition of ruminants, in addition to obtaining rapid digestibility, thus adhering to reproduction with high nutritional content, due to incident levels of protein, lipids, and minerals in M. domestica and Lucilia sericata , making it a target for inclusion in the diet of farm animals. In addition, it is concluded that both species are studied for their sustainable potential as well as for offering greater economic and nutritional viability when compared to ingredients present in production animal feed.

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10-15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. Notably, drugs that block abnormal functions of these pathways remarkably improve survival in uLMS patients. However, due to chemotherapy resistance, there remains a need for novel drugs that can target these pathways effectively. In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. In addition, we discuss serum markers, artificial intelligence (AI) combined with machine learning, shear wave elastography, current management and medical treatment options, and ongoing clinical trials for patients with uLMS. Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

The objective of this study was to evaluate the thermal comfort of Nelore cattle ( Bos indicus ) managed in silvopastoral and traditional systems associated with rumination behavior in a humid tropical environment in the Eastern Amazon, Brazil. The study was carried out on a rural property in Mojuí dos Campos, Pará, Brazil, during the transition period of the year, from June to July 2023. Over these two months, six consecutive data collection days were held. We selected 20 clinically healthy non-castrated male Nelore cattle, aged between 18 and 20 months, with an average weight of 250 kg and body condition score of 3.5 (1-5). These animals were randomly divided into two groups: traditional system (TS) and silvopastoral system (SS). The physiological variables evaluated included RR, RT and BST. The variables were analyzed using the linear mixed model. For agrometeorological variables, higher values were observed between 10:00 a.m. (33 °C) and 6:00 p.m. (30 °C), with the highest temperature observed at 4:00 p.m. (40 °C). The RR showed interactions ( p = 0.0214) between systems and times; in general, higher RR were obtained in the Traditional. The animals' RT showed no significant difference ( p < 0.05) between the production systems, but there was a statistically significant difference in relation to the time of collection ( p < 0.0001). In the BGHI, it was possible to observe that there was mild stress in the period from 22:00 at night to 6:00 in the morning and moderate stress in the period of greatest increase in temperature, from 10:00 in the morning to 18:00 at night. BST showed no statistical difference between the regions studied or between the SP (35.6 °C) and TS (36.25 °C) systems. RT in the TS showed a positive correlation with AT (r = 0.31507; p = 0.0477). RT in the SP showed a positive correlation with THI (r = 35583; p = 0.0242). On the other hand, RT in the SP (r = 0.42873; p = 0.0058) and ST (r = 0.51015; p = 0.0008) showed a positive correlation with BGHI. RR in the TS showed a positive correlation with BGHI (r = 0.44908; p = 0.0037). The greatest amounts of rumination were carried out by animals in the SP system, generally ruminating lying down ( p < 0.05). With regard to rumination behavior in the morning and afternoon, there were higher numbers of WS and LD in the TS ( p > 0.05). Most of the time, the cattle were LD during the morning and afternoon shifts, and at night and dawn they were WS in the TS. Therefore, the SP offers more thermal comfort advantages compared to the TS system.

Objective: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis., Methods: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes., Results: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated., Conclusions: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest and funding disclosures., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Objective  To evaluate the effects of estrogen, raloxifene and genistein on the expression of KISS1 (kisspeptin), KISS1R (kisspeptin receptor), AR (androgen receptor) and INSR (insulin receptor) in the bones of ovariectomized rats. Methods  Forty-eight adult rats were randomly divided into 6 groups, containing 8 animals each: G1-nonovariectomized control; G2-ovariectomized and treated with conjugated equine estrogens (50 µg/Kg/day); G3-ovariectomized and treated with raloxifene (0.75 mg/kg/day); G4-ovariectomized animal that received soy extract with genistein (300 mg/kg/day); G5-ovariectomized animal that received estrogen and genistein; and G6-ovariectomized animal that received estrogen and raloxifene. Three months after surgery, the castrated animals received the drugs orally daily for 120 days. All animals were sacrificed after this period, by deepening the anesthesia. The left tibia was removed for total RNA extraction and analysis of gene expression of KISS1 , KISS1R , AR and INSR , by quantitative real-time polymerase chain reaction (qRT-PCR). Results   KISS1 was not detected in any of the treated groups. KISS1R , INSR and AR showed higher expression in the G3 group ( p  < 0.001), while lower levels of transcripts for these genes were observed in G4 and G5. G2 animals showed hypoexpression of the evaluated genes. Conclusion  The results indicate that raloxifene, alone or combined with estrogen, was able to induce the expression of genes associated with the recovery of bone tissue homeostasis in ovariectomized rats., Competing Interests: Conflito de Interesses Os autores declaram não haver conflito de interesses., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit ( https://creativecommons.org/licenses/by/4.0/ ).)

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM&#95;000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM&#95;001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM&#95;005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

The emergence of therapies acting on specific molecular targets for Duchenne and Becker muscular dystrophies (DBMD) led to expanded access of diagnostic DMD analysis. However, it is unclear how much of these advances have also improved healthcare and access to genetic testing for women at-risk of being carriers. This study evaluates the process of genetic counseling and empowerment of genetic information by women from DBMD families. We carried out a cross-sectional study between February and June 2022 in Brazil. The online survey with items regarding sociodemographic data; family history; access to health services; reproductive decisions; and the Genomic Outcome Scale was answered by 123 women recruited from a rare diseases reference service and a nationwide patient advocacy group. Genetic counseling was reported by 77/123 (62.6%) of women and 53.7% reported having performed genetic analysis of DMD. Although the majority knew about the risks for carriers of developing heart disease and muscle weakness, only 35% of potential carriers have had cardiac studies performed at least once in their lives. Country region, type of kinship, number of affected males in the family, age, notion of genetic risk, education level, and participation in advocacy groups were the main factors associated with adequate healthcare access to women and empowerment of genetic information. Education to health professionals and policies to expand access to carrier genetic testing, whether public policies or regulation of pharmaceutical companies' diagnostic programs, is paramount to improve the care of families with DBMD in Brazil., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease whose pattern of weakness is predominantly distal. Limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) is another neuromuscular disease, which presents an autosomal recessive inheritance and is marked by proximal muscle weakness. Even if uncommon, comorbid inherited pathologies must be considered in cases of atypical presentations, especially in those with family history of consanguinity., Case Presentation: Herein, we report the unique case of a patient diagnosed with both DM1 and LGMD2B/R2: a 38-year-old woman in follow-up of DM1 in a neuromuscular disease service presenting prominent proximal weakness. The patient's parents were consanguineous, and creatine kinase levels were elevated. A multi-gene panel test was performed and revealed the diagnosis of LGMD2B/R2., Conclusion: Genetic diseases with atypical presentations should raise the possibility of a second disorder, prompting an appropriate investigation. Overlooking a second diagnosis can implicate in not offering adequate genetic counseling, support, or specific treatment., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In Brazil, the National Neonatal Screening Program tests for six diseases, with a new law issued in 2021 stating that it should incorporate more diseases, including SMA. In the present study, dried blood spot (DBS) samples collected by the Reference Services of Neonatal Screening of RS and SP, to perform the conventional test were also screened for SMA, using real-time PCR, with SALSA MC002 technique. A total of 40,000 samples were analyzed, enabling the identification of four positive cases of SMA, that were confirmed by MLPA. Considering our sampling, Brazil seems to have an incidence comparable to the described in other regions. This work demonstrated that the use of the MC002 technique in samples routinely collected for the conventional NBS program is suitable to screen for SMA in our conditions and can be included in the expansion of the neonatal screening programs.

Long COVID is characterized by persistent signs and symptoms that continue or develop for more than 4 weeks after acute COVID-19 infection. Patients with Long COVID experience a cardiovascular autonomic imbalance known as dysautonomia. However, the underlying autonomic pathophysiological mechanisms behind this remain unclear. Current hypotheses include neurotropism, cytokine storms, and inflammatory persistence. Certain immunological factors indicate autoimmune dysfunction, which can be used to identify patients at a higher risk of Long COVID. Heart rate variability can indicate autonomic imbalances in individuals suffering from Long COVID, and measurement is a non-invasive and low-cost method for assessing cardiovascular autonomic modulation. Additionally, biochemical inflammatory markers are used for diagnosing and monitoring Long COVID. These inflammatory markers can be used to improve the understanding of the mechanisms driving the inflammatory response and its effects on the sympathetic and parasympathetic pathways of the autonomic nervous system. Autonomic imbalances in patients with Long COVID may result in lower heart rate variability, impaired vagal activity, and substantial sympathovagal imbalance. New research on this subject must be encouraged to enhance the understanding of the long-term risks that cardiovascular autonomic imbalances can cause in individuals with Long COVID., Competing Interests: JASQ is a member of the editorial board of Frontiers in Cardiovascular Medicine. This had no impact on the peer review process and the final decision. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Marques, Quaresma and Falcão.)

In the Lower Amazon mesoregion, there are basically three types of production systems: the traditional (without shade and no bathing area), the silvopastoral (with shade and no bathing area), and the integrated (with shade and bathing area). It is considered that the type of production system influences the thermal comfort and productivity of cattle, so this research aims to evaluate the influence of these three types of production systems on the thermoregulation of Nellore cattle. The experiment was carried out on a rural property for raising cattle, located in Mojuí dos Campos, Pará, Brazil, during the transition period (June/July). Thirty bovine males (not castrated, aged between 18 and 20 months, average weight of 250 ± 36 kg, body condition score of 3.5, clinically healthy) were randomly divided into three groups: Silvopastoral System-SS ( n = 10), Traditional System-TS ( n = 10), and Integrated System-IS ( n = 10). Climate variables were collected (air temperature (AT °C), relative humidity (RH %), wind speed (WS, m/s), solar radiation (SR), black globe temperature (BGT °C), and physiological parameters, such as respiratory rate (RR) and rectal temperature (RT)) at 6 a.m., 12 p.m., 6 p.m., and 12 a.m. to determine the thermal comfort situation of the animals. Thermographic images of the environment and animals were captured in order to obtain the body surface temperature (BST) through infrared thermography. The Benezra Thermal Comfort Index (BTCI), Environmental Stress Index (ESI), Equivalent Temperature Index (ETI), and Iberian Heat Tolerance Index (Iberian HTI) were used. The results showed that the silvopastoral system, with shading by chestnut trees and an ample vegetative area, presented better thermal conditions, with an average of 28.98 °C, in comparison with the traditional system (35.93 °C) and the integrated one (34.11 °C). It was observed that the body surface temperature of cattle did not differ significantly between the anatomical regions of the body and the studied systems ( p > 0.05). As for the respiratory rate, the traditional system registered higher values, with an average of 41 movements per minute, indicating possible thermal stress ( p < 0.05). The thermal comfort indices revealed that all systems presented moderate stress conditions during times of higher solar intensity. It is concluded that the silvopastoral system proved to be more favorable for cattle, providing shade and reducing thermal stress, which may have a positive impact on animal welfare and productivity in this region.

Objective: To evaluate otolith function by comparing the findings of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential tests in patients in the inter-crisis period of unilateral definite Meniere's disease., Methods: The sample consisted of an experimental group (n=22; 10 men and 12 women, mean age 47.32±12.82 years) with definite unilateral Meniere's disease and a control group (n=14; 5 men and 9 women, with a mean age of 41.64±13.45 years). They all underwent vestibular evaluation by means of Subjective Visual Vertical with the bucket method and, cervical and ocular Vestibular Evoked Myogenic Potential tests. The data were collected and subjected to statistical analysis., Results: The results of the comparison of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential, the ocular Vestibular Evoked Myogenic Potential and, the association of cervical Vestibular Evoked Myogenic Potential with the ocular Vestibular Evoked Myogenic Potential showed no significant difference, indicating concordance among the tests., Conclusion: The identified abnormalities and the concordance between the combined proportion of the Subjective Visual Vertical, the cervical Vestibular Evoked Myogenic Potential and the ocular Vestibular Evoked Myogenic Potential findings indicate that the association of these three tests contributes to the identification of sustained and transient otolith dysfunction in the inter-crisis of unilateral definite Meniere's disease., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Copy number variations (CNV) may represent a significant proportion of SPG4 and SPG3A diagnosis, the most frequent autosomal dominant subtypes of hereditary spastic paraplegias (HSP). We aimed to assess the frequency of CNVs in SPAST and ATL1 and to update the molecular epidemiology of HSP families in southern Brazil. A cohort study that included 95 Brazilian index cases with clinical suspicion of HSP was conducted between April 2011 and September 2022. Multiplex Ligation Dependent Probe Amplification (MLPA) was performed in 41 cases without defined diagnosis by different massive parallel sequencing techniques (MPS). Diagnosis was obtained in 57/95 (60%) index cases, 15/57 (26.3%) being SPG4. Most frequent autosomal recessive HSP subtypes were SPG7 followed by SPG11, SPG76 and cerebrotendinous xanthomatosis. No CNVs in SPAST and ATL1 were found. Copy number variations are rare among SPG4 and SPG3A families in Brazil. Considering the possibility of CNVs detection by specific algorithms with MPS data, we consider that this is likely the most cost-effective approach to investigate CNVs in these genes in low-risk populations, with MLPA being reserved as an orthogonal confirmatory test., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Healthy brain aging can be defined as aging without neurological or psychiatric disorders, sustaining functional independence. In addition to the absence of disease and preserved functionality, there are individuals who stand out for their superior performance to that considered normal for their age in cognitive tests. These individuals are called "high-performance older adults" (HPOA)., Objectives: To investigate the presence of HPOA in an oldest-old population with low education, and if present, to investigate associations with sociodemographic, clinical, and lifestyle variables., Methods: We evaluated 132 cognitively healthy individuals from the Pietà Study, a population-based investigation with 639 participants. We used the delayed recall from the Rey Auditory-Verbal Learning Test to verify the existence of HPOA and to classify participants based on their performance. Sociodemographic, clinical, and lifestyle variables associated with HPOA were investigated., Results: We identified 18 individuals fulfilling HPOA criteria (age: 77.4 ± 2.6 years old; 14 women; education: 4.6 ± 3.4 years). The other participants, 114 total (age: 79.8 ± 4.5 years old; 69 women; education: 3.0 ± 2.7 years) were classified as "standard performance older adults" (SPOA). In multivariate analysis, younger age (odds ratio [OR] = 0.672; 95% confidence interval [CI]: 0.462-0.979; p  = 0.037) and lower scores on the Geriatric Depression Scale (OR = 0.831; 95%CI: 0.688-0.989; p  = 0.038) were associated with HPOA., Conclusions: The present study identifies for the first time HPOA with low educational level, thereby reinforcing the existence of biological substrates related to this condition. Furthermore, the data suggest an association between younger age and less depressive symptoms with HPOA., Competing Interests: The authors have no conflict of interests to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Leiomyomas (LMs) are the most frequent uterine benign tumors, representing the leading cause of hysterectomy indications worldwide. They are highly associated with women's reproductive complications, and endocrine disruptors may influence their etiology. In this sense, air pollution represents a relevant hormonal disruptor that acts on key signaling pathways, resulting in tumor development and infertility. Our goal was to evaluate submucosal LM samples from patients living in the metropolitan and Sao Paulo city regions, focusing on genes involved in tumor development and infertility features. Twenty-four patients were selected based on their region of residence and clinical information availability. Several genes were differentially expressed between women living in metropolitan areas and Sao Paulo city. Significant associations were observed between BCL-2 , DVL1 , FGFR3 , and WNT5b downregulation and contraceptive use in the samples from women living in Sao Paulo city. ESR1 and HHAT downregulation was associated with ethnicity. WNT5b and GREM were associated with LM treatment and related pathologies, respectively. In the samples from women living in other cities of the metropolitan region, abortion occurrence was associated with BMP4 upregulation. Although further studies may be necessary, our results showed that air pollution exposure influences the expression of genes related to LM development and female reproductive features.

FOXO3a dysregulation is frequently implicated in tumorigenesis, and its inhibition can occur by several molecular mechanisms. Among these, post-transcriptional suppression by miRNAs has been associated with various cancers initiation. Here, we assessed the expression profiles of the most relevant miRNAs for breast tumorigenesis, using Luminal A (LA) and Triple-Negative (TN) breast cancer from Brazilian patients, by the quantitative real time-PCR method. Their potential prognostic role for the patients was also evaluated. We identified the miRNAs miR-96-5p and miR-182-5p, de-scribed as negative regulators of FOXO3A, with differential expression both in LA and TN tumors when compared to normal tissue. The miR-96-5p and miR-182-5p miRNAs were upregulated in LA (7.82 times, p < 0.005; 6.12 times, p < 0.005, respectively) and TN breast cancer samples (9.42 times, p < 0.0001; 8.51 times, p < 0.0001) compared to normal tissues. The samples with higher miR-96-5p and miR-182-5p expression (FR ≥ 4) were submitted for FOXO3a immunostaining. Reduced protein detection was observed in all of the tumors compared to normal tissues. The most prominent miRNA expression and FOXO3a protein suppression were observed in TN samples (p < 0.001), indicating the relevant role of these molecules in this tumor biology and clinical behavior. Our results corroborate the literature regarding to the relevance of FOXO3a in the breast cancer, and they open new perspectives for alternative target therapy options for Brazilian patients expressing both FOXO3a and its regulatory miRNAs., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Studies assessing the management of laryngopharyngeal reflux by otolaryngologists have reported an important heterogeneity regarding the definition, diagnosis, and treatment, which leads to discrepancies in the management of the patient. Information about the current knowledge and practices of Brazilian otolaryngologists in laryngopharyngeal reflux is lacking., Objective: To investigate the trends in management of laryngopharyngeal reflux disease among Brazilian otolaryngologists., Methods: A survey was sent by email to the members of the Brazilian Association of Otolaryngology-Head Neck Surgery. This survey has initially been conducted by the laryngopharyngeal reflux study group of young otolaryngologists of the International Federation of Otolaryngological Societies., Results: According to the survey responders, the prevalence of laryngopharyngeal reflux was estimated to be 26.8% of patients consulting in otolaryngology and the most common symptoms were globus sensation, throat clearing, cough and stomach acid reflux. Nasal obstruction, Eustachian tube dysfunction, acute and chronic otitis media, vocal fold nodules and hemorrhage were considered not associated with laryngopharyngeal reflux by the majority of responders. About 2/3 of Brazilian otolaryngologists based the diagnosis of laryngopharyngeal reflux on the assessment of both symptoms and findings and a positive response to empiric therapeutic trials. Proton pump inhibitor utilized once or twice daily, was the most commonly used therapeutic scheme. Only 21.4% of Brazilian otolaryngologists have heard about nonacid and mixed laryngopharyngeal reflux and the awareness about the usefulness of multichannel intraluminal impedance pH monitoring (MII-pH) was minimal; 30.5% of responders did not consider themselves as well-informed about laryngopharyngeal reflux., Conclusion: Although the laryngopharyngeal reflux-related symptoms, main diagnostic and treatment approaches referred by Brazilian otolaryngologists are consistent with the literature, the survey identified some limitations, such as the insufficient awareness of the role of laryngopharyngeal reflux in many otolaryngological conditions and of the possibility of non-acid or mixed reflux in refractory cases. Future studies are needed to establish international recommendations for the management of laryngopharyngeal reflux disease., (Copyright © 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Objectives: To perform vestibular assessment using cervical and ocular vestibular evoked myogenic potential, video head impulse test and caloric testing in patients with sudden hearing loss. Moreover, to evaluate the correlation of dizziness with vestibular tests and the correlation of vestibular tests with hearing prognosis., Methods: This is an observational, longitudinal and prospective study, including participants diagnosed with sudden hearing loss. The participants underwent cervical and ocular vestibular evoked myogenic potential, video head impulse test and caloric testing. The audiometric assessment was performed at the beginning and at the end of the follow-up. A value of p≤0.05 was considered statistically significant., Results: Seventeen patients were included in the study sample, with a mean age of 45.4±11.1 years. Five participants (29.41%) had dizziness and 15 (88.23%) had tinnitus. All participants underwent vestibular evaluation through cervical and ocular vestibular evoked myogenic potential and video head impulse test, and 13 of them were evaluated through caloric testing. The cervical vestibular evoked myogenic potential was considered altered in five (29.41%) participants, while 11 (64.71%) showed alterations at the ocular vestibular evoked myogenic potential. The video head impulse test and the caloric testing were considered altered in seven (41.18%) and five (38.46%) participants, respectively. There was no statistically significant correlation between the clinical data and the results of vestibular tests or hearing recovery, nor between the results of vestibular tests and hearing recovery., Conclusion: The assessment through vestibular evoked myogenic potential, video head impulse test and caloric testing showed vestibular involvement in some participants. However, it cannot be stated that the results of the vestibular tests are related to the hearing prognosis of sudden hearing loss., (Copyright © 2022 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of "pure" uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.

Objective: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrinopathy, which etiology encompasses complex genetic traits associated with epigenetic factors, including differences in microRNA (miRNA) expression in a variety of tissues. The circulating form of these molecules is raising attention in the syndrome not only as potential biomarkers of PCOS but also as possible therapeutic targets. The aim of this study was to explore the circulating miRNA profiles present in a cohort of Brazilian women with and without PCOS and to evaluate the potential role of miRNAs in the pathophysiology of the syndrome., Methods: Cross-sectional study of 36 well-characterized PCOS women and 16 healthy controls. Clinical, hormone and metabolic data were recorded and evaluated. The expression profile of the 201 circulating miRNA selected were analyzed by taqman quantitative real time polymerase chain reactions (RT-PCR) using a customized Open Array platform. Statistical and bioinformatic analyzed were performed., Results: Circulating miR-21-5p, miR-23a-3p and miR-26a-5p were upregulated, and miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p were downregulated in women with PCOS compared to healthy normo-ovulatory controls. miR-21-5p, miR-103a-3p and miR-376a-3p levels correlated positively with androgen levels. These miRNAs, in combination, were related to pathways involved in insulin signaling, steroids biosynthesis and endothelial regulation as well as in folliculogenesis., Conclusion: In this study, we identified a specific circulating miRNA signature in Brazilian women with PCOS. According to our data, circulating miR-21-5p, miR-23a-3p, miR-26a-5p, miR-103a-3p, miR-376a-3p, miR-19b-3p and miR-222-3p may represent potential candidates for differential diagnosis of PCOS in the future., Competing Interests: The authors have declared that no competing interests exist.

Although several clinical manifestations of persistent long coronavirus disease (COVID-19) have been documented, their effects on the cardiovascular and autonomic nervous system over the long term remain unclear. Thus, we examined the presence of alterations in cardiac autonomic functioning in individuals with long-term manifestations. The study was conducted from October 2020 to May 2021, and an autonomic assessment was performed to collect heart rate data for the heart rate variability (HRV) analysis. The study participants were divided into the long COVID clinical group, the intragroup, which included patients who were hospitalized, and those who were not hospitalized and were symptomatic for different periods (≤3, >3, ≤6, and >6 months), with and without dyspnoea. The control group, the intergroup, comprised of COVID-free individuals. Our results demonstrated that the long COVID clinical group showed reduced HRV compared with the COVID-19-uninfected control group. Patients aged 23-59 years developed COVID symptoms within 30 days after infection, whose diagnosis was confirmed by serologic or reverse-transcription polymerase chain reaction (swab) tests, were included in the study. A total of 155 patients with long COVID [95 women (61.29%), mean age 43.88 ± 10.88 years and 60 men (38.71%), mean age 43.93 ± 10.11 years] and 94 controls [61 women (64.89%), mean age 40.83 ± 6.31 and 33 men (35.11%), mean age 40.69 ± 6.35 years] were included. The intragroup and intergroup comparisons revealed a reduction in global HRV, increased sympathetic modulation influence, and a decrease in parasympathetic modulation in long COVID. The intragroup showed normal sympathovagal balance, while the intergroup showed reduced sympathovagal balance. Our findings indicate that long COVID leads to sympathetic excitation influence and parasympathetic reduction. The excitation can increase the heart rate and blood pressure and predispose to cardiovascular complications. Short-term HRV analysis showed good reproducibility to verify the cardiac autonomic involvement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marques, Silva, Trindade, Santos, Rocha, Vasconcelos, Quaresma and Falcão.)

The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was performed at five centers in Brazil, in which probands and affected relatives' data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020. One hundred and six individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4. Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases., (© 2021. The Author(s).)

Background: Colonoscopy is the gold standard for the diagnosis and treatment of adenomas. It is related with decreased colorectal cancer incidence and mortality. However, an important problem is missed colorectal adenoma. All efforts should be undertaken to reduce this rate. Enhancing imaging technologies including electronic chromoendoscopy and magnification has been increasingly adopted for improving the colorectal neoplasia detection rate and the detailed study of its surface, as well. I-scan images (Pentax, Tokyo, Japan) provides virtual chromoendoscopy in real-time during the examination to view the surface pattern, highlighting the microvasculature of the neoplastic lesion. The evidence on the impact of the use of I-scan on the colorectal adenoma detection rate is scarce., Objective: To evaluate whether the use of I-scan has impact on the adenoma miss rate (AMR) of screening colonoscopy exams., Methods: Observational and prospective study conducted by monitoring patients over 50 years undergoing colonoscopy. There were two groups: Group 1 - first inspection with standard high-definition white-light (HDWL) followed by a second inspection with I-scan 1; Group 2 - first inspection with I-scan 1 followed by a second inspection with standard HDWL. The primary outcome was the AMR from the first exam, calculated with the number of adenomas detected in the second exam, divided by the total number of adenomas detected in both exams., Results: A total of 85 patients participated in the study. 14 were excluded, with a final sample of 71 patients, in the Group 1, 34 patients, and the Group 2, 37. A total of 58 adenomas were detected, 40 in the first inspection (20 in each group) and 18 in the second inspection in group 1. The overall AMR was higher for the Group 1 than the Group 2 (47.4% vs 0% P=0.0002)., Conclusion: The use of I-scan 1 during colonoscopy exam reduces the AMR.

The optimization of the Beetle readout ASIC and the performance of the software for the signal processing based on machine learning methods are presented. The Beetle readout chip was developed for the LHCb (Large Hadron Collider beauty) tracking detectors and was used in the VELO (Vertex Locator) during Run 1 and 2 of LHC data taking. The VELO, surrounding the LHC beam crossing region, was a leading part of the LHCb tracking system. The Beetle chip was used to read out the signal from silicon microstrips, integrating and amplifying it. The studies presented in this paper cover the optimization of its electronic configuration to achieve the lower power consumption footprint and the lower operational temperature of the sensors, while maintaining a good condition of the analogue response of the whole chip. The studies have shown that optimizing the operational temperature is possible and can be beneficial when the detector is highly irradiated. Even a single degree drop in silicon temperature can result in a significant reduction in the leakage current. Similar studies are being performed for the future silicon tracker, the Upstream Tracker (UT), which will start operating at LHC in 2021. It is expected that the inner part of the UT detector will suffer radiation damage similar to the most irradiated VELO sensors in Run 2. In the course of analysis we also developed a general approach for the pulse shape reconstruction using an ANN approach. This technique can be reused in case of any type of front-end readout chip.

Cooperation among unrelated individuals can evolve through reciprocity. Reciprocal cooperation is the process in which lasting social interactions provide the opportunity to learn about others' behavior, and to further predict the outcome of future encounters. Lasting social interactions may also decrease aversion to unequal distribution of gains - when individuals accept inequity payoffs knowing about the possibility of future encounters. Thus, reciprocal cooperation and aversion to inequity can be complementary phenomena. The present study investigated the effects of cooperative and uncooperative interactions on participants' aversion to disadvantageous inequity. Participants played an experimental task in the presence of a confederate who acted as a second participant. In reality, the participant interacted with a computer programed to make cooperative and uncooperative choices. After interacting with a cooperative or uncooperative computer, participants chose between blue cards to produce larger gains to the computer and smaller for him/her or green cards to produce equal and smaller gains for both. Results confirmed our first hypothesis that uncooperative interactions would produce aversion to disadvantageous inequity. Lastly, half of the participants were informed that points received during the experiment could be later exchanged for money, and half were not. Results indicated that information about monetary outcomes did not affect aversion to inequity, contradicting our second hypothesis. We discuss these results in the light of theories of reciprocal cooperation, inequity aversion, and conformity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suarez, Benvenuti, Couto, Siqueira, Abreu-Rodrigues, Lionello-DeNolf and Sandaker.)

Purpose: To describe the otorhinolaryngological adverse effects of the main drugs used in urological practice., Materials and Methods: A review of the scientific literature was performed using a combination of specific descriptors (side effect, adverse effect, scopolamine, sildenafil, tadalafil, vardenafil, oxybutynin, tolterodine, spironolactone, furosemide, hydrochlorothiazide, doxazosin, alfuzosin, terazosin, prazosin, tamsulosin, desmopressin) contained in publications until April 2020. Manuscripts written in English, Portuguese, and Spanish were manually selected from the title and abstract. The main drugs used in Urology were divided into five groups to describe their possible adverse effects: alpha-blockers, anticholinergics, diuretics, hormones, and phosphodiesterase inhibitors., Results: The main drugs used in Urology may cause several otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported and varies among drug classes., Conclusions: Most of the drugs used in urological practice have otorhinolaryngological adverse effects. Dizziness was most common, but dry mouth, rhinitis, nasal congestion, epistaxis, hearing loss, tinnitus, and rhinorrhea were also reported. Therefore, doctors must be aware of these adverse effects to improve adherence to the treatment and to minimize damage to the health of patients., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Introduction: Meniere's disease is a labyrinth disease that usually presents with episodes of spontaneous vertigo associated with sensorineural hearing loss, tinnitus and ipsi- and unilateral aural fullness in most cases. Vestibular function tests, video-head-impulse test and the caloric test, are not specific for diagnosis of the disease, but may show alterations that help to evaluate the functional impairment., Objective: To describe the results obtained at the caloric test and video-head-impulse test in patients with definite Meniere's disease and compare them between symptomatic, asymptomatic ears and those of the control group., Methods: Cross-sectional and observational study including patients with definite Meniere's disease diagnosed according to the Bárány Society criteria (2015) and healthy individuals (control group) undergoing caloric test and video-head-impulse test. All subjects were assessed by neurotological anamnesis and audiological evaluation (pure-tone, vocal and immittance audiometry) to characterize the sample. The findings obtained at the caloric test and video-head-impulse test were described and compared between the symptomatic and asymptomatic ears of patients with Meniere's disease and those of the control group., Results: Thirty-two patients with definite Meniere's disease were evaluated, with a mean age of 45.7 years, mostly females (68.8%) and unilateral disease. The control group consisted of 20 healthy individuals, with a mean age of 44.7 years, mostly females (70.0%). The groups were homogeneous in relation to age and gender. The patients' main complaint was vertigo (71.9%), and most patients had more than six episodes in the last six months (71.9%). Moderate sensorineural hearing loss was present in 38.5% of patients. The prevalence of hyporeflexia at the caloric test was higher in symptomatic (56.4%) and asymptomatic (36%) ears of patients with Meniere's disease compared to the ears of control subjects (7.5%), p<0.001 and p=0.004, respectively. Video-head-impulse test alterations in the lateral semicircular canals were more frequent in the symptomatic ears of patients with Meniere's disease than in the ears of control subjects (p=0.026)., Conclusion: Most patients with definite Meniere's disease showed hyporeflexia at the caloric test and video-head-impulse test with normal function in the symptomatic ear. Vestibular hyporeflexia at the caloric test was more frequent in the symptomatic and asymptomatic ears of patients with Meniere's disease than in the control group. The video-head-impulse test showed more alterations in the lateral semicircular canals., (Copyright © 2019 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples ( n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.

Objectives: The present study aimed to contribute to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs), which may assist in the accurate diagnosis of, and selection of treatment regimens for, these conditions., Methods: We performed gene-targeted next-generation sequencing (NGS) of 409 cancer-related genes in 15 US (7 uterine leiomyosarcoma [ULMS], 7 endometrial stromal sarcoma [ESS], 1 adenosarcoma [ADS]), 5 UCS, and 3 uterine leiomyoma (ULM) samples. Quality, frequency, and functional filters were applied to select putative somatic variants., Results: Among the 23 samples evaluated in this study, 42 loss-of-function (LOF) mutations and 111 missense mutations were detected, with a total of 153 mutations. Among them, 66 mutations were observed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. TP53 (48%), ATM (22%), and PIK3CA (17%) were the most frequently mutated genes. With respect to specific tumor subtypes, ESS showed mutations in the PDE4DIP, IGTA10, and DST genes, UCS exhibited mutations in ERBB4, and ULMS showed exclusive alterations in NOTCH2 and HER2. Mutations in the KMT2A gene were observed exclusively in ULM and ULMS. In silico pathway analyses demonstrated that many genes mutated in ULMS and ESS have functions associated with the cellular response to hypoxia and cellular response to peptide hormone stimulus. In UCS and ADS, genes with most alterations have functions associated with phosphatidylinositol kinase activity and glycerophospholipid metabolic process., Conclusion: This preliminary study observed pathogenic mutations in US and UCS samples. Further studies with a larger cohort and functional analyses will foster the development of a precision medicine-based approach for the treatment of US and UCS.

Uterine leiomyosarcoma (LMS) is an aggressive tumor that presents poor prognosis, high rates of recurrence and metastasis. Because of its rarity, there is no information available concerning LMS molecular mechanisms of origin and development. Here, we assessed the expression profile of Hedgehog (HH) signaling pathway markers and the effects of their pharmacological inhibition on uterine smooth muscle (UTSM), leiomyoma and LMS cells. Additionally, we also evaluated the effects of DNMTs inhibition on LMS cells behavior. Cell proliferation, migration and apoptosis rates were evaluated by MTT, Scratch and Annexin V assays, respectively. RNA expression and protein levels were assessed by qRT-PCR and Western blot. We found that SMO and GLIs (1, 2 and 3) expression was upregulated in LMS cells, with increased nuclear levels of GLI proteins. Treatment with LDE225 (SMOi) and Gant61 (GLIi) resulted in a significant reduction in Glis protein levels in LMS ( p < 0.05). Additionally, the expression of DNMT (1, 3a, and 3b), as well as GLI1 nuclear expression, was significantly decreased after treatment with HH inhibitor in LMS cells. Our results showed that blocking of SMO, GLI and DNMTs is able to inhibit LMS proliferation, migration and invasion. Importantly, the combination of those treatments exhibited a potentiated effect on LMS malignant features due to HH pathway deactivation.

Objective: describe cardiovascular findings from echocardiograms and electrocardiograms in patients with Classic Homocystinuria., Methods: this retrospective exploratory study evaluated fourteen subjects with Classic Homocystinuria (median age = 27.3 years; male n  = 8, B6-non-responsive n  = 9 patients), recruited by convenience sampling from patients seen Hospital de Clínicas de Porto Alegre (Brazil), between January 1997 and July 2020. Data on clinical findings, echocardiogram and electrocardiogram were retrieved from medical records., Results: Eight patients presented some abnormalities on echocardiogram ( n  = 6) or electrocardiogram ( n  = 5). The most frequent finding was mild tricuspid regurgitation ( n  = 3), followed by mitral valve prolapse, mild mitral regurgitation, enlarged left atrium and aortic valve sclerosis ( n  = 2 patients each). Aortic root ectasia was found in one patient. Venous thrombosis was reported in six patients: deep vein thrombosis of lower limbs (n = 3), ischaemic stroke ( n  = 1), cerebral venous sinus thrombosis (n = 1) and pulmonary vein thrombosis (n = 1)., Conclusion: mild valvulopathies seen to be common in patients with Classic Homocystinuria, but more studies regarding echocardiogram and electrocardiogram in this population are needed to draw absolute conclusions., (© 2020 Published by Elsevier Inc.)

Until pharmacological measures are effective at containing the COVID-19 outbreak, adopting protective behaviors is paramount. In this work, we aim at informing interventions to limit the spread of the contagion and prepare against any future outbreaks by developing a behavioral framework to interpret and prescribe both the individual and large-scale uptake of non-pharmaceutical measures. First, we analyze the barriers and facilitators to adherence to protective behaviors according to a three-term contingency by exploring potential gaps in terms of setting stimuli, motivating operations, delayed consequences, and positive or negative consequences. We explore their roles in the likelihood of individual compliance to protective behaviors, taking physical distancing as an example of functional analysis. Second, we interpret contagion control as the cumulative effect of large-scale adherence to protective behaviors. We explore the interrelations between societal problems caused or amplified by similar behaviors presented by many individuals and the coordination of agents or agencies aiming at promoting large-scale behavioral change. Then, we highlight the potential of developing a behavioral vaccine, and practical steps for applying it to promote sustainable cultural change that may protect against health, social, and economic losses in future outbreaks.

Introduction: Ménière's disease is among the most frequent causes of vestibular disorders. Although it is a clinical diagnosis, a better understanding of the pathophysiology and clinical course of the disease through tests would allow improvement in the prognosis and more effective treatments., Objectives: To describe the results of the cervical vestibular evoked myogenic and video head impulse test in patients with a defined diagnosis of Ménière's disease and to correlate them with disease duration., Methods: The sample consisted of 50 participants, of whom 29 comprised the study group and 21 the control group. The individuals were submitted to a questionnaire, otoscopy, audiometry and vestibular function assessment through the cervical vestibular evoked myogenic potential and video head impulse test., Results: For the video head impulse test, lateral canal gain values below 0.77 were considered abnormal and for the vertical channels, below 0.61. The percentages of normality were 82.76% for lateral, 89.65% for posterior and 91.37% for anterior canals. For the cervical vestibular evoked myogenic potential, the upper limits of normal for latencies were defined as 18.07ms for p13 and 28.47ms for n23; and in the SG, 19.57% showed prolongation of latency of p13 and 4.35% of wave n23, whereas 18.96% did not show biphasic potential., Conclusions: For the video head impulse test, a decreased gain of the vestibulo-ocular reflex for the lateral canal was observed, with a higher incidence of overt type corrective saccades compared to the control group. For the cervical vestibular evoked myogenic potential, there was a significant difference between the groups for the inter-amplitude parameter, including for asymptomatic ears. There was no correlation between the results of the tests and disease duration., (Copyright © 2019. Published by Elsevier Editora Ltda.)

Diagnostic yield of genetic studies for Charcot-Marie-Tooth disease (CMT) is little known, with a lack of epidemiological data to build better diagnostic strategies outside the United States and Europe. We aimed to evaluate the performance of two molecular diagnostic strategies for patients with CMT, and to characterize epidemiological findings of these conditions in southern Brazil. We performed a single-center cross-sectional study, in which 94 patients (55 families) with CMT suspicion were evaluated. Overall, the diagnostic yield of the combined strategy of Multiplex-ligation-dependent-probe-amplification (MLPA) of PMP22/GJB1/MPZ and GJB1/MPZ/PMP22 Sanger sequencing was 63.6% (28/44) for index cases with demyelinating/intermediate CMT suspicion (21 CMT1A-PMP22, 5 CMTX1-GJB1 and 2 with probably CMT1B-MPZ diagnosis). Five of the 11 index cases (45.4%) with axonal CMT had at least a possible diagnosis with next generation sequencing (NGS) panel of 104 inherited neuropathies-related genes (one each with CMT1A-PMP22, CMT2A-MFN2, CMT2K-GDAP1, CMT2U-MARS, CMT2W-HARS1). Detailed clinical, neurophysiological and molecular data of families are provided. Sequential molecular diagnosis strategies with MLPA plus target Sanger sequencing for demyelinating/intermediate CMT had high diagnostic yield, and almost half of axonal CMT families had at least a possible diagnosis with the comprehensive NGS panel. Most frequent subtypes of CMT in our region are CMT1A-PMP22 and CMTX1-GJB1., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Sudden hearing loss is an otorhinolaryngological emergency that often leads to severe damage to the auditory and vestibular function. The vestibular evoked myogenic potential is a test that allows a noninvasive evaluation of the otolithic system function and vestibulospinal and vestibulo-ocular pathways., Objective: To evaluate the importance of vestibular evoked myogenic potential in determining the prognosis of patients with sudden hearing loss., Methods: A search for articles published up to December 2018 was performed in the PubMed, Cochrane, VHL and LILACS databases using MeSH descriptors. Retrospective and prospective articles were included containing cervical or ocular vestibular evoked myogenic potential in sudden hearing loss patients and information on associated vertigo and/or dizziness., Results: Sixteen of 62 initially selected articles met the inclusion criteria and were analyzed. Regarding the methodology of the evaluated studies, 8 studies were prospective, six were retrospective, one contained part of the data from a retrospective analysis and another part from a prospective analysis, and one study was cross-sectional. A total of 872 patients were evaluated (50.22% males and 49.77% females) with a mean age of 51.26 years. Four hundred and twenty-six patients (50.35%) had vertigo and/or dizziness associated with sudden hearing loss. The cervical vestibular evoked myogenic potential was performed in all studies, but only seven assessed the ocular vestibular evoked myogenic potential. The cervical vestibular evoked myogenic potential showed alterations in 38.65% of 846 evaluated ears, whereas ocular vestibular evoked myogenic potential showed alterations in 47.88% of 368 evaluated ears. The hearing recovery rate was analyzed by 8 articles, with 63.4% of 410 evaluated ears showing hearing recovery., Conclusions: The studies suggest that the assessment of the vestibular system using vestibular evoked myogenic potential seems to be important in the prognosis of sudden hearing loss. For better follow-up of patients with sudden hearing loss, the emphasis should not be limited to the cochlea, but also include the diagnosis and treatment of vestibular abnormalities, regardless of the presence of vertigo., (Copyright © 2019 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Neurotology is a rapidly expanding field of knowledge. The study of the vestibular system has advanced so much that even basic definitions, such as the meaning of vestibular symptoms, have only recently been standardized., Objective: To present a review of the main subjects of neurotology, including concepts, diagnosis and treatment of Neurotology, defining current scientific evidence to facilitate decision-making and to point out the most evidence-lacking areas to stimulate further new research., Methods: This text is the result of the I Brazilian Forum of Neurotology, which brought together the foremost Brazilian researchers in this area for a literature review. In all, there will be three review papers to be published. This first review will address definitions and therapies, the second one will address diagnostic tools, and the third will define the main diseases diagnoses. Each author performed a bibliographic search in the LILACS, SciELO, PubMed and MEDLINE databases on a given subject. The text was then submitted to the other Forum participants for a period of 30 days for analysis. A special chapter, on the definition of vestibular symptoms, was translated by an official translation service, and equally submitted to the other stages of the process. There was then a in-person meeting in which all the texts were orally presented, and there was a discussion among the participants to define a consensual text for each chapter. The consensual texts were then submitted to a final review by four professors of neurotology disciplines from three Brazilian universities and finally concluded. Based on the full text, available on the website of the Brazilian Association of Otorhinolaryngology and Cervical-Facial Surgery, this summary version was written as a review article., Result: The text presents the official translation into Portuguese of the definition of vestibular symptoms proposed by the Bárány Society and brings together the main scientific evidence for each of the main existing therapies for neurotological diseases., Conclusion: This text rationally grouped the main topics of knowledge regarding the definitions and therapies of Neurotology, allowing the reader a broad view of the approach of neurotological patients based on scientific evidence and national experience, which should assist them in clinical decision-making, and show the most evidence-lacking topics to stimulate further study., (Copyright © 2019 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

The temporomandibular muscle dysfunction is characterized by myofascial pain and is more prevalent in women of reproductive age. Sex steroid hormones are hypothetically involved in the dysfunction, but few are the studies of steroid receptors in masticatory and mastication-related muscles. Our aim was to determine estrogen and testosterone receptor expression in rat masticatory and mastication-related muscles within the context of age and gender. Twelve rats were equally divided into four groups: (a) 10-month-old females; (b) 10-month-old males; (c) 24-month-old females; and (d) 24-month-old males. Euthanasia of the females was performed in the proestrous phase (vaginal smears) and the masticatory and accessory muscles were removed for immunohistochemical analysis. Statistical analysis was performed with ANOVA and the Tukey test. Estrogen receptor expression was similarly low in all muscles and groups. Testosterone receptor expression in the Masseter muscle of the 24-month-old male rats was higher than that in the other groups and significantly superior to its expression in the Posterior Digastric muscle. In short, testosterone receptor expression was highest in old male rats. If we generalize to humans, this fact could indicate age- and sex-related hormonal influence on temporomandibular muscle dysfunction. Further studies, however, are necessary to strengthen this hypothesis.

The lethal-7 (let -7 ) family is an important microRNA (miRNA) group that usually exerts functions as a tumor suppressor. We aimed to evaluate the expression profile of let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g , and let-7i and to assess their value as prognostic markers in uterine leiomyosarcoma (LMS) patients. The miRNAs expression profile was assessed in 34 LMS and 13 normal myometrium (MM) paraffin-embedded samples. All let-7 family members showed downregulation in LMS. Our findings showed that patients with let-7e downregulation had worse overall survival (OS) and is an independent prognostic factor (hazard ratio [HR] = 2.24 ). In addition, almost half the patients had distant metastasis . LMS patients with downregulated let-7b and let-7d had worse disease-free survival (DFS); they are not independent prognostic factors (HR = 2.65 ). Patients' ages were associated with let-7d, let-7e and let-7f (p = 0.0160 ) downregulation. In conclusion, all the let-7 family members were downregulated in LMS patients, and the greater the loss of expression of these molecules, the greater their relationship with worse prognosis of patients. L et-7e expression might influence the OS, while let-7b and le-7d might influence the DFS. The l owest expression levels of l et-7d, let-7e , and let-7f were associated with the oldest patients. Our findings indicate strong evidence of let- 7 ' s role as a potential prognostic biomarker in LMS., Competing Interests: The authors declare no conflict of interest.

Rare diseases are defined as conditions with a prevalence of no more than 6.5 per 10,000 people. Although each rare disease individually affects a small number of people, collectively, the 6,000 to 8,000 rare conditions (80% of them with genetic cause) affect around 8% of the world's population. Research about the natural history and underlying pathophysiological mechanisms of rare diseases, as well as clinical trials with new drugs, are important and necessary to develop new strategies for the treatment of these conditions. This report describes the experience of a clinical research group working with rare diseases in a reference center for lysosomal diseases in Brazil (Medical Genetics Service, Hospital de Clínicas de Porto Alegre). The activities of this research group enabled its participation in several international multicenter clinical research protocols related to the natural history or therapy development for rare genetic diseases. This participation has allowed the development of personal skills and institutional facilities for clinical research. The clinical research developed in our center has raised the quality of the medical assistance provided to non-clinical research patients in addition to enabling early access to new therapies to many patients with orphan conditions.

Background: Posterior tibial tendon (PTT) insufficiency is considered as the main cause of adult acquired flat foot and is three times more frequent in females. High estrogen levels exert a positive effect on the overall collagen synthesis in tendons. We have previously demonstrated the association between some genetic single-nucleotide polymorphism (SNP) and tendinopathy. In the present study, we investigated the association of PvuII c454-397T>C (NCBI ID: rs2234693) and XbaI c454-351A>G (NCBI ID: rs9340799) SNPs in estrogen receptor alfa (ER-α) gene with PPT dysfunction., Methods: A total of 92 female subjects with PTT dysfunction, with histopathological examination of the tendon and magnetic resonance image (MRI) evidence of tendinopathy, were compared to 92 asymptomatic females who presented an intact PPT at MRI for PvuII and XbaI SNPs in the ER-α gene. Genomic DNA was extracted from saliva and genotypes were obtained by polymerase chain reaction restriction fragment length polymorphism., Results: The analysis of PvuII SNPs showed no significant differences in the frequency of alleles and genotypes between control and PTT dysfunction groups. The XbaI SNPs in the ER-α gene showed significant differences in the frequency of genotypes between control and test groups (p = 0.01; OR 95% 1.14 (0.55-2.33)., Conclusions: The XbaI SNP in the ERα gene may contribute to tendinopathy, and the A/A genotype could be a risk factor for PTT tendinopathy in this population. The PvuII SNP studied was not associated with PTT tendinopathy.

Selenium (Se) is essential to humans and animals due to its antioxidant properties. Although it is not considered an essential nutrient for higher plants. Many studies show that Se in low concentrations (up to 0.5 mg kg -1 ) provides beneficial effects to non-hyperaccumulating plants by participating in antioxidant defense systems and enhancing tolerance to abiotic stress. Therefore, this study aimed to evaluate the effects of Se application rates on rice plants under different soil water conditions. The experiment was conducted on an Oxisol using four Se rates (0, 0.5, 1.0 and 2.0 mg kg -1 ) and two soil water conditions (irrigated and water deficit). Selenium application via soil up to 0.5 mg kg -1 increased the plant height, chlorophyll index, sulfur and copper accumulation in shoots, carbon dioxide assimilation, superoxide dismutase (EC 1.15.1.1) activity and decreased the hydrogen peroxide concentration in rice leaves. The accumulation of Se in shoot biomass and Se concentration in seeds increased linearly with the applied rates. Water deficit strongly decreased the plant growth and yield. However, rice plants treated with Se showed higher net photosynthesis, water use efficiency and antioxidant system. This study provides useful information about the roles of Se in protecting rice plants from water deficit stress., (Copyright © 2018 Elsevier Inc. All rights reserved.)

According to the cognitive reserve theory, intellectual stimuli acquired during life can prevent against developing cognitive impairment. The underlying cognitive reserve mechanisms were underexplored in low-educated individuals. Because episodic memory impairment due to hippocampal dysfunction is a key feature of Alzheimer's dementia (AD), we sought to look at a possible cognitive reserve mechanism by determining whether few years of education moderated the relationship between the hippocampal volumes and the episodic-memory scores. The sample was composed by 183 older adults, 40.1% male, with the median age of 78[76,82] years and the median years of education of 4[2,10] who had undergone an episodic-memory test and a 3-Tesla MRI scan to access the hippocampal volumes. Overall, 112 were cognitively healthy, 26 had cognitive impairment-no dementia (CIND) and 45 had dementia. We used multiple linear regression to assess whether the interaction between years of education and each hippocampal volume significantly predicted the episodic-memory scores' variance, controlling for cognitive diagnosis and nuisance variables. The interaction term with the left hippocampus (ß = 0.2, p = 0.043, CI = 1.0, 1.4), but not with the right (ß = 0.1, p = 0.218, CI = 0.9, 1.2) significantly predicted the variation on memory scores. The mechanism by which the left hippocampus seems to play a more important role on memory processing in more educated individuals needs to be further investigated and might be associated with a better use of mnemonic strategies or higher hippocampal connectivity. Because the sample's median years of education was four, which corresponds to primary school, we may infer that this level might be sufficient to contribute for building cognitive reserve.

Purpose: Eye closure sensitivity (ECS) has been described as a reflex trait in juvenile myoclonic epilepsy (JME). However, there is no consensus regarding its significance on prognosis. The aim of this study is to clarify the long-term impact of ECS documented by a clinical interview and a video-EEG neuropsychological protocol (VNPP) in a series of 133 JME patients., Methods: Data from 22 JME patients with ECS confirmed by a VNPP (Group 1) were compared with those of 20 JME patients without any reflex traits (Group 2). They were followed for a mean of 8.21 years (SD=±5.044). The frequency of seizures was assessed using a diary. Except for photosensitivity (PS), any other reflex traits occurrence, drugs/alcohol abuse intake, noncompliance, and Jeavons syndrome, were considered exclusion criteria., Results: Group 1 had a lower age at epilepsy onset (p = 0.028), higher incidence of febrile seizures (13.6%), and familial history of epilepsy (p = 0.023). Only 18.2% had self-perception of eyelid myoclonia (EM) (kappa coefficient = 0.193), which persisted in 77.3% of patients. Limb myoclonia, tonic-clonic seizures (TCS) and/or myoclonic-tonic-clonic seizures (MTCS), as well as absences were more frequent (p = 0.015; p = 0.013; p = 0.011, respectively) in Group 1. PS did not influenced frequency of EM (p = 1.0), absences (p = 0.648), or TCS/MTCS (p = 0.934). Psychiatric comorbidities were not different between groups., Conclusions: ECS is related to a worse outcome regarding control of all seizure types, persistence of EM, and higher frequency of limb myoclonia, as well as the total number of TCS and/or MTCS., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Changes in microRNA (miRNA) expression may lead to cancer development and/or contribute to its progression; however, their role in uterine sarcomas is poorly understood. Uterine sarcomas (US) belong to a rare class of heterogeneous tumors, representing about 1% of all gynecologic neoplasms. This study aimed to assess the expression profile of 84 cancer-related miRNAs and to evaluate their correlation with clinical pathological features. Eighty-two formalin-fixed paraffin-embedded (FFPE) samples were selected. In leiomyosarcoma (LMS), there was an association of lower cancer-specific survival (CSS) with the downregulation of miR-125a-5p and miR-10a-5p, and the upregulation of miR-196a-5p and miR-34c-5p. In carcinosarcoma (CS), lower CSS was associated with the upregulation of miR-184, and the downregulation of let-7b-5p and miR-124. In endometrial stromal sarcomas (ESS), the upregulation of miR-373-3p, miR-372-3p, and let-7b-5p, and the down-expression of let-7f-5p, miR-23-3p, and let-7b-5p were associated with lower CSS. Only miR-138-5p upregulation was associated with higher survival rates. miR-335-5p, miR-301a-3p, and miR-210-3p were more highly expressed in patients with tumor metastasis and relapse. miR-138-5p, miR-146b-5p, and miR-218-5p expression were associated with higher disease-free survival (DFS) in treated patients. These miRNAs represent potential prediction markers for prognosis and treatment response in these tumors.

Background: Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline., Results: Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1±7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion., Conclusion: Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6-phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI., Trial Registration: Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017.

Recently, there has been an increasing number of studies on exceptional cognitive aging. Herein, we aim to objectively provide the operationalized characterization of older adults with unusually high memory ability. Some authors have defined them as "SuperAgers", individuals aged 80 years or older with memory ability similar or superior to middle-aged subjects. On the other hand, the terminology "high-performing older adults" (HPOA) seems to appropriately conceptualize these individuals without exaggeration. A threshold for age is not a reliable criterion, but may be defined as 75 and 80 years of age for developing and developed countries, respectively. We propose that HPOA may exhibit episodic memory test scores equal to or greater than those of individuals aged 50-60 years, according to the validated tables for the respective country. This group must also have global cognition scores within expected average values for age and education. Executive functioning may play a central role in the exceptional memory performance of this group. Further studies are essential to confirm existing findings and may provide important evidence for cognitive aging theory and the neurobiology of dementia., Competing Interests: Disclosure: The authors report no conflicts of interest.