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The use of recreational waters is a widespread activity worldwide, and one of the risks associated with this practice is the exposure of bathers to microorganisms that may arise due to pollution caused by inadequate infrastructure and sanitation. In the present work, we isolated Candida spp. (n = 24) from five recreational beaches in Rio de Janeiro, Brazil, in order to evaluate their susceptibility to antifungals, the production of virulence attributes and the in vivo virulence using Tenebrio molitor larvae as a model. The ITS1-5.8S-ITS2 gene sequencing identified thirteen isolates (54.1 %) as C. tropicalis, seven (29.1 %) as C. krusei (Pichia kudriavzevii), one (4.2 %) as C. rugosa (Diutina rugosa), one (4.2 %) as C. mesorugosa (Diutina mesorugosa), one (4.2 %) as C. utilis (Cyberlindnera jadinii) and one (4.2 %) as C. parapsilosis. C. tropicalis isolates showed resistance to azoles and susceptibility to amphotericin B, flucytosine and caspofungin. C. krusei isolates were resistant to fluconazole, caspofungin and itraconazole, with 42.8 % resistance to flucytosine, besides susceptibility to voriconazole and amphotericin B. The remaining species were susceptible to all tested antifungals. All Candida isolates adhered to abiotic surfaces and formed biofilm on polystyrene, albeit to varying degrees, and produced aspartic protease and hemolytic activity, which are considered fungal virulence attributes. C. tropicalis, C. krusei and C. utilis isolates produced phytase, while the only esterase producer was C. tropicalis. Regarding resistance to osmotic stress, all isolates of C. tropicalis, C. parapsilosis and C. mesorugosa grew up to 7.5 % NaCl; the remaining isolates grew up to 1.87-3.75 % NaCl. The mortality caused by fungal challenges in T. molitor larvae was variable, with C. tropicalis, C. utilis and C. parapsilosis being more virulent than C. krusei and C. rugosa complex. Collectively, the presence of these yeasts, particularly the virulent and resistant isolates, in recreational waters can pose a significant health risk to bathers.
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Antifúngicos , Candida , Farmacorresistencia Fúngica , Brasil , Antifúngicos/farmacología , Candida/efectos de los fármacos , Candida/patogenicidad , Candida/genética , Virulencia , Pruebas de Sensibilidad Microbiana , Animales , PlayasRESUMEN
BACKGROUND: Globally, the counting of deaths based on gender identity and sexual orientation has been a challenge for health systems. In most cases, non-governmental organizations have dedicated themselves to this work. Despite these efforts in generating information, the scarcity of official data presents significant limitations in policy formulation and actions guided by population needs. Therefore, this manuscript aims to evaluate the accuracy, potential, and limits of probabilistic data relationships to yield information on deaths according to gender identity and sexual orientation in the State of Rio de Janeiro. METHODS: This study evaluated the accuracy of the probabilistic record linkage to obtain information on deaths according to gender and sexual orientation. Data from two information systems were used from June 15, 2015 to December 31, 2020. We constructed nine probabilistic data relationship strategies and identified the performance and cutoff points of the best strategy. RESULTS: The best data blocking strategy was established through logical blocks with the first and last names, birthdate, and mother's name in the pairing strategy. With a population base of 80,178 records, 1556 deaths were retrieved. With an area under the curve of 0.979, this strategy presented 93.26% accuracy, 98.46% sensitivity, and 90.04% specificity for the cutoff point ≥ 17.9 of the data relationship score. The adoption of the cutoff point optimized the manual review phase, identifying 2259 (90.04%) of the 2509 false pairs and identifying 1532 (98.46%) of the 1556 true pairs. CONCLUSION: With the identification of possible strategies for determining probabilistic data relationships, the retrieval of information on mortality according to sexual and gender markers has become feasible. Based on information from the daily routine of health services, the formulation of public policies that consider the LGBTQ + population more closely reflects the reality experienced by these population groups.
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Identidad de Género , Conducta Sexual , Humanos , Brasil/epidemiología , Femenino , Masculino , Conducta Sexual/estadística & datos numéricos , Registro Médico Coordinado , Exactitud de los Datos , Certificado de Defunción , AdultoRESUMEN
We aimed to estimate the proportions of childhood parental neglect, abuse, and rejection and to evaluate the co-occurrence of these experiences among transgender women in Rio de Janeiro, Brazil. This was a cross-sectional study with a convenience sample enrolled between July 2019 and March 2020, using an adapted version of the Childhood Trauma Questionnaire. Proportions and corresponding confidence intervals (CI) were calculated. Kendall correlation with Tau-b estimator was used in the bivariate analyses. We gathered data from 139 participants. The most prevalent types of childhood traumas were emotional abuse (60.43%, 95% CI [51.79, 68.62]), physical abuse (57.55%, 95% CI [48.90, 65.89]) and sexual abuse (44.60%, 95% CI [36.18, 53.27]). Severe to extreme physical and emotional abuse occurred among 40.29% (95% CI [32.06, 48.93]) and 5.75% (95% CI [2.51, 11.02]) of participants, respectively. The proportion of parental rejection (eviction) was 32.37% (95% CI [25.04, 40.69]) and occurred with the other forms of abuse, except sexual abuse. Multiple types of childhood abuse, neglect, and parental rejection were observed among transgender women in our sample. The harmful effects of childhood abuse on the mental and physical health of people in the transgender population are of concern, particularly considering the cumulative effect produced by the co-occurrence of such events and their harmful lifetime effects. It is urgently necessary to debate and formulate public policies to ensure the right to gender expression from childhood.
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The gut microbiome reflects health and predicts possible disease in hosts. A holistic view of this community is needed, focusing on identifying species and dissecting how species interact with their host and each other, regardless of whether their presence is beneficial, inconsequential, or detrimental. The distribution of gut-associated eukaryotes within and across non-human primates is likely driven by host behavior and ecology. To ascertain the existence of free-living amoebae (FLA) in the gut of wild and captive non-human primates, 101 stool samples were collected and submitted to culture-dependent microscopy examination and DNA sequencing. Free-living amoebae were detected in 45.4% (46/101) of fecal samples analyzed, and their morphological characteristics matched those of Acanthamoeba spp., Vermamoeba spp., heterolobosean amoeboflagellates and fan-shaped amoebae of the family Vannellidae. Sequence analysis of the PCR products revealed that the suspected amoebae are highly homologous (99% identity and 100% query coverage) with Acanthamoeba T4 genotype and Vermamoeba vermiformis amoebae. The results showed a great diversity of amoebae in the non-human primate's microbiome, which may pose a potential risk to the health of NHPs. To our knowledge, this is the first report of free-living amoebae in non-human primates that are naturally infected. However, it is unknown whether gut-borne amoebae exploit a viable ecological niche or are simply transient residents in the gut.
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Precision nuclear run-on (PRO) sequencing (PRO-seq) is a powerful technique for mapping polymerase active sites with nucleotide resolution and measuring newly synthesized transcripts at both promoters and enhancer elements. The current PRO-seq protocol is time-intensive, technically challenging, and requires a large amount of starting material. To overcome these limitations, we developed rapid PRO-seq (rPRO-seq) which utilizes pre-adenylated single-stranded DNAs (AppDNA), a dimer blocking oligonucleotide (DBO), on-bead 5' RNA end repair, and column-based purification. These modifications enabled efficient transcriptome mapping within a single day (â¼12 hours) increasing ligation efficiency, abolished adapter dimers, and reduced sample loss and RNA degradation. We demonstrate the reproducibility of rPRO-seq in measuring polymerases at promoters, gene bodies, and enhancers as compared to original PRO-seq protocols. Additionally, rPRO-seq is scalable, allowing for transcriptome mapping with as little as 25,000 cells. We apply rPRO-seq to study the role of Integrator in mouse hematopoietic stem and progenitor cell (mHSPC) homeostasis, identifying Ints11 as an essential component of transcriptional regulation and RNA processing in mHSPC homeostasis. Overall, rPRO-seq represents a significant advance in the field of nascent transcript analyses and will be a valuable tool for generating patient-specific genome-wide transcription profiles with minimal sample requirements.
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PURPOSE: Cross-language studies suggest more similarities than differences in how dysarthria affects the speech of people with Parkinson's disease (PwPD) who speak different languages. In this study, we aimed to identify the relative contribution of acoustic variables to distinguish PwPD from controls who spoke varieties of two Romance languages, French and Portuguese. METHOD: This bi-national, cross-sectional, and case-controlled study included 129 PwPD and 124 healthy controls who spoke French or Portuguese. All participants underwent the same clinical examinations, voice/speech recordings, and self-assessment questionnaires. PwPD were evaluated off and on optimal medication. Inferential analyses included Disease (controls vs. PwPD) and Language (French vs. Portuguese) as factors, and random decision forest algorithms identified relevant acoustic variables able to distinguish participants: (a) by language (French vs. Portuguese) and (b) by clinical status (PwPD on and off medication vs. controls). RESULTS: French-speaking and Portuguese-speaking individuals were distinguished from each other with over 90% accuracy by five acoustic variables (the mean fundamental frequency and the shimmer of the sustained vowel /a/ production, the oral diadochokinesis performance index, the relative sound level pressure and the relative sound pressure level standard deviation of the text reading). A distinct set of parameters discriminated between controls and PwPD: for men, maximum phonation time and the oral diadochokinesis speech proportion were the most significant variables; for women, variables calculated from the oral diadochokinesis were the most discriminative. CONCLUSIONS: Acoustic variables related to phonation and voice quality distinguished between speakers of the two languages. Variables related to pneumophonic coordination and articulation rate were the more effective in distinguishing PwPD from controls. Thus, our research findings support that respiration and diadochokinesis tasks appear to be the most appropriate to pinpoint signs of dysarthria, which are largely homogeneous and language-universal. In contrast, identifying language-specific variables with the speech tasks and acoustic variables studied was less conclusive.
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Repressor element-1 silencing transcription factor (REST) is required for the formation of mature neurons. REST dysregulation underlies a key mechanism of neurodegeneration associated with neurological disorders. However, the mechanisms leading to alterations of REST-mediated silencing of key neurogenesis genes are not known. Here, we show that BRCA1 Associated ATM Activator 1 (BRAT1), a gene linked to neurodegenerative diseases, is required for the activation of REST-responsive genes during neuronal differentiation. We find that INTS11 and INTS9 subunits of Integrator complex interact with BRAT1 as a distinct trimeric complex to activate critical neuronal genes during differentiation. BRAT1 depletion results in persistence of REST residence on critical neuronal genes disrupting the differentiation of NT2 cells into astrocytes and neuronal cells. We identified BRAT1 and INTS11 co-occupying the promoter region of these genes and pinpoint a role for BRAT1 in recruiting INTS11 to their promoters. Disease-causing mutations in BRAT1 diminish its association with INTS11/INTS9, linking the manifestation of disease phenotypes with a defect in transcriptional activation of key neuronal genes by BRAT1/INTS11/INTS9 complex. Finally, loss of Brat1 in mouse embryonic stem cells leads to a defect in neuronal differentiation assay. Importantly, while reconstitution with wild-type BRAT1 restores neuronal differentiation, the addition of a BRAT1 mutant is unable to associate with INTS11/INTS9 and fails to rescue the neuronal phenotype. Taken together, our study highlights the importance of BRAT1 association with INTS11 and INTS9 in the development of the nervous system.
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Diferenciación Celular , Cromatina , Neurogénesis , Neuronas , Proteínas Represoras , Humanos , Cromatina/metabolismo , Cromatina/genética , Proteínas Co-Represoras , Proteínas del Tejido Nervioso , Neurogénesis/genética , Neuronas/metabolismo , Regiones Promotoras Genéticas , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.
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Antirreumáticos , Espondiloartritis Axial , Espondilitis Anquilosante , Humanos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adalimumab/uso terapéutico , Antirreumáticos/uso terapéutico , Factor de Necrosis Tumoral alfa , Resultado del TratamientoRESUMEN
INTRODUCTION: Epilepsy, a neurological disorder characterized by recurring unprovoked seizures due to excessive neuronal excitability, is primarily attributed to genetic factors, accounting for an estimated 70 % of cases. Array-comparative genomic hybridization (aCGH) is a crucial genetic test for detecting copy number variants (CNVs) associated with epilepsy. This study aimed to analyze a cohort of epilepsy patients with CNVs detected through aCGH to enhance our understanding of the genetic underpinnings of epilepsy. METHODS: A retrospective cross-sectional study was conducted using the aCGH database from the Genetics Department of the Faculty of Medicine of the University of Porto, encompassing 146 patients diagnosed with epilepsy, epileptic encephalopathy, or seizures. Clinical data were collected, and aCGH was performed following established guidelines. CNVs were classified based on ACMG standards, and patients were categorized into four groups according to their clinical phenotype. RESULTS: Among the 146 included patients, 94 (64 %) had at least one CNV, with 22 (15.1 %) classified as pathogenic or likely pathogenic. Chromosomes 1, 2, 16, and X were frequently implicated, with Xp22.33 being the most reported region (8 CNVs). The phenotype "Epilepsy and global developmental delay/intellectual disability" showed the highest prevalence of clinically relevant CNVs. Various CNVs were identified across different groups, suggesting potential roles in epilepsy. CONCLUSIONS: This study highlights the significance of aCGH in unraveling the genetic basis of epilepsy and tailoring treatment strategies. It contributes valuable insights to the expanding knowledge in the field, emphasizing the need for research to elucidate the diverse genetic causes of epilepsy.
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Variaciones en el Número de Copia de ADN , Epilepsia , Trastornos del Neurodesarrollo , Humanos , Variaciones en el Número de Copia de ADN/genética , Epilepsia/genética , Masculino , Femenino , Estudios Retrospectivos , Estudios Transversales , Niño , Trastornos del Neurodesarrollo/genética , Preescolar , Adolescente , Hibridación Genómica Comparativa , Adulto , Adulto Joven , LactanteRESUMEN
OBJECTIVES: To estimate digit circumference and the impact of sex and body mass index (BMI) for the calculation of the Leeds Dactylitis Index (LDI) in psoriatic arthritis (PsA) patients with bilateral dactylitis. METHODS: Digit circumference of the hands and the foot were measured with a dactylometer and were studied according to sex and BMI (divided in 4 weight categories) in healthy Portuguese subjects, using Student's t-test and One-way ANOVA, respectively. The effect size of sex and BMI were calculated using Cohen's d test and Eta squared, respectively. Multiple linear regression was used to calculate the effect of sex and BMI, as well as their interaction, to create a formula to predict digit circumference. RESULTS: Fifty-nine participants (33 women, 26 men) with a mean BMI of 24.8 were included. Men's mean digit circumferences were statistically higher than those of women (p<0.001), with a large sex effect size in most of the digits. Differences in the mean circumference between the four BMI categories were statistically significant (p<0.05) for all digits, with a large BMI effect size. Sex and BMI were independent variables to predict mean digit circumference (p<0.001). A new tool (based on regression analysis) allowing to estimate the circumference of digits for males and females of different BMIs is presented. CONCLUSIONS: Our data allows the calculation of digit circumference for males and females of different BMIs in the Portuguese population; and shows that BMI influences digital circumference supporting BMI inclusion in LDI references tables.
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Artritis Psoriásica , Masculino , Humanos , Femenino , Índice de Masa Corporal , Artritis Psoriásica/diagnóstico , Mano , Análisis de Regresión , Circunferencia de la CinturaRESUMEN
Introducción: la trisomía 21 o síndrome de Down (SD) es la alteración cromosómica más frecuente, con una incidencia general de 1 en 600 a 800 recién nacidos vivos. Su diagnóstico es de sospecha clínica y confirmación citogenética. Las cardiopatías congénitas y las malformaciones gastrointestinales son frecuentes, al igual que las alteraciones hematológicas y desórdenes tiroideos. Material y método: estudio descriptivo con el objetivo de detallar las características fenotípicas, genéticas, malformaciones y morbilidades asociadas en los pacientes con trisomía 21 nacidos en el Servicio de Neonatología del Centro Hospitalario Pereira Rossell entre el 1 de julio de 2017 y el 1 de julio de 2021. Resultados: se incluyeron 56 pacientes, 30/56 fueron de sexo masculino, la media de edad gestacional fue de 37 semanas. Un total de 17 pacientes fue pretérmino. De los pacientes estudiados, 45/56 presentaron trisomía libre en el cariotipo. La hipotonía fue el signo más frecuentemente observado en el examen clínico. El defecto congénito más frecuente, en 34 pacientes, fue la cardiopatía congénita. La más frecuente fue la comunicación interauricular (CIA), seguida de la comunicación interventricular (CIV) en segundo lugar y el canal atrioventricular (canal AV) en tercer lugar. Se encontraron 23 pacientes con alteraciones en el hemograma, siendo la plaquetopenia la alteración más observada. A nueve pacientes se les realizó diagnóstico de hipotiroidismo y la mortalidad global durante la internación fue de 1,78%. Conclusiones: se destaca la alta prevalencia de prematurez y de defectos congénitos asociados, siendo la cardiopatía congénita la más frecuente.
Introduction: trisomy 21 or Down Syndrome is the most frequent chromosomal alteration, with a general incidence of 1 in 600 to 800 live newborns. Diagnosis is based on clinical suspicion and cytogenetic confirmation. Congenital heart disease and gastrointestinal malformations are frequent, as are hematological abnormalities and thyroid disorders. Materials and Methods: descriptive study with the objective of describing the phenotypic and genetic characteristics, malformations and associated morbidities in patients with trisomy 21 born in the neonatology service of the Pereira Rossell Hospital between July 1, 2017 and July 1, 2021. Results: 56 patients were included, 30/56 were male, the mean gestational age was 37 weeks. A total of 17 patients were preterm. Of the patients studied, 45/56 presented free trisomy in the karyotype. Hypotonia was the most frequently observed sign on clinical examination. The most common birth defect, in 34 patients, was congenital heart disease. Among them, the most frequent defect was interatrial septal defect (CIA), followed by interventricular septal defect (VSD) and thirdly, atrioventricular canal (AV canal). Twenty-three patients with alterations in the complete blood count were found, being thrombocytopenia the most observed alteration. Nine patients were diagnosed with hypothyroidism and overall mortality during hospitalization was 1.78%. Conclusions: we must highlight the high prevalence of prematurity and associated congenital defects, being congenital heart disease the most frequent.
Introdução: a Trissomia do 21 ou Síndrome de Down é a alteração cromossômica mais frequente, com incidência geral de 1 em 600 a 800 recém-nascidos vivos. Seu diagnóstico é baseado na suspeita clínica e na confirmação citogenética. Doenças cardíacas congênitas e malformações gastrointestinais são frequentes, assim como anomalias hematológicas e distúrbios da tireoide. Materiais e métodos: estudo descritivo com objetivo de descrever as características fenotípicas e genéticas, malformações e morbidades associadas em pacientes com trissomia dos 21 nascidos no serviço de Neonatologia do Hospital Pereira Rossell entre 1º de julho de 2017 e 1º de julho de 2021. Resultados: foram incluídos 56 pacientes, 30/56 do sexo masculino, idade gestacional média de 37 semanas. Um total de 17 pacientes foram prematuros. Dos pacientes estudados, 45/56 apresentavam trissomia livre no cariótipo. A hipotonia foi o sinal mais frequentemente observado no exame clínico. O defeito congênito mais comum, em 34 pacientes, foi a cardiopatia congênita. Dentre eles, o mais frequente foi a comunicação interatrial (CIA), seguida pela comunicação interventricular (CIV) em segundo lugar e pelo canal atrioventricular (canal AV) em terceiro lugar. Foram encontrados 23 pacientes com alterações no hemograma completo, sendo a trombocitopenia a alteração mais observada. Nove pacientes foram diagnosticados com hipotireoidismo e a mortalidade geral durante a internação foi de 1,78%. Conclusões: destaca-se a alta prevalência de prematuridade e defeitos congênitos associados, sendo as cardiopatias congênitas as mais frequentes.
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Humanos , Masculino , Femenino , Embarazo , Recién Nacido , Anomalías Congénitas/etiología , Síndrome de Down/epidemiología , Uruguay/epidemiología , Síndrome de Down/complicaciones , Nacimiento PrematuroRESUMEN
INTRODUCTION: Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. METHODS: Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. RESULTS/CASE REPORT: Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. CONCLUSION: In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.
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Glucose homeostasis is essential for energy production and the central nervous system function, depending on glycogen metabolism. Glycogen storage diseases (GSD) are caused by enzymatic defects of the glycogen degradation and mainly involve the liver since the inhibition of hepatic glycogen breakdown results in its excessive storage and hepatomegaly. Other findings are hypoglycemia and hyperlactatemia and consequent neurological symptoms. GSD Type Ia is a severe disease with clinical manifestations usually occurring in the first months. Morbidity and mortality are high, when not treated. The patient was a male newborn, with nonconsanguineous couple, born by eutocic delivery and weight 3760 g. On Day 2, weight loss >10% and jaundice were noticed, and physical examination was as normal. The investigation showed low glucose that only respond to iv glucose, metabolic acidosis, hyperlactatemia and elevated liver enzymes. Considering his inherited metabolic disease, he was transferred to the Reference Center. Complementary tests showed hypertriglyceridemia and absence of ketone bodies. Abdominal US revealed a liver in the upper limit of normal. Most likely clinical diagnosis was GSD type Ia, confirmed by genetic test. He needed iv glucose, but then stabilized with formula without galactose, supplemented with dextrin every 2 hours. He is now 7 months old, has flash glucose self-monitoring system, maintaining frequent feedings, with sporadic hypoglycemia with normal physical development and no hepatomegaly. Hypoglycemia and early weight loss in newborns are red flags for metabolic diseases or other conditions. When accompanied by other metabolic findings, such as hyperlactatemia and metabolic acidosis, associated with short fasting periods, glycogen metabolism disorders must be considered. Patients with GSD Type Ia generally appear normal at birth and an early presentation is not frequent within the first hours after birth. Moreover, avoiding fasting and hypoglycemia are of vital importance for better cognitive outcome, global prognosis, and prevention of other metabolic abnormalities.
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The inclusion of the "gender identity" field in the Brazilian violence surveillance system, although representing a step forward, still has limitations that may compromise epidemiological data validity. Existing response options for victims' identities do not adequately cover the diversity of this analysis category, resulting in classification biases. Additionally, the absence of options for cisgender identities reflects an approach that naturalizes these identities, while trans identities are considered deviant and subject to surveillance. To overcome these limitations, it is imperative to adopt a broader understanding of gender as a social and performative construction. This requires a reassessment of social structures and data collection instruments. In this context of discussion, this theoretical-methodological essay aims to reflect on gender identity measurement in the Reporting Diseases System interpersonal and self-inflicted violence surveillance system, taking as frameworks the theoretical conceptions about gender as a performative act and the foundations of validity in epidemiological investigations.
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Identidad de Género , Transexualidad , Humanos , Masculino , Femenino , Violencia , BrasilRESUMEN
OBJECTIVES: We aim to identify determinants of health-related quality of life (HRQoL) and global functioning and health (GH) in axial spondyloarthritis (axSpA), peripheral spondyloarthritis (pSpA), and psoriatic arthritis (PsA). METHODS: ASAS-perSpA study data were analyzed. Models for the three patient groups were performed separately to explore factors associated with HRQoL and GH, assessed by EQ-5D and ASAS-HI, respectively. RESULTS: The analyses included 4185 patients: 2719 with axSpA, 433 with pSpA, and 1033 with PsA.In axSpA, disease activity (DA) (ß=-0.061), physical function (ß=-0.041), female sex (ß=-0.019), and fibromyalgia (ß=-0.068) were associated with worse HRQoL; age (ß = 0.001) and university education (ß = 0.014) with better HRQoL. In pSpA, DA (ß=-0.04) and physical function (ß=-0.054) were associated with worse HRQoL. In PsA, DA (ß=-0.045), physical function (ß=-0.053), axial disease (ß=-0.041), and female sex (ß=-0.028) were associated with worse HRQoL.In axSpA, DA (ß = 0.889), physical function (ß = 0.887), peripheral disease (ß = 0.564), female sex (ß = 0.812) and fibromyalgia (ß = 1.639) were associated with worse GH; age (ß=-0.013) and university education (ß=-0.274) with better GH. In pSpA, physical function (ß = 1.142), and female sex (ß = 1.060) were associated with worse GH; university education (ß=-0.611) with better GH. In PsA, DA (ß = 0.703), physical function (ß = 1.025), axial involvement (ß = 0.659), female sex (ß = 0.924), and fibromyalgia (ß = 1.387) were associated with worse GH; age (ß=-0.024) and university education (ß=-0.856) with better GH. CONCLUSIONS: DA and physical function are major HRQoL and GH determinants across spondyloarthritis types, and clinical characteristics and sociodemographic factors play an important role, highlighting the importance of a holistic approach for individual patients.
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OBJECTIVE: To compare the 2-year retention rate between a second tumor necrosis factor alpha inhibitor (TNFi) and secukinumab (SEK) or ustekinumab (UST), in Psoriatic Arthritis (PsA) patients with previous inadequate response to their first TNFi. METHODS: Prospective longitudinal cohort study with a follow-up period of 2 years using the Nationwide Portuguese Reuma.pt database. Patients with a clinical diagnosis of PsA who also fulfill the CASPAR classification criteria, with previous treatment failure to a first-line TNFi and having started a second biotechnological drug (TNFi, SEK or UST) were included. The Cycling group was defined as switching from a first TNFi to a second TNFi, and the Swapping group as switching from a first TNFi to SEK or UST. Sociodemographic data, disease characteristics, disease activity scores and physical function at baseline and after 6, 12 and 24 months were recorded. Cox-proportional hazards regression was used to compare retention rates between Cycling and Swapping groups. To obtain a predictor model of 2-year discontinuation, a multivariable Cox regression model was performed. RESULTS: In total, 439 patients were included, 58% were female, with a mean age (standard deviation) of 49 (12) years. Globally, 75.6% initiated a second TNFi (Cycling group), and 24.4% started SEK/UST (Swapping group). The retention rates after 6, 12 and 24 months were 72%/66%/59% in the Cycling group; and 77%/66%/59% in the Swapping group. There were no significant differences in retention rates between both strategies (HR: 1.06, 95% CI 0.72-1.16). After 2 years of follow-up, 34.4% of patients discontinued their second biologic, mainly due to inefficacy (72.8%), with no differences found between groups. Baseline treatment with glucocorticoids was the only predictor of discontinuation after 2 years of follow-up (HR:1.668, 95% CI 1.154-2.409). CONCLUSIONS: After failure of a first TNF inhibitor, Cycling and Swapping strategies result in similar retention rates suggesting that both are acceptable in the management of patients with psoriatic arthritis.
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Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.
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Enfermedad de Leigh , Niño , Lactante , Humanos , Enfermedad de Leigh/genética , Portugal , ADN Mitocondrial/genética , Mitocondrias , Evolución BiológicaRESUMEN
Integrator is a multi-subunits protein complex involved in regulation of gene expression. Several Integrator subunits have been found to be mutated in human neurodevelopmental disorders, suggesting a key role for the complex in the development of nervous system. BRAT1 is similarly linked with neurodegenerative diseases and neurodevelopmental disorders such as rigidity and multifocal-seizure syndrome. Here, we show that INTS11 and INTS9 subunits of Integrator complex interact with BRAT1 and form a trimeric complex in human HEK293T cells as well as in pluripotent human embryonal carcinoma cell line (NT2). We find that BRAT1 depletion disrupts the differentiation of NT2 cells into astrocytes and neural cells. Loss of BRAT1 results in inability to activate many neuronal genes that are targets of REST, a neuronal silencer. We identified BRAT1 and INTS11 co-occupying the promoter region of these genes and pinpoint a role for BRAT1 in recruiting INTS11 to their promoters. Disease-causing mutations in BRAT1 diminish its association with INTS11/INTS9, linking the manifestation of disease phenotypes with a defect in transcriptional activation of key neuronal genes by BRAT1/INTS11/INTS9 complex. Highlights: Integrator subunits INTS9 and INTS11 tightly interact with BRAT1 Depletion of BRAT1 causes a dramatic delay in human neural differentiation BRAT1 and INTS11 module targets the promoters of neural marker genes and co-regulates their expression. The recruitment of INTS11 to these sites is BRAT1-dependent. Pathogenic E522K mutation in BRAT1 disrupts its interaction with INTS11/INTS9 heterodimer.
RESUMEN
Abnormal prion proteins (PrPSc) are the disease-associated isoform of cellular prion protein and diagnostic markers of transmissible spongiform encephalopathies (TSEs). These neurodegenerative diseases affect humans and several animal species and include scrapie, zoonotic bovine spongiform encephalopathy (BSE), chronic wasting disease of cervids (CWD), and the newly identified camel prion disease (CPD). Diagnosis of TSEs relies on immunodetection of PrPSc by application of both immunohistochemistry (IHC) and western immunoblot methods (WB) on encephalon tissues, namely, the brainstem (obex level). IHC is a widely used method that uses primary antibodies (monoclonal or polyclonal) against antigens of interest in cells of a tissue section. The antibody-antigen binding can be visualized by a color reaction that remains localized in the area of the tissue or cell where the antibody was targeted. As such, in prion diseases, as in other fields of research, the immunohistochemistry techniques are not solely used for diagnostic purposes but also in pathogenesis studies. Such studies involve detecting the PrPSc patterns and types from those previously described to identify the new prion strains. As BSE can infect humans, it is recommended that biosafety laboratory level-3 (BSL-3) facilities and/or practices are used to handle cattle, small ruminants, and cervid samples included in the TSE surveillance. Additionally, containment and prion-dedicated equipment are recommended, whenever possible, to limit contamination. The PrPSc IHC procedure consists of a formic acid epitope-demasking step also acting as a prion inactivation measure, as formalin-fixed and paraffin-embedded tissues used in this technique remain infectious. When interpreting the results, care must be taken to distinguish non-specific immunolabeling from target labeling. For this purpose, it is important to recognize artifacts of immunolabeling obtained in known TSE-negative control animals to differentiate those from specific PrPSc immunolabeling types, which can vary between TSE strains, host species, and prnp genotype, further described herein.