Frequency of CFTR variants in southern Brazil and indication for modulators therapy in patients with cystic fibrosis.

This is a descriptive cross-sectional study that aims to determine the distribution of the CFTR causing variant in a group of patients at a cystic fibrosis (CF) center in southern Brazil, as well as to describe causing variants that are treatable with mutation-specific drugs. Ninety-two patients from a CF reference center were assessed in this research, all of them with a clinical diagnosis of CF and both alleles identified with pathogenic variants. The most prevalent causing variants were F508del, R1162X, G542X, and N1303K. As for patients with a mutation-specific drug indication, 69.6 % were candidates for the use of Elexacaftor/Tezacaftor/Ivacaftor (Trikafta®), 44.6 % for the use of Tezacaftor/Ivacaftor (Symdeko®), and 35.9 % for the use of Lumacaftor/Ivacaftor (Orkambi®). For the use of Ivacaftor (Kalydeco®), only two patients (2.2 %) were candidates following the Brazilian agency approval. According to the FDA, 10 patients would be candidates for Ivacaftor (10.9 %). Causing variants of classes I and II, which are related to a major severity of the illness, were identified in 135 of 184 alleles (73.3 %). In this study, more than 2/3 of the patients were candidates for the use of CFTR modulators therapy.

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil / Características genéticas e fenotípicas de crianças e adolescentes com fibrose cística no Sul do Brasil

ABSTRACT Objectives: To characterize the main identified mutations on cystic fibrosis transmembrane conductance regulator (CFTR) in a group of children and adolescents at a cystic fibrosis center and its association with the clinical and laboratorial characteristics. Method: Descriptive cross-sectional study including patients with cystic fibrosis who had two alleles identified with CFTR mutation. Clinical, anthropometrical, laboratorial and pulmonary function (spirometry) data were collected from patients' records in charts and described with the results of the sample genotyping. Results: 42 patients with cystic fibrosis were included in the study. The most frequent mutation was F508del, covering 60 alleles (71.4%). The second most common mutation was G542X (six alleles, 7.1%), followed by N1303K and R1162X mutations (both with four alleles each). Three patients (7.14%) presented type III and IV mutations, and 22 patients (52.38%) presented homozygous mutation for F508del. Thirty three patients (78.6%) suffered of pancreatic insufficiency, 26.2% presented meconium ileus, and 16.7%, nutritional deficit. Of the patients in the study, 59.52% would be potential candidates for the use of CFTR-modulating drugs. Conclusions: The mutations of CFTR identified more frequently were F508del and G542X. These are type II and I mutations, respectively. Along with type III, they present a more severe cystic fibrosis phenotype. More than half of the sample (52.38%) presented homozygous mutation for F508del, that is, patients who could be treated with Lumacaftor/Ivacaftor. Approximately 7% of the patients (7.14%) presented type III and IV mutations, therefore becoming candidates for the treatment with Ivacaftor.

RESUMO Objetivos: Caracterizar as principais mutações identificadas no cystic fibrosis transmembrane conductance regulator (CFTR) em um grupo de crianças e adolescentes de um centro multidisciplinar de tratamento de fibrose cística e sua associação com características clínicas e laboratoriais. Método: Estudo transversal descritivo que incluiu pacientes com fibrose cística que possuíam dois alelos identificados com mutação no CFTR. Dados clínicos, antropométricos, laboratoriais e de função pulmonar (espirometria) foram coletados de registros em prontuários e descritos com os resultados de genotipagem da amostra. Resultados: Foram incluídos 42 pacientes com fibrose cística. A mutação mais frequente foi a F508del, abrangendo 60 alelos (71,4%). A segunda mutação mais comum foi a G542X (seis alelos, 7,1%), seguida das mutações N1303K e R1162X (ambas com quatro alelos cada uma). Três pacientes (7,14%) apresentaram mutações de classes III e IV, e 22 pacientes (52,38%), homozigose para F508del. Trinta e três pacientes (78,6%) tinham insuficiência pancreática, 11 (26,2%) apresentaram íleo meconial e sete (16,7%) déficit nutricional. Dos pacientes do estudo, 59,52% seriam potenciais candidatos ao uso de fármacos moduladores de CFTR. Conclusões: As mutações do CFTR identificadas com mais frequência foram F508del e G542X, as quais são mutações pertencentes às classes II e I, respectivamente, e que, juntamente à classe III, conferem um fenótipo de fibrose cística com mais gravidade. Mais da metade (52,38%) da amostra apresentava F508del em homozigose, população candidata ao novo tratamento com Lumacaftor/Ivacaftor. Aproximadamente 7% dos pacientes apresentavam mutações de classes III e IV, sendo candidatos ao tratamento com Ivacaftor.

Genetic and phenotypic traits of children and adolescents with cystic fibrosis in Southern Brazil.

OBJECTIVES: To characterize the main identified mutations on cystic fibrosis transmembrane conductance regulator (CFTR) in a group of children and adolescents at a cystic fibrosis center and its association with the clinical and laboratorial characteristics. METHOD: Descriptive cross-sectional study including patients with cystic fibrosis who had two alleles identified with CFTR mutation. Clinical, anthropometrical, laboratorial and pulmonary function (spirometry) data were collected from patients' records in charts and described with the results of the sample genotyping. RESULTS: 42 patients with cystic fibrosis were included in the study. The most frequent mutation was F508del, covering 60 alleles (71.4%). The second most common mutation was G542X (six alleles, 7.1%), followed by N1303K and R1162X mutations (both with four alleles each). Three patients (7.14%) presented type III and IV mutations, and 22 patients (52.38%) presented homozygous mutation for F508del. Thirty three patients (78.6%) suffered of pancreatic insufficiency, 26.2% presented meconium ileus, and 16.7%, nutritional deficit. Of the patients in the study, 59.52% would be potential candidates for the use of CFTR-modulating drugs. CONCLUSIONS: The mutations of CFTR identified more frequently were F508del and G542X. These are type II and I mutations, respectively. Along with type III, they present a more severe cystic fibrosis phenotype. More than half of the sample (52.38%) presented homozygous mutation for F508del, that is, patients who could be treated with Lumacaftor/Ivacaftor. Approximately 7% of the patients (7.14%) presented type III and IV mutations, therefore becoming candidates for the treatment with Ivacaftor.

Incidence and endoscopic characteristics of acute laryngeal lesions in children undergoing endotracheal intubation / Incidência e características endoscópicas de lesões agudas laríngeas em crianças submetidas à intubação endotraqueal

ABSTRACT INTRODUCTION: Acute laryngeal lesions after intubation appear to be precursors of chronic lesions. OBJECTIVE: To describe the incidence and type of acute laryngeal lesions after extubation in a pediatric intensive care unit (PICU). METHODS: A cohort study involving children from birth to <5 years, submitted to intubation for more than 24 h in the PICU of an university hospital. In the first eight hours after extubation, a flexible fiberoptic laryngoscopy (FFL) was performed at the bedside. Those with moderate to severe abnormalities underwent a second examination seven to ten days later. RESULTS: 177 patients were included, with a median age of 2.46 months. The mean intubation time was 8.19 days. Seventy-three (41.2%) patients had moderate or severe alterations at the FFL, with the remaining showing only minor alterations or normal results. During follow-up, 16 children from the group with moderate to severe lesions developed subglottic stenosis. One patient from the normal FFL group had subglottic stenosis, resulting in an incidence of 9.6% of chronic lesions. CONCLUSION: Most children in the study developed mild acute laryngeal lesions caused by endotracheal intubation, which improved in a few days after extubation.

Resumo Introdução: As lesões laríngeas agudas após a intubação parecem ser precursoras das lesões crônicas. Objetivo: Descrever a incidência e o tipo de lesões laríngeas agudas após extubação em Unidade de Terapia Intensiva Pediátrica (UTIP). Método: Estudo de coorte envolvendo crianças de 0 a 5 anos incompletos, com intubação por mais de 24 horas na UTIP de um hospital universitário. Nas primeiras 8 horas após extubação, uma nasofibrolaringoscopia à beira do leito foi realizada. Aqueles com anormalidades moderadas a graves foram submetidos a novo exame entre 7-10 dias após. Resultados: 177 pacientes foram incluídos, com idade mediana de 2,46 meses. O tempo médio de intubação foi de 8,19 dias. Setenta e três (41,2%) pacientes apresentaram alterações moderadas ou graves à laringoscopia, o restante mostrando apenas alterações leves ou exame normal. Durante o acompanhamento, 16 crianças do grupo lesões moderada a grave desenvolveram estenose subglótica. Um paciente do grupo laringoscopia normal teve estenose subglótica, somando-se uma incidência de 9,6% de lesões crônicas. Conclusão: A maioria das crianças do estudo desenvolveu lesões laríngeas agudas leves decorrentes da intubação endotraqueal, com melhora em alguns dias após a extubação.

Incidence and endoscopic characteristics of acute laryngeal lesions in children undergoing endotracheal intubation.

INTRODUCTION: Acute laryngeal lesions after intubation appear to be precursors of chronic lesions. OBJECTIVE: To describe the incidence and type of acute laryngeal lesions after extubation in a pediatric intensive care unit (PICU). METHODS: A cohort study involving children from birth to <5 years, submitted to intubation for more than 24h in the PICU of an university hospital. In the first eight hours after extubation, a flexible fiberoptic laryngoscopy (FFL) was performed at the bedside. Those with moderate to severe abnormalities underwent a second examination seven to ten days later. RESULTS: 177 patients were included, with a median age of 2.46 months. The mean intubation time was 8.19 days. Seventy-three (41.2%) patients had moderate or severe alterations at the FFL, with the remaining showing only minor alterations or normal results. During follow-up, 16 children from the group with moderate to severe lesions developed subglottic stenosis. One patient from the normal FFL group had subglottic stenosis, resulting in an incidence of 9.6% of chronic lesions. CONCLUSION: Most children in the study developed mild acute laryngeal lesions caused by endotracheal intubation, which improved in a few days after extubation.

Blood pressure variability and its association with echocardiographic parameters in hypertensive diabetic patients.

BACKGROUND: Blood pressure (BP) variability is associated with target organ damage in hypertension and diabetes. The 24 h ambulatory blood pressure monitoring (24 h-ABPM) has been proposed as an evaluation for BP variability using several indexes [standard deviation (SD) of mean BP, coefficient of variation (CV), BP variation over time (time-rate index)]. METHODS: We evaluated the association between BP variability measured by 24 h-ABPM indexes and echocardiographic variables in a cross-sectional study in 305 diabetic-hypertensive patients. RESULTS: Two groups were defined by the median (0.55 mmHg/min) of time-rate systolic BP (SBP) index and classified as low or high variability. Age was 57.3 ± 6.2 years, 196 (64.3%) were female. Diabetes duration was 10.0 (5.0-16.2) years, HbA1c was 8.2 ± 1.9%. Baseline clinical characteristics were similar between low (n = 148) and high (n = 157) variability groups. Office SBP and systolic 24 h-ABPM were higher in the high variability group (139.9 mmHg vs 146.0 mmHg, P = 0.006; 128.3 mmHg vs 132.9 mmHg, P = 0.019, respectively). Time-rate index, SD and CV of SBP, were higher in high variability group (P < 0.001; P < 0.001 and P = 0.003, respectively). Time-rate index was not independently associated with the echocardiography's variables in multiple linear model when adjusting for age, 24 h-ABPM, diabetes duration and HbA1c. The multiple linear regression model revealed that the significant and independent determinants for septum thickness, relative wall thickness and posterior wall thickness (parameters of left ventricular hypertrophy) were: age (p = 0.025; p = 0.010; p = 0.032, respectively) and 24 h-SBP (p < 0.001 in the three parameters). CONCLUSION: BP variability estimated by 24 h-ABPM is not independently associated with echocardiographic parameters in diabetic-hypertensive patients.

Exercise on Progenitor Cells in Healthy Subjects and Patients with Type 1 Diabetes.

PURPOSE: To evaluate the acute effect of aerobic exercise (AE) and resistance exercise (RE) on the release of endothelial progenitor cell (EPCs, CD34+/KDR+/CD45 dim) and vascular function in type 1 diabetes (T1DM). METHODS: Fourteen men with T1DM and 5 nondiabetic controls were randomly assigned to 40-min AE (60% VO 2peak) and RE sessions (60% 1-RM). The study had a crossover design, and interventions were 1 wk apart. Venous occlusion plethysmography (blood flow, reactive hyperemia, and vascular resistance) and blood collection (EPC levels, flow cytometry) were done immediately before and after exercise sessions. RESULTS: Patients were 30.3 ± 1.6 yr-old, HbA1c 7.7% ± 0.2%; controls were 26.8 ± 2.3 yr-old. Groups did not differ in EPC levels at baseline or in relation to exercise. Over time, exercise did not induce changes in patients with T1DM, whereas, in controls, EPCs were decreased after AE (-10.7%, P = 0.017) and increased after RE (+12.2%, P = 0.004). Compared with baseline, blood flow increased and vascular resistance decreased after RE in both groups. Reactive hyperemia was increased 10 min after AE and RE sessions in patients with T1DM (36.5% and 42.0%, respectively) and in controls (35.4% and 74.3%), but no group differences were observed between groups in response to exercise. CONCLUSIONS: Despite the increased vascular reactivity in both groups after both exercise sessions, EPCs were only influenced by exercise in controls. The unchanged number of EPCs in T1DM after exercise sessions might indicate a blunted endothelium regenerating capacity, revealing an early deterioration of the functional arterial characteristics not disclosed by only evaluating vascular functional variables.

Síndrome nefrótica idiopática na infância: diagnóstico e manejo / Idiopathic nephrotic syndrome in children: diagnosis and management

A síndrome nefrótica é um conjunto de sinais, de sintomas e de achados laboratoriais, comum a diferentes doenças. Aproximadamente 90% das crianças com síndrome nefrótica apresentam síndrome nefrótica idiopática. É importante termos o conhecimento de como identificar essa síndrome e de como realizar o manejo adequado dos pacientes, visto que, estes podem desenvolver insuficiência renal crônica, podendo necessitar de transplante renal precoce.

Nephrotic syndrome is a group of sign, symptons and laboratorial findings commonly seen in children. Approximately 90% of children with Nephrotic syndrome have idiopathic Nephrotic syndrome. It's important to acknowledge how to identify this syndrome and how to have an adequate management of these patients, since they can develop chronic kidney disease, and may need early kidney transplant.

Controle glicêmico em pacientes com diabetes mellitus e doença cardiovascular acompanhados em ambulatório de referência / Glycemic control in patients with diabetes mellitus and cardiovascular disease monitored at a reference outpatient clinic

INTRODUÇÃO: O controle da hiperglicemia característica do diabetes mellitus é parte importante do seu tratamento, e se associa, em longo prazo, à redução de complicações crônicas da doença. No entanto, atingir bom controle glicêmico não é tarefa fácil; múltiplas abordagens têm sido buscadas com este intuito. Nosso objetivo foi descrever o controle glicêmico de uma amostra de pacientes atendidos em nível terciário e analisar possíveis preditores de alcance de bom controle glicêmico no seguimento. MÉTODOS: Estudo observacional, coletados dados de pacientes com diabetes tipo 2 em acompanhamento ambulatorial, através de dados do prontuário eletrônico. Coletadas variáveis demográficas, clínicas e laboratoriais (glicemia, hemoglobina glicada (HbA1c), lipídios, creatinina e microalbuminúria). RESULTADOS: Foram incluídos 57 pacientes; 61,4% alcançaram HbA1c ≤8% (grupo Diabetes Mellitus controlado, DMC) e 22 (38,6%) não atingiram este valor (grupo Diabetes Mellitus não controlado, DMNC) em 1 ano. A maioria dos pacientes do grupo DMNC eram homens (p = 0,030); idade, associação com outras comorbidades, escolaridade, tempo de diabetes não foram diferentes entre os grupos. Número de consultas marcadas foi semelhante entre os grupos, mas o de consultas realizadas foi maior no grupo DMNC. O controle glicêmico inicial era pior no grupo DMNC (HbA1c 9,2 ±1,4 vs.11,0 ±1,5%, p < 0,001). Alta ambulatorial foi mais frequente no grupo DMC (p = 0,01). CONCLUSÃO: A intensificação do cuidado ao diabetes por equipe especializada em nível terciário é capaz de trazer melhor controle glicêmico para a maioria destes pacientes, especialmente quando encaminhados ainda com HbA1c não muito elevada

INTRODUCTION: Controlling hyperglycemia in diabetes mellitus is an important part of the treatment and is associated with long-term reduction of chronic complications. However, it is difficult to achieve, and different approaches to glycemic control are being investigated. We aimed to analyze glycemic control in a sample of patients treated at a tertiary hospital, as well as to analyze possible predictors of good glycemic control during follow-up. METHODS: In this observational study, we collected data from the electronic medical records of patients with type 2 diabetes treated at a reference outpatient clinic. We analyzed demographic, clinical and laboratory variables (blood glucose, glycosylated hemoglobin (HbA1c), lipids, creatinine and microalbuminuria). RESULTS: Out of 57 patients, 61.4% had HbA1c levels ≤8% (controlled diabetes mellitus group, CDM), and 38.6% (n = 22) did not reach this value (uncontrolled diabetes mellitus group, UDM) in 1 year. Most patients in the UDM group were men (p = 0.030). Age, association with other comorbidities, educational attainment, and duration of diabetes were not different between groups. The number of scheduled appointments was similar between groups, but the number of attended appointments was higher in the UDM group. Initial glycemic control was worse in the UDM group (HbA1c 9.2 ±1.4 vs. 11.0 ±1.5%, p < 0.001). Outpatient discharge was more frequent in the CDM group (p = 0.01). CONCLUSION: Intensifying diabetes care by a specialized team at tertiary centers can improve metabolic control for the majority of these patients, especially for those with a lower HbA1c at the time of referral