RESUMO

OBJECTIVE: This study aimed to provide a long-term follow-up of PRKAG2 syndrome and describe the new phenotypic aspects of the condition. PRKAG2 syndrome is a rare autosomal-dominant glycogen storage disease characterized by cardiac hypertrophy, ventricular pre-excitation, and conduction system disease. Fatal arrhythmias occur frequently. METHODS: A family cohort of 66 participants was recruited. Clinical and genetic analyses were performed. RESULTS: Median age of 36.97±17.28 years, with 69.9% being men. Nineteen subjects carried the deleterious variant p.K290I of the PRKAG2 gene. This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes, four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures. Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations. Palpitations, Syncope, atrial fibrillation, atrial flutter, sinus pauses, and bradycardia were strongly and significantly associated with major or severe adverse events (sudden cardiac death, aborted cardiac arrest, pacemaker use, stroke, and congestive heart failure). Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates. Mutations carriers were advised to avoid pregnancy. CONCLUSION: This study identified that the p.K291I_PRKAG2 mutation is associated with poor prognosis, highlighting the need for early intervention. Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome.

Assuntos

Cardiomiopatia Hipertrófica , Humanos , Feminino , Masculino , Adulto , Seguimentos , Adulto Jovem , Pessoa de Meia-Idade , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/complicações , Brasil/epidemiologia , Adolescente , Mutação , Proteínas Quinases Ativadas por AMP/genética , Fenótipo , Criança , Arritmias Cardíacas/genética , Arritmias Cardíacas/etiologia , Síndrome , Idoso

Assuntos

Cardiologia , Guias de Prática Clínica como Assunto , Sociedades Médicas , Humanos , Brasil , Cardiologia/normas , Guias de Prática Clínica como Assunto/normas , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/prevenção & controle

RESUMO

BACKGROUND: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. OBJECTIVES: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. METHODS: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ -17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant. RESULTS: The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was -19% (-16% to -20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). CONCLUSION: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.

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FUNDAMENTO: A amiloidose por transtirretina (ATTR) é uma doença infiltrativa causada pela deposição anormal de proteína principalmente no coração e no sistema nervoso periférico. Quando acomete o coração, a doença manifesta-se como uma cardiomiopatia restritiva e, quando afeta o sistema nervoso periférico e autônomo, apresenta-se como uma polineuropatia, podendo ser chamada de Polineuropatia Amiloidótica Familiar (PAF). Existem dois subtipos de ATTR, a ATTR selvagem, em que não há variantes genéticas, e a ATTR hereditária, caracterizada por uma variante no gene que codifica a proteína transtirretina (T\TR). Em ambos os subtipos, o envolvimento cardíaco é o principal marcador prognóstico. OBJETIVOS: Avaliar a prevalência do envolvimento cardíaco subclínico em uma amostra de pacientes com variantes genéticas no gene TTR usando a cintilografia com pirofosfato e o ecocardiograma com strain; comparar os achados cintilográficos e as medidas de strain; avaliar a associação entre PAF e o envolvimento subclínico; e analisar se existe uma associação entre uma variante genética específica e o envolvimento cardíaco. MÉTODOS: Estudo transversal com carreadores de variantes no gene TTR sem sintomas cardiovasculares e sem alterações nos parâmetros da eletrocardiografia ou do ecocardiograma convencional. Todos os pacientes foram submetidos à cintilografia com pirofosfato e à ecocardiografia com análise de strain. O envolvimento cardíaco subclínico, definido como um escore de Perugini ≥ 2, razão Coração (C)/ Hemitórax Contralateral (CL) ≥ 1,5 em uma hora, C/CL ≥ 1,3 na terceira hora, ou um strain longitudinal global (SGL) ≤ −17%. Realizadas análises descritiva e analítica, e aplicados o teste exato de Fisher e o teste de Mann-Whitney. Um valor de p<0,05 foi considerado significativo. RESULTADOS: Os 23 pacientes avaliados apresentavam uma idade mediana de 51 (37-57) anos, 15 (65,2%) eram do sexo feminino, 12 (52,2%) eram pardos, nove (39,1%) apresentavam hipertensão arterial sistêmica, e nove (39,1%) tinham um diagnóstico prévio de PAF. Dos nove pacientes com PAF, oito (34,8%) usavam tafamidis. As variantes genéticas identificadas foram Val142IIe, Val50Met e IIe127Val. O valor mediano do SGL foi −19% (-16% ­ −20%). Dos 23 pacientes, nove (39,1%; 95% CI = 29­49%) preencheram os critérios de envolvimento cardíaco, seis (26%) somente pelo critério do SGL. Não houve associação entre PAF e um carreador assintomático avaliado por ecocardiograma com análise de strain e pela cintilografia com pirofostato (p=0,19). A prevalência de hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo e SGL reduzido não foi diferente entre os grupos. A velocidade da onda e' septal foi a única variável que apresentou diferença significativa entre os indivíduos com e sem SGL reduzido, com uma área sob a curva ROC de 0,80 (IC95% = 0,61­0,98, p = 0,027). A melhor acurácia diagnóstica foi alcançada com uma velocidade e' septal ≤ 8,5 cm/s. Não houve associação entre o tipo de variante genética e o envolvimento cardíaco pré-clínico, nem entre o uso de tafamidis e este mesmo envolvimento (37,5% versus 40,0%, p = 0,90). CONCLUSÃO: O envolvimento cardíaco subclínico foi frequente em uma amostra de carreadores da variante genética do gene TTR. Um valor do SGL reduzido foi o achado mais comum. Não houve associação entre a presença de polineuropatia amiloidótica e o envolvimento subclínico. O tipo de variante genética não foi associado com envolvimento cardíaco precoce. Nesta amostra, o uso de tafamidis (20mg/dia) não foi associado com uma menor prevalência de envolvimento cardíaco subclínico.

Assuntos

Neuropatias Amiloides Familiares , Ecocardiografia , Pré-Albumina , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/diagnóstico por imagem , Estudos Transversais , Pré-Albumina/genética , Cintilografia , Valores de Referência , Estatísticas não Paramétricas

RESUMO

Resumo Fundamento: A amiloidose por transtirretina (ATTR) é uma doença infiltrativa causada pela deposição anormal de proteína principalmente no coração e no sistema nervoso periférico. Quando acomete o coração, a doença manifesta-se como uma cardiomiopatia restritiva e, quando afeta o sistema nervoso periférico e autônomo, apresenta-se como uma polineuropatia, podendo ser chamada de Polineuropatia Amiloidótica Familiar (PAF). Existem dois subtipos de ATTR, a ATTR selvagem, em que não há variantes genéticas, e a ATTR hereditária, caracterizada por uma variante no gene que codifica a proteína transtirretina (T/TR). Em ambos os subtipos, o envolvimento cardíaco é o principal marcador prognóstico. Objetivos: Avaliar a prevalência do envolvimento cardíaco subclínico em uma amostra de pacientes com variantes genéticas no gene TTR usando a cintilografia com pirofosfato e o ecocardiograma com strain; comparar os achados cintilográficos e as medidas de strain; avaliar a associação entre PAF e o envolvimento subclínico; e analisar se existe uma associação entre uma variante genética específica e o envolvimento cardíaco. Métodos: Estudo transversal com carreadores de variantes no gene TTR sem sintomas cardiovasculares e sem alterações nos parâmetros da eletrocardiografia ou do ecocardiograma convencional. Todos os pacientes foram submetidos à cintilografia com pirofosfato e à ecocardiografia com análise de strain. O envolvimento cardíaco subclínico, definido como um escore de Perugini ≥ 2, razão Coração (C)/ Hemitórax Contralateral (CL) ≥ 1,5 em uma hora, C/CL ≥ 1,3 na terceira hora, ou um strain longitudinal global (SGL) ≤ −17%. Realizadas análises descritiva e analítica, e aplicados o teste exato de Fisher e o teste de Mann-Whitney. Um valor de p<0,05 foi considerado significativo. Resultados: Os 23 pacientes avaliados apresentavam uma idade mediana de 51 (37-57) anos, 15 (65,2%) eram do sexo feminino, 12 (52,2%) eram pardos, nove (39,1%) apresentavam hipertensão arterial sistêmica, e nove (39,1%) tinham um diagnóstico prévio de PAF. Dos nove pacientes com PAF, oito (34,8%) usavam tafamidis. As variantes genéticas identificadas foram Val142IIe, Val50Met e IIe127Val. O valor mediano do SGL foi −19% (-16% - −20%). Dos 23 pacientes, nove (39,1%; 95% CI = 29-49%) preencheram os critérios de envolvimento cardíaco, seis (26%) somente pelo critério do SGL. Não houve associação entre PAF e um carreador assintomático avaliado por ecocardiograma com análise de strain e pela cintilografia com pirofostato (p=0,19). A prevalência de hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo e SGL reduzido não foi diferente entre os grupos. A velocidade da onda e' septal foi a única variável que apresentou diferença significativa entre os indivíduos com e sem SGL reduzido, com uma área sob a curva ROC de 0,80 (IC95% = 0,61-0,98, p = 0,027). A melhor acurácia diagnóstica foi alcançada com uma velocidade e' septal ≤ 8,5 cm/s. Não houve associação entre o tipo de variante genética e o envolvimento cardíaco pré-clínico, nem entre o uso de tafamidis e este mesmo envolvimento (37,5% versus 40,0%, p = 0,90). Conclusão: O envolvimento cardíaco subclínico foi frequente em uma amostra de carreadores da variante genética do gene TTR. Um valor do SGL reduzido foi o achado mais comum. Não houve associação entre a presença de polineuropatia amiloidótica e o envolvimento subclínico. O tipo de variante genética não foi associado com envolvimento cardíaco precoce. Nesta amostra, o uso de tafamidis (20mg/dia) não foi associado com uma menor prevalência de envolvimento cardíaco subclínico.

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Abstract Background: Transthyretin amyloidosis (ATTR) is an infiltrative disease caused by abnormal protein deposition mainly in the heart and peripheral nervous system. When it affects the heart, the disease presents as restrictive cardiomyopathy; when it affects the peripheral and autonomic nervous system, it manifests as polyneuropathy, and is called familial amyloid polyneuropathy (FAP). There are two ATTR subtypes: wild-type ATTR, where there is no mutation, and mutant ATTR (ATTRm), which is characterized by a mutation in the gene encoding the transthyretin protein (TTR). In both subtypes, cardiac involvement is the major marker of poor prognosis. Objectives: To assess the prevalence of subclinical cardiac involvement in a sample of patients with TTR gene mutation by using pyrophosphate scintigraphy and strain echocardiography; to compare scintigraphy and strain findings; to evaluate the association between neurological manifestations (FAP) and subclinical cardiac involvement; and to analyze whether there is an association between any specific mutation and cardiac involvement. Methods: This is a cross-sectional study with carriers of the TTR gene mutation, without cardiovascular symptoms or changes in electrocardiographic or conventional echocardiographic parameters. All patients underwent pyrophosphate scintigraphy and strain echocardiography. Subclinical cardiac involvement was defined as a Perugini score ≥ 2, heart-to-contralateral lung (H/CL) ratio ≥ 1.5 at 1 h, H/CL ≥1.3 at 3 h, or global longitudinal strain (GLS) ≤ −17%. Descriptive and analytical analyses were performed and Fisher's exact test and Mann-Whitney test were applied. A value of p < 0.05 was considered significant. Results: The 23 patients evaluated had a median age of 51 years (IQR 37-57 years), 15 (65.2%) were female, 12 (52.2%) were Pardo, nine (39.1%) had systemic arterial hypertension, and nine (39.1%) had a previous diagnosis of FAP. Of the nine patients with FAP, 8 (34.8%) were on tafamidis. The associated mutations were Val142IIe, Val50Met, and IIe127Val. The median GLS in the sample was −19% (−16% to −20%). Of the 23 patients, nine (39.1%; 95% CI = 29-49%) met criteria for cardiac involvement, six (26%) by the GLS-based criteria only. There was no association between having FAP and being an asymptomatic carrier, as assessed by strain echocardiography and pyrophosphate scintigraphy (p = 0.19). The prevalence of systemic arterial hypertension, diabetes mellitus, dyslipidemia, smoking, and reduced GLS did not differ between groups. Septal e' wave velocity was the only variable that significantly differed between individuals with and without reduced GLS, with an area under the ROC curve of 0.80 (95% CI = 0.61-0.98, p = 0.027). The best diagnostic accuracy was achieved with a septal e' velocity ≤ 8.5 cm/s. There was no association between mutation type and preclinical cardiac involvement, nor between tafamidis use and lower degree of cardiac involvement (37.5% versus 40.0%, p = 0.90). Conclusion: Subclinical cardiac involvement was common in a sample of TTR mutation carriers without cardiac involvement. Reduced left ventricular GLS was the most frequent finding. There was no association between the presence of amyloid polyneuropathy and subclinical cardiac involvement. Type of mutation was not associated with early cardiac involvement. In this sample, the use of tafamidis 20 mg/day was not associated with a lower prevalence of subclinical cardiac involvement.

Assuntos

Cardiologia , Sistema Cardiovascular , Sistemas Eletrônicos de Liberação de Nicotina , Humanos , Brasil

RESUMO

ABSTRACT Objective This study aimed to provide a long-term follow-up of PRKAG2 syndrome and describe the new phenotypic aspects of the condition. PRKAG2 syndrome is a rare autosomal-dominant glycogen storage disease characterized by cardiac hypertrophy, ventricular pre-excitation, and conduction system disease. Fatal arrhythmias occur frequently. Methods A family cohort of 66 participants was recruited. Clinical and genetic analyses were performed. Results Median age of 36.97±17.28 years, with 69.9% being men. Nineteen subjects carried the deleterious variant p.K290I of the PRKAG2 gene. This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes, four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures. Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations. Palpitations, Syncope, atrial fibrillation, atrial flutter, sinus pauses, and bradycardia were strongly and significantly associated with major or severe adverse events (sudden cardiac death, aborted cardiac arrest, pacemaker use, stroke, and congestive heart failure). Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates. Mutations carriers were advised to avoid pregnancy. Conclusion This study identified that the p.K291I_PRKAG2 mutation is associated with poor prognosis, highlighting the need for early intervention. Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome.

RESUMO

BACKGROUND: Religiosity and spirituality have been associated with higher recovery rates, greater adherence to treatments, and better levels of quality of life in patients with heart disease. OBJECTIVES: To evaluate the association between spirituality, functional gain, and improved quality of life in patients in a cardiovascular rehabilitation program. METHODS: This prospective cohort study evaluated the association between functional and quality of life gains during a cardiovascular rehabilitation program and a religiosity/spirituality index based on a validated scale. Depression, anxiety, and stress symptoms were screened for control purposes. P values < 0.05 were considered significant for all analyses. RESULTS: The study followed 57 patients (66 ± 12 years old; 71.7% male; 76% with coronary artery disease). The Spearman correlation coefficient did not show any associations between increases in functional capacity and organizational (rs = 0.110; p = 0.421), non-organizational (rs = -0.007; p = 0.421), or intrinsic (rs = -0.083; p = 0.543) religiosity. Furthermore, no associations were detected between the results of a quality of life score and organizational (rs = 0.22; p = 0.871), non-organizational (rs = 0.191; p = 0.159), or intrinsic (rs = 0.108; p = 0.429) religiosity. CONCLUSION: No association was detected between functional and quality of life gains and organizational, non-organizational, or intrinsic religiosity in this sample of patients undergoing cardiovascular rehabilitation.

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FUNDAMENTO: Religiosidade e espiritualidade têm sido associadas a maiores taxas de recuperação, maior adesão a tratamentos e melhores níveis de qualidade de vida em pacientes cardiopatas. OBJETIVOS: Avaliar a associação entre espiritualidade, ganho funcional e melhoria de qualidade de vida em pacientes de um programa de reabilitação cardiovascular. MÉTODOS: Estudo de coorte prospectiva, no qual foi avaliada a associação entre os ganhos funcional e em qualidade de vida obtidos durante um programa de reabilitação cardiovascular e o índice de religiosidade/espiritualidade a partir de escala validada. Sintomas de depressão, ansiedade e estresse foram rastreados, para fins de controle. Um p < 0,05 foi adotado como padrão significante para todas as análises. RESULTADOS: Foram acompanhados 57 pacientes (66 ± 12 anos; 71,7% masculinos, 76% com doença arterial coronariana). O cálculo do coeficiente de correlação de Spearman não evidenciou associações entre incrementos na capacidade funcional e religiosidade organizacional (rs = 0,110; p = 0,421), não organizacional (rs = −0,007; p = 0,421) ou intrínseca (rs = −0,083; p = 0,543). Também não foram detectadas associações entre os resultados de um escore de qualidade de vida e religiosidade organizacional (rs = 0,22; p = 0,871), não organizacional (rs = 0,191; p = 0,159) ou intrínseca (rs = 0,108; p = 0,429). CONCLUSÃO: Não foi detectada associação entre ganho funcional ou em qualidade de vida e religiosidade organizacional, não organizacional ou intrínseca, nesta amostra de pacientes em reabilitação cardiovascular.

Assuntos

Reabilitação Cardíaca , Espiritualidade , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Qualidade de Vida , Estudos Prospectivos , Religião

RESUMO

Resumo Fundamento Religiosidade e espiritualidade têm sido associadas a maiores taxas de recuperação, maior adesão a tratamentos e melhores níveis de qualidade de vida em pacientes cardiopatas. Objetivos Avaliar a associação entre espiritualidade, ganho funcional e melhoria de qualidade de vida em pacientes de um programa de reabilitação cardiovascular. Métodos Estudo de coorte prospectiva, no qual foi avaliada a associação entre os ganhos funcional e em qualidade de vida obtidos durante um programa de reabilitação cardiovascular e o índice de religiosidade/espiritualidade a partir de escala validada. Sintomas de depressão, ansiedade e estresse foram rastreados, para fins de controle. Um p < 0,05 foi adotado como padrão significante para todas as análises. Resultados Foram acompanhados 57 pacientes (66 ± 12 anos; 71,7% masculinos, 76% com doença arterial coronariana). O cálculo do coeficiente de correlação de Spearman não evidenciou associações entre incrementos na capacidade funcional e religiosidade organizacional (rs = 0,110; p = 0,421), não organizacional (rs = −0,007; p = 0,421) ou intrínseca (rs = −0,083; p = 0,543). Também não foram detectadas associações entre os resultados de um escore de qualidade de vida e religiosidade organizacional (rs = 0,22; p = 0,871), não organizacional (rs = 0,191; p = 0,159) ou intrínseca (rs = 0,108; p = 0,429). Conclusão Não foi detectada associação entre ganho funcional ou em qualidade de vida e religiosidade organizacional, não organizacional ou intrínseca, nesta amostra de pacientes em reabilitação cardiovascular.

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Abstract Background Religiosity and spirituality have been associated with higher recovery rates, greater adherence to treatments, and better levels of quality of life in patients with heart disease. Objectives To evaluate the association between spirituality, functional gain, and improved quality of life in patients in a cardiovascular rehabilitation program. Methods This prospective cohort study evaluated the association between functional and quality of life gains during a cardiovascular rehabilitation program and a religiosity/spirituality index based on a validated scale. Depression, anxiety, and stress symptoms were screened for control purposes. P values < 0.05 were considered significant for all analyses. Results The study followed 57 patients (66 ± 12 years old; 71.7% male; 76% with coronary artery disease). The Spearman correlation coefficient did not show any associations between increases in functional capacity and organizational (rs = 0.110; p = 0.421), non-organizational (rs = −0.007; p = 0.421), or intrinsic (rs = −0.083; p = 0.543) religiosity. Furthermore, no associations were detected between the results of a quality of life score and organizational (rs = 0.22; p = 0.871), non-organizational (rs = 0.191; p = 0.159), or intrinsic (rs = 0.108; p = 0.429) religiosity. Conclusion No association was detected between functional and quality of life gains and organizational, non-organizational, or intrinsic religiosity in this sample of patients undergoing cardiovascular rehabilitation.

RESUMO

Abstract Background Sudden cardiac death is the main lethal mechanism associated with Chagas cardiomyopathy. Studies suggest that dysautonomia may represent a relevant, intense, independent, and early phenomenon in the natural history of the disease, even when ventricular systolic function is preserved, and may also be the mechanism that triggers malignant ventricular arrhythmias. Objective To evaluate the degree of dysautonomia and its possible association with ventricular arrhythmias in patients with Chagas cardiomyopathy, according to different categories of mortality risk, as defined by the score proposed by Rassi, used as a surrogate outcome for death. Methods A cross-sectional study involving 43 patients with Chagas cardiomyopathy stratified into risk categories based on the Rassi score, with 23 being classified as low risk and 20 as intermediate-to-high risk. Heart rate variability (HRV) was assessed using Holter monitoring for long-term recordings of 24 hours (time domain) and for short-term recordings of 5 minutes (frequency domain) at rest and after autonomic tests: deep breathing and Valsalva maneuver. The HRV variables were compared between the groups using the Student's t-test and α=0.05. Results Comparison of the results between the risk stratification groups showed no differences in HRV indexes, either in the time or frequency domain. However, results showed a significant increase in the number of arrhythmias as a function of increased risk (p=0.02). Conclusion There was no association between the degree of dysautonomia, evaluated by Holter monitoring, and the categories of mortality risk, despite a direct association between the rate of arrhythmias and the higher risk group.

RESUMO

The fungus Aspergillus parasiticus is a contaminant in agricultural crops and its eradication involves the indiscriminate use of harmful synthetic pesticides. In the search for antifungal agents of natural origin, chitosan (Q) and capsaicin (C) are coupled in the form of nanoparticles (Np), which can possess a direct application under specific conditions. Due to their small size, Np can cross through the cell wall, taking the cells into a pro-oxidant environment known as "oxidative stress", which presents when the reactive oxygen species (ROS) surpass the number of antioxidants in the cell. In the present investigation, nanoparticles of chitosan (Np Q) and nanoparticles of chitosan-capsaicin (Np QC) with an average diameter of 44.8 ± 20.6 nm and 111.1 ± 14.1 nm, respectively, were synthesized, and there was a zeta potential of + 25.6 ± 0.7 mV and + 26.8 ± 6.1 mV, respectively. The effect of the concentration of Np Q (A, B, C, and D), of Np QC (A, B, C, and D), and capsaicin in a solution (control) was evaluated on the viability of the spores, the accumulation of intracellular ROS, and the morphometric changes of A. parasiticus. Acute toxicity of the Np was determined utilizing bioassays with Artemia salina, and acute phytotoxicity was evaluated in lettuce seeds (Lactuca sativa). According to ROS results, capsaicin (control) did not induce oxidative stress in the cell; otherwise, it was observed to have an elevated (p < 0.05) accumulation of ROS when the concentration of Np Q increased. For both, Np Q and Np QC, an inverse physiological pattern relating spore viability and ROS accumulation in the fungus was found; the viability of spores decreased as the ROS accumulation increased. The spore viability of A. parasiticus diminished upon increasing the concentration of chitosan (0.3−0.4 mg/mL) in the Np, while the intracellular accumulation of ROS increased proportionally to the concentration of the nanomaterials in the treatments of Np Q and Np QC. On the other hand, Np QC presented a lower (p < 0.05) toxicological effect in comparison with Np Q, which indicates that the incorporation of bioactive compounds, such as capsaicin, into nanoparticles of chitosan is a strategy that permits the reduction of the toxicity associated with nanostructured materials.

RESUMO

BACKGROUND: Bacterial infections occur in 43-59% of cirrhotic patients admitted to the intensive care unit with impact in morbidity and mortality. An increase in the frequency of multidrug-resistant (MDRO) and extensively drug-resistant (XDRO) organisms has been described in bacterial infections in cirrhotic patients with an adverse impact on survival. OBJECTIVE: To characterize community-acquired (CA), healthcare-associated (HCA), and hospital-acquired (HA) infections in cirrhotic patients and their impact in the occurrence of adverse outcomes. METHODS: This study included all cirrhotic patients admitted in an intensive care unit specialized in liver and gastrointestinal diseases in Brazil between January 2012 and June 2018. Frequency and topography of infections were retrospectively evaluated, as well as the frequency of MDRO and XDRO organisms, and their impact in occurrence of acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, sepsis and mortality. RESULTS: A total of 374 infections were observed and classified as CA (22%), HCA (34%) and hospital-acquired (44%). Eighty-nine (54%) episodes of hospital-acquired infections were second infections. Spontaneous bacterial peritonitis (32%) and urinary tract infection (23%) were the most common infections. Culture-proven infections were positive in 61% of the cases, mainly gram-negative bacteria (73%). Acute kidney injury, hepatorenal syndrome and sepsis were observed, respectively, in 48%, 15% and 53% of the cases. MDRO and XDRO were seen, respectively, in 35% and 16%, mainly in HCA (48% vs 26% in CA infections, P=0.02) and hospital-acquired (58% vs 26% in CA infections, P=0.0009). Adverse outcomes were more frequently observed in subjects with hospital-acquired infections when compared to HCA and CA infections. Hospital-acquired, HCA and second infections were independently associated with in-hospital mortality. CONCLUSION: Hospital-acquired, HCA and second infections are increasingly associated with either MDRO and/or XDRO and are independent predictors of in-hospital mortality. Their recognition and proper selection of appropriate empiric antibiotic regimens are important measures to reduce in-hospital mortality.

Assuntos

Injúria Renal Aguda , Infecções Bacterianas , Infecções Comunitárias Adquiridas , Infecção Hospitalar , Síndrome Hepatorrenal , Sepse , Antibacterianos/uso terapêutico , Infecções Bacterianas/complicações , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Estado Terminal , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Atenção à Saúde , Feminino , Síndrome Hepatorrenal/tratamento farmacológico , Hospitais , Humanos , Cirrose Hepática , Masculino , Estudos Retrospectivos , Sepse/complicações , Sepse/tratamento farmacológico

RESUMO

ABSTRACT Background Bacterial infections occur in 43—59% of cirrhotic patients admitted to the intensive care unit with impact in morbidity and mortality. An increase in the frequency of multidrug-resistant (MDRO) and extensively drug-resistant (XDRO) organisms has been described in bacterial infections in cirrhotic patients with an adverse impact on survival. Objective To characterize community-acquired (CA), healthcare-associated (HCA), and hospital-acquired (HA) infections in cirrhotic patients and their impact in the occurrence of adverse outcomes. Methods This study included all cirrhotic patients admitted in an intensive care unit specialized in liver and gastrointestinal diseases in Brazil between January 2012 and June 2018. Frequency and topography of infections were retrospectively evaluated, as well as the frequency of MDRO and XDRO organisms, and their impact in occurrence of acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, sepsis and mortality. Results A total of 374 infections were observed and classified as CA (22%), HCA (34%) and hospital-acquired (44%). Eighty-nine (54%) episodes of hospital-acquired infections were second infections. Spontaneous bacterial peritonitis (32%) and urinary tract infection (23%) were the most common infections. Culture-proven infections were positive in 61% of the cases, mainly gram-negative bacteria (73%). Acute kidney injury, hepatorenal syndrome and sepsis were observed, respectively, in 48%, 15% and 53% of the cases. MDRO and XDRO were seen, respectively, in 35% and 16%, mainly in HCA (48% vs 26% in CA infections, P=0.02) and hospital-acquired (58% vs 26% in CA infections, P=0.0009). Adverse outcomes were more frequently observed in subjects with hospital-acquired infections when compared to HCA and CA infections. Hospital-acquired, HCA and second infections were independently associated with in-hospital mortality. Conclusion Hospital-acquired, HCA and second infections are increasingly associated with either MDRO and/or XDRO and are independent predictors of in-hospital mortality. Their recognition and proper selection of appropriate empiric antibiotic regimens are important measures to reduce in-hospital mortality.

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RESUMO Contexto As infecções bacterianas ocorrem em 43—59% dos pacientes cirróticos internados em unidade de terapia intensiva com impacto na morbimortalidade. Um aumento na frequência de bactérias multirresistentes e com resistência estendida foi descrito em infecções bacterianas em pacientes cirróticos, com um impacto adverso na sobrevida. Objetivo Caracterizar as infecções adquiridas na comunidade, relacionadas aos cuidados de saúde (RCS) e hospitalares em pacientes cirróticos e seu impacto na ocorrência de desfechos adversos. Métodos Este estudo incluiu todos os pacientes cirróticos internados em uma unidade de terapia intensiva especializada em doenças hepáticas e gastrointestinais no Brasil entre janeiro de 2012 e junho de 2018. A frequência e topografia das infecções foram avaliadas retrospectivamente, bem como a frequência de bactérias multirresistentes e resistência estendida, e seu impacto na ocorrência de lesão renal aguda, síndrome hepatorrenal, insuficiência hepática crônica agudizada, sepse e mortalidade. Resultados Um total de 374 infecções foram observadas e classificadas como infecções adquiridas na comunidade (22%), RCS (34%) e infecções hospitalares (44%). Oitenta e nove (54%) episódios de infecções hospitalares foram identificadas como segunda infecção. Peritonite bacteriana espontânea (32%) e infecção do trato urinário (23%) foram as infecções mais comuns. As infecções comprovadas por cultura foram positivas em 61% dos casos, principalmente ocasionadas por bactérias gram-negativas (73%). Lesão renal aguda, síndrome hepatorrenal e sepse foram observados respectivamente, em 48%, 15% e 53% dos casos. Bactérias multirresistentes e resistência estendida foram observadas respectivamente, em 35% e 16%, principalmente nos RCS (48% vs 26% em infecções adquiridas na comunidade, P=0,02) e infecções hospitalares (58% vs 26% em infecções adquiridas na comunidade, P=0,0009). Os resultados adversos foram observados com mais frequência em indivíduos com infecções nosocomiais em comparação com infecções relacionadas aos cuidados de saúde e comunitárias. Infecções hospitalares, RCS e ocorrência de uma segunda infecção foram independentemente associadas à mortalidade intra-hospitalar. Conclusão Infecções hospitalares, relacionadas aos cuidados de saúde e reinfecções estão cada vez mais associadas a bactérias multirresistentes e/ou resistência estendida e são preditores independentes de mortalidade intra-hospitalar. Seu reconhecimento e seleção adequada de regimes antibióticos empíricos apropriados são medidas importantes para reduzir a mortalidade intra-hospitalar.

RESUMO

Abstract Introduction: Hemodialysis (HD) is a complex therapy that imposes several changes in the patient's life. Failure to follow therapy recommendations is called non-adherence (NA). The patient's illness perception, severity of chronic kidney disease, and individual strategies for coping with HD can have an impact on NA to the demands of therapy. Methods: This was a cross-sectional study with end-stage renal disease patients on conventional HD in Salvador, Bahia. We evaluated attendance to treatment and interdialytic weight gain (IDWG) as parameters of NA to HD, and investigated its association with clinical aspects and measures of disease perception (illness effects questionnaire - IEQ) and severity of nephropathy (end stage renal disease severity index - ESRD-SI), by analyzing Pearson or Spearman correlation. Results: 79 patients were evaluated, 57% male, aged 53.1 ± 12.3 years, with length of HD of 108 (89 - 131.5) months. Age correlated with ESRD-SI (r = 0.43) and NA parameters: negative correlation with relative IDWG (r = -0.41) and reduction in sessions (r = -0.31) and positive correlation with %HD performed (r = 0.25). The scores on the IEQ and ESRD-SI showed a positive correlation (r = 0.44; p <0.001), but did not show any correlation with the analyzed NA parameters. Conclusions: We did not find a correlation between illness perception and severity index of advanced nephropathy with the behaviors of NA to chronic HD. In this study, age correlated both with the perception of severity of advanced nephropathy and the parameters of NA to chronic HD.

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Resumo Introdução: A hemodiálise (HD) é uma terapia complexa que impõe diversas mudanças à vida do paciente. O não seguimento das recomendações da terapia é denominado não aderência (NA). Percepção do paciente sobre a doença, gravidade de doença renal crônica e estratégias individuais de enfrentamento da HD podem repercutir em NA às demandas da terapia. Métodos: Estudo de corte transversal com pacientes de doença renal em estágio final em HD convencional em Salvador, Bahia. Avaliamos assiduidade ao tratamento e ganho ponderal interdialítico (GPID) como parâmetros de NA à HD, e pesquisamos sua associação com aspectos clínicos e medidas de percepção de doença (IEQ) e de severidade da nefropatia (ESRD-SI), mediante análise de Correlação de Pearson ou Spearman. Resultados: Foram avaliados 79 pacientes, 57% masculino, idade 53,1 ± 12,3 anos, em HD há 108 (89 - 131,5) meses. Idade apresentou correlação com ESRD-SI (r = 0,43) e parâmetros de NA: correlação negativa com GPID relativo (r = -0,41) e redução das sessões (r = -0,31) e correlação positiva com %HD realizada (r = 0,25). As pontuações no IEQ e ESRD-SI demonstraram correlação positiva (r = 0,44; p < 0,001), porém não apresentaram correlação com os parâmetros de NA analisados. Conclusões: Não encontramos correlação entre percepção de doença e índice de gravidade da nefropatia avançada com os comportamentos de NA à HD crônica. Neste estudo, idade teve correlação com percepção de gravidade de nefropatia avançada e parâmetros de NA à HD crônica.

Assuntos

Humanos , Masculino , Feminino , Insuficiência Renal Crônica , Falência Renal Crônica/terapia , Percepção , Estudos Transversais , Diálise Renal

RESUMO

INTRODUCTION: Hemodialysis (HD) is a complex therapy that imposes several changes in the patient's life. Failure to follow therapy recommendations is called non-adherence (NA). The patient's illness perception, severity of chronic kidney disease, and individual strategies for coping with HD can have an impact on NA to the demands of therapy. METHODS: This was a cross-sectional study with end-stage renal disease patients on conventional HD in Salvador, Bahia. We evaluated attendance to treatment and interdialytic weight gain (IDWG) as parameters of NA to HD, and investigated its association with clinical aspects and measures of disease perception (illness effects questionnaire - IEQ) and severity of nephropathy (end stage renal disease severity index - ESRD-SI), by analyzing Pearson or Spearman correlation. RESULTS: 79 patients were evaluated, 57% male, aged 53.1 ± 12.3 years, with length of HD of 108 (89 - 131.5) months. Age correlated with ESRD-SI (r = 0.43) and NA parameters: negative correlation with relative IDWG (r = -0.41) and reduction in sessions (r = -0.31) and positive correlation with %HD performed (r = 0.25). The scores on the IEQ and ESRD-SI showed a positive correlation (r = 0.44; p <0.001), but did not show any correlation with the analyzed NA parameters. CONCLUSIONS: We did not find a correlation between illness perception and severity index of advanced nephropathy with the behaviors of NA to chronic HD. In this study, age correlated both with the perception of severity of advanced nephropathy and the parameters of NA to chronic HD.

Assuntos

Falência Renal Crônica , Insuficiência Renal Crônica , Estudos Transversais , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Percepção , Diálise Renal

RESUMO

Heavy metals are toxic especially when they are introduced into the environment due to anthropogenic activities such as metallurgy, mining, and tanning. Removing these pollutants has become a worldwide concern since they cannot be degraded into nontoxic forms causing extended effects in the ecosystems. The use of an Aspergillus australensis was evaluated in order to remove Cu2+ from simulated wastewater. The fungus was isolated from river sludges contaminated with heavy metals and was first evaluated for the determination of Cu2+ tolerance levels. Microscopic fluorescence analysis was carried out to determine the effect of Cu2+ presence on the viability, cellular components, polyhydroxyalkanoates production, and oxidative stress of the fungus, as a response to the stress caused by exposure to metal. In order to achieve copper removal, the A. australensis biomass was produced using batch cultures, and the mycelium was immobilized on a textile media in order to compare the copper-removal efficiency of live or dead biomass. The optimal values of pH and temperature for biomass production were established by using a surface response analysis. Live immobilized biomass was capable of removing Cu2+ from 1.54 ± 0.19 to 2.66 ± 0.26 mg of copper/ g of dry biomass, while values of 1.93 ± 0.03 to 2.36 ± 0.29 mg of copper/g of dry biomass were observed when dead biomass was used. As was expected, copper removal using biomass varied depending on the pH and temperature used.

Assuntos

Cobre , Poli-Hidroxialcanoatos , Adsorção , Aspergillus , Biomassa , Ecossistema , Concentração de Íons de Hidrogênio , Estresse Oxidativo

RESUMO

BACKGROUND: Patients with chronic kidney diseases (CKD) on haemodialysis (HD) have high morbidity and mortality rates, which are also due to the inherent risks associated with nephropathy. Non-adherence (NA) to the different demands of the treatment can have consequences for the outcome of patients undergoing HD; nevertheless, there are still doubts about such repercussions. This study was conducted to evaluate the association between NA to conventional HD and all-cause mortality and cardiovascular mortality. METHODS: We prospectively evaluated mortality in a 6-year period in a cohort of 255 patients on HD in northeast Brazil. The evaluated parameters of NA to HD were interdialytic weight gain (IDWG) ≥ 4% of dry weight (DW), hyperphosphatemia and regular attendance at treatment, assessed as the correlation between the periods on HD completed and those prescribed. We used the Cox multivariate regression model to analyse survival and the predictors of all-cause mortality and cardiovascular mortality. RESULTS: With a median follow-up period of 1493 days and a mortality rate of 9.1 per 100 people-years, there were 87 deaths, of which 54% were cardiovascular deaths. IDWG ≥4% of DW was associated with a risk of all-cause mortality however presenting a borderline outcome for cardiovascular mortality, with hazard ratios of 2.02 (CI 95% 1.17-3.49, p = 0.012) and 2.09 (CI 95% 1.01-4.35, p = 0.047), respectively. No significant association was found between other parameters of NA and mortality. Subgroup analysis showed that for patients with IDWG ≥4% of DW, malnutrition, age and diagnosis of cardiovascular and cerebrovascular diseases were associated with higher all-cause mortality. CONCLUSIONS: IDWG ≥4% of DW was identified as an independent predictor of all-cause mortality and demonstrated a borderline outcome for cardiovascular mortality in patients on conventional HD. The occurrence of excessive IDWG in the presence of malnutrition represented a significant increase in the risk of death, indicating a subgroup of patients with a worse prognosis.

Assuntos

Doenças Cardiovasculares/mortalidade , Cooperação do Paciente , Diálise Renal , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapia , Aumento de Peso , Fatores Etários , Idoso , Brasil , Causas de Morte , Estudos de Coortes , Feminino , Humanos , Hiperfosfatemia/mortalidade , Masculino , Desnutrição/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Acidente Vascular Cerebral/mortalidade

RESUMO

A wide variety of chitosan (CS) biomaterials have been loaded with different antimicrobial agents to improve the activity of CS against phytopathogenic fungi. Recently, the antimicrobial activity of 1H-pyrrole-2-carboxylic acid (PCA) has been reported as a secondary metabolite of Streptomyces griseus, which was identified as the main bioactive compound in the biological control. However, it is sensitive to light and its activity against filamentous fungi has not yet been reported. The aim of the present research work was to evaluate the biological activity of CS-PCA biocomposites for the control of Aspergillus niger. CS-PCA biocomposites were obtained through nanoprecipitation. In vitro antifungal activity was determined by viability assay, spore germination, morphometric analysis of spores and hyphae, and the analysis of cellular components by fluorescence microscopy. CS-PCA showed an average size and Z potential of 502 ± 72 nm and + 54.7 ± 15 mV, respectively. Micrographs demonstrated well-distributed biocomposites with an apparently spherical shape. A new signal at 1473 cm-1 in the FT-IR spectrum of the CS-PCA biocomposite was observed, confirming the presence of PCA in the composition of the CS-PCA nanosystem. CS-PCA biocomposites reduced the spores' viability by up to 58%. Effects on fungi morphometry, observed as an increase in the spores' average diameter, swelling, distortion, and an increase in the branching of hyphae, were observed. Fluorescence analysis showed oxidative stress and membrane and cell wall damage, mainly at early growth stages. The inhibitory effect against CS-resistant fungi, such as A. niger, opens a door for the control of CS-sensitive fungi.

Assuntos

Antifúngicos/farmacologia , Aspergillus niger/efeitos dos fármacos , Quitosana/química , Quitosana/farmacologia , Prolina/análogos & derivados , Antifúngicos/química , Fluorescência , Teste de Materiais , Testes de Sensibilidade Microbiana , Prolina/química , Metabolismo Secundário , Espectroscopia de Infravermelho com Transformada de Fourier , Esporos Fúngicos/crescimento & desenvolvimento

RESUMO

To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Ninth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on October 15, 2016. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

Assuntos

Anticoagulantes/uso terapêutico , Congressos como Assunto , Trombose/tratamento farmacológico , Brasil , Humanos

RESUMO

OBJECTIVE: To test the use of diffusion-weighted imaging (DWI) in stratifying suspicious breast lesions (BI-RADS 4), correlating them with histopathology. We also investigated the performance of DWI related to the main enhancement patterns (mass and non-mass) and tested its reproducibility. MATERIALS AND METHODS: Seventy-six patients presented 92 lesions during the sampling period. Two independent examiners reviewed magnetic resonance imaging studies, described the lesions, and determined the apparent diffusion coefficient (ADC) values. Differences among benign, indeterminate- to high-risk, and malignant findings, in terms of the ADCs, were assessed by analysis of variance. Using receiver operating characteristic (ROC) curves, we compared the performance of ADC values in masses and non-mass lesions, and tested the reproducibility of measurements by determining the coefficient of variation and smallest real difference. RESULTS: Among the 92 lesions evaluated, the histopathology showed that 37 were benign, 11 were indeterminate- to high-risk, and 44 were malignant. The mean ADC differed significantly among those histopathological groups, the value obtained for the malignant lesions (1.10 × 10-3 mm2/s) being significantly lower than that obtained for the other groups (p < 0.001). ROC curves demonstrated that DWI performed better when applied to masses than when applied to non-mass lesions (area under the curve, 0.88 vs. 0.67). Reproducibility was good (coefficient of variation, 7.03%; and smallest real difference, ± 0.242 × 10-3 mm2/s). CONCLUSION: DWI can differentiate between malignant and nonmalignant (benign or indeterminate- to high-risk) lesions, showing better performance for masses. Nevertheless, stratification based on histopathological criteria that are more refined has yet to be achieved.

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OBJETIVO: Testar a sequência ponderada em difusão (SPD) para estratificação de lesões suspeitas (BI-RADS 4) por ressonância magnética em correlação com a histopatologia. Também investigamos o desempenho da SPD relacionada a padrões de realce (nódulo e não nódulo) e testamos sua reprodutibilidade. MATERIAIS E MÉTODOS: Setenta e seis pacientes apresentaram 92 lesões durante o período amostral. Dois examinadores independentes revisaram os estudos, descreveram as lesões e mediram os coeficientes de difusão aparente (CDAs). Diferenças de CDA entre achados benignos, indeterminados/de alto risco e malignos foram avaliadas por análise de variância. Comparamos o desempenho dos CDAs em nódulos e não nódulos por curvas receiver operating characteristic (ROC) e testamos a reprodutibilidade das mensurações pelo coeficiente de variação e menor diferença real. RESULTADOS: Obtivemos 37 lesões benignas, 11 indeterminadas/de alto-risco e 44 cânceres. As médias dos CDAs desses grupos histopatológicos foram significativamente diferentes (p < 0,001), devido aos valores mais baixos em achados malignos (1,10 × 10-3 mm2/s). Curvas ROC demonstraram melhor desempenho da SPD aplicada a nódulos (área sob a curva de 0,88 contra 0,67 para não nódulos). A reprodutibilidade foi boa (coeficiente de variação de 7,03% e menor diferença real de ± 0,242 × 10-3 mm2/s). CONCLUSÃO: A SPD pode diferenciar achados malignos de não malignos, com melhor desempenho para nódulos. Entretanto, a estratificação baseada em critérios histopatológicos mais refinados ainda não foi alcançada.