Clinical Utility of Protein Language Models in Resolution of Variants of Uncertain Significance in KCNQ1, KCNH2, and SCN5A Compared With Patch-Clamp Functional Characterization.

BACKGROUND: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp. METHODS: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2, and 50 SCN5A) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, ESM1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp. RESULTS: Considering variants in all 3 genes, the ESM1b model had a receiver operator curve-area under the curve of 0.75 (P=0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operator curve-area under the curve of 0.85 (P<0.0001), sensitivity of 80%, and specificity of 76%. CONCLUSIONS: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.

BCG vaccination and its possible effects on the acceleration of incidence and mortality by the new coronavirus: second step

Introduction: The pandemic caused by the new coronavirus brought difficulties to global health and the economy. The race for an effective therapy to control the disease is launched, and an understanding of the pathophysiology is necessary. The BCG (bacillus Calmette­Guérin) vaccine activates and modulates innate immunity, and its protective effect against the new coronavirus should be investigated. Objective: To compare the incidence, mortality, and lethality rates of COVID-19 according to the vaccination program for BCG of the main countries affected by the pandemic. Methods: The second of three phases of a data survey was carried out from official sources on the number of cases and number of deaths by COVID-19 between April 11 and May 11, 2020, and the incidence, mortality and lethality rates were calculated and compared among predefined groups according to their BCG vaccination programs. In the same way, the acceleration rate between the groups in the period under analysis was performed. Results: Similar to the results found in the first phase in April, the countries without an active BCG vaccine program had, on average, 3.96, 9.34, and 2.35 (p < 0.001) higher ratios in the incidence, mortality and lethality rates, respectively. Conclusion: There is a protective connection between the presence of active BCG vaccination programs and the number of cases and deaths per inhabitant in the countries studied, showing a possible cross effect of innate immunity against the new coronavirus.

 Introdução: A pandemia pelo novo Coronavírus trouxe dificuldades para a saúde e economia do mundo. A corrida por uma terapia efetiva para o controle da doença está lançada e o entendimento da fisiopatologia se faz necessário. A vacina BCG (bacillus Calmette-Guérin) ativa e modula a imunidade inata e o seu efeito protetivo contra o novo Coronavírus deverá ser investigado. Objetivo: Comparar os índices de incidência, mortalidade e letalidade do Covid-19 conforme programa de vacinação para BCG dos principais países acometidos pela pandemia. Métodos: Realizado a segunda fase de três de um levantamento de dados a partir de fontes oficiais do número de casos e número de óbitos pela COVID-19 entre os dias 11 de abril e 11 de maio de 2020, sendo calculados os coeficientes de incidência, mortalidade e letalidade e comparado entre grupos pré definidos conforme seus programas de vacinação com BCG. Da mesma forma, foi realizado a taxa de aceleração entre os grupos no período analisado. Resultados: Semelhante aos resultados encontrados na primeira fase de abril, os países sem programa vacinal ativo com BCG apresentaram em média 3.96, 9.34 e 2.35 (p<0,001) maiores razões nos coeficientes de incidência, mortalidade e letalidade respectivamente. Conclusão: Há uma relação protetora entre a presença de programas de vacinação com BCG ativos e o número de casos e mortes por habitante nos países estudados, mostrando um possível efeito cruzado da imunidade inata com o novo Coronavírus.

Terapia de ressincronização cardíaca em portador de coração univentricular para correção de dissincroniomiopatia causada por mudança do sítio de estimulação / Cardiac resynchronization therapy in severe systolic dysfunction in a univentricular heart patient to correct dyssynchrony cardiomyopathy caused by change of stimulation site

Paciente com 6 anos de idade, do sexo masculino, portador de coração univentricular decorrente deatresia tricúspide com hipoplasia de ventrículo direito tipo IIC e submetido a implante de marcapasso por bloqueio atrioventricular total no pós-operatório de cirurgia de Fontan, em 2012. Houve necessidade de troca do sistema de estimulação em decorrência de infecção de loja logo após a troca do marcapasso, em 2014. Seis meses após amudança do sítio de estimulação, começou a apresentar quadro de insuficiência cardíaca refratária e disfunção sistólica grave, e o transplante cardíaco foi indicado. O paciente foi submetido a terapia de ressincronização cardíaca orientada por eletrocardiografia triaxial como ponte para transplante e apresentou melhora clínico-estrutural após10 semanas, recebendo alta hospitalar...

We report the case of a 6-year-old male patient with univentricular heart due to tricuspid atresia with right ventricular hypoplasia (IIc), who had a pacemaker implanted for complete heart block after a Fontan surgery in 2012. The stimulation system had to be exchanged due to a pocket infection soon after the pacemaker was exchanged in 2014. Six months after the stimulation site was exchanged he presented refractory heart failure and severe systolic dysfunction and a heart transplantation was indicated. He was submitted to cardiac resynchronization therapy guided by triaxial electrocardiography as a bridge for transplantation. The patient presented clinical and structural improvement after 10 weeks and was discharged...