Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia.

Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells (n = 98 CLL patients) and healthy volunteers (n = 9). We measured intron/exon ratio to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 was observed in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein, was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.

Public health surveillance and the data, information, knowledge, intelligence and wisdom paradigm / Vigilancia de salud pública y el paradigma de datos, información, conocimiento, inteligencia y sabiduría / Vigilância em saúde pública e o paradigma de dados, informações, conhecimento, inteligência e sabedoria

[ABSTRACT]. This article points out deficiencies in present-day definitions of public health surveillance, which include data collection, analysis, interpretation and dissemination, but not public health action. Controlling a public health problem of concern requires a public health response that goes beyond information dissemination. It is unde- sirable to have public health divided into data generation processes (public health surveillance) and data use processes (public health response), managed by two separate groups (surveillance experts and policy-makers). It is time to rethink the need to modernize the definition of public health surveillance, inspired by the authors’ enhanced Data, Information, Knowledge, Intelligence and Wisdom model. Our recommendations include expanding the scope of public health surveillance beyond information dissemination to comprise actionable knowledge (intelligence); mandating surveillance experts to assist policy-makers in making evidence-informed decisions; encouraging surveillance experts to become policy-makers; and incorporating public health literacy training – from data to knowledge to wisdom – into the curricula for all public health professionals. Work on modernizing the scope and definition of public health surveillance will be a good starting point.

[RESUMEN]. En este artículo se señalan las deficiencias de las definiciones actuales de la vigilancia de salud pública, que incluyen la recopilación, el análisis, la interpretación y la difusión de los datos, pero no las medidas de salud pública. El control de un problema de salud pública de interés exige una respuesta de salud pública que vaya más allá de la difusión de información. No es deseable que la salud pública esté dividida por un lado en procesos de generación de datos (vigilancia de salud pública) y por otro en procesos de uso de datos (respuesta de salud pública), gestionados por dos grupos diferentes (expertos en vigilancia y responsables de la formulación de políticas). Ha llegado el momento de replantear la necesidad de modernizar la definición de la vigilancia de salud pública tomando como referencia el modelo mejorado de Datos, Información, Cono- cimiento, Inteligencia y Sabiduría de los autores. Entre las recomendaciones que se proponen se encuentran las de ampliar el alcance de la vigilancia de salud pública más allá de la difusión de información para que incluya también el conocimiento aplicable (inteligencia); instar a los expertos en vigilancia a que presten ayuda a los responsables de la formulación de políticas en la toma de decisiones basadas en la evidencia; alentar a los expertos en vigilancia a que se conviertan en responsables de la formulación de políticas; e incorporar la formación en conocimientos básicos de salud pública (desde los datos hasta los conocimientos y la sabiduría) en los planes de estudio de todos los profesionales de la salud pública. Un buen punto de partida será trabajar en la modernización del alcance y la definición de la vigilancia de salud pública.

[RESUMO]. Este artigo aponta deficiências nas definições atuais de vigilância em saúde pública, que incluem coleta, análise, interpretação e disseminação de dados, mas não ações de saúde pública. O controle de um prob- lema preocupante de saúde pública exige uma resposta de saúde pública que vá além da disseminação de informações. A saúde pública não deve ser dividida em processos de geração de dados (vigilância em saúde pública) e processos de uso de dados (resposta de saúde pública) gerenciados por dois grupos distintos (especialistas em vigilância e formuladores de políticas). É hora de repensar a necessidade de modernizar a definição de vigilância em saúde pública, inspirada no modelo aprimorado de Dados, Informações, Con- hecimento, Inteligência e Sabedoria dos autores. Nossas recomendações incluem: expansão do escopo da vigilância em saúde pública para além da disseminação de informações, de modo a abranger conhecimentos acionáveis (inteligência); obrigatoriedade de que os especialistas em vigilância auxiliem os formuladores de políticas na tomada de decisões baseadas em evidências; incentivo para que os especialistas em vigilân- cia se tornem formuladores de políticas; e incorporação de capacitação em letramento em saúde pública (partindo dos dados para o conhecimento e em seguida para a sabedoria) nos currículos de todos os profis- sionais de saúde pública. O trabalho de modernizar o escopo e a definição de vigilância em saúde pública será um bom ponto de partida.

Public health surveillance and the data, information, knowledge, intelligence and wisdom paradigm.

This article points out deficiencies in present-day definitions of public health surveillance, which include data collection, analysis, interpretation and dissemination, but not public health action. Controlling a public health problem of concern requires a public health response that goes beyond information dissemination. It is undesirable to have public health divided into data generation processes (public health surveillance) and data use processes (public health response), managed by two separate groups (surveillance experts and policy-makers). It is time to rethink the need to modernize the definition of public health surveillance, inspired by the authors' enhanced Data, Information, Knowledge, Intelligence and Wisdom model. Our recommendations include expanding the scope of public health surveillance beyond information dissemination to comprise actionable knowledge (intelligence); mandating surveillance experts to assist policy-makers in making evidence-informed decisions; encouraging surveillance experts to become policy-makers; and incorporating public health literacy training - from data to knowledge to wisdom - into the curricula for all public health professionals. Work on modernizing the scope and definition of public health surveillance will be a good starting point.

En este artículo se señalan las deficiencias de las definiciones actuales de la vigilancia de salud pública, que incluyen la recopilación, el análisis, la interpretación y la difusión de los datos, pero no las medidas de salud pública. El control de un problema de salud pública de interés exige una respuesta de salud pública que vaya más allá de la difusión de información. No es deseable que la salud pública esté dividida por un lado en procesos de generación de datos (vigilancia de salud pública) y por otro en procesos de uso de datos (respuesta de salud pública), gestionados por dos grupos diferentes (expertos en vigilancia y responsables de la formulación de políticas). Ha llegado el momento de replantear la necesidad de modernizar la definición de la vigilancia de salud pública tomando como referencia el modelo mejorado de Datos, Información, Conocimiento, Inteligencia y Sabiduría de los autores. Entre las recomendaciones que se proponen se encuentran las de ampliar el alcance de la vigilancia de salud pública más allá de la difusión de información para que incluya también el conocimiento aplicable (inteligencia); instar a los expertos en vigilancia a que presten ayuda a los responsables de la formulación de políticas en la toma de decisiones basadas en la evidencia; alentar a los expertos en vigilancia a que se conviertan en responsables de la formulación de políticas; e incorporar la formación en conocimientos básicos de salud pública (desde los datos hasta los conocimientos y la sabiduría) en los planes de estudio de todos los profesionales de la salud pública. Un buen punto de partida será trabajar en la modernización del alcance y la definición de la vigilancia de salud pública.

Este artigo aponta deficiências nas definições atuais de vigilância em saúde pública, que incluem coleta, análise, interpretação e disseminação de dados, mas não ações de saúde pública. O controle de um problema preocupante de saúde pública exige uma resposta de saúde pública que vá além da disseminação de informações. A saúde pública não deve ser dividida em processos de geração de dados (vigilância em saúde pública) e processos de uso de dados (resposta de saúde pública) gerenciados por dois grupos distintos (especialistas em vigilância e formuladores de políticas). É hora de repensar a necessidade de modernizar a definição de vigilância em saúde pública, inspirada no modelo aprimorado de Dados, Informações, Conhecimento, Inteligência e Sabedoria dos autores. Nossas recomendações incluem: expansão do escopo da vigilância em saúde pública para além da disseminação de informações, de modo a abranger conhecimentos acionáveis (inteligência); obrigatoriedade de que os especialistas em vigilância auxiliem os formuladores de políticas na tomada de decisões baseadas em evidências; incentivo para que os especialistas em vigilância se tornem formuladores de políticas; e incorporação de capacitação em letramento em saúde pública (partindo dos dados para o conhecimento e em seguida para a sabedoria) nos currículos de todos os profissionais de saúde pública. O trabalho de modernizar o escopo e a definição de vigilância em saúde pública será um bom ponto de partida.

Public health surveillance and the data, information, knowledge, intelligence and wisdom paradigm / Vigilancia de salud pública y el paradigma de datos, información, conocimiento, inteligencia y sabiduría / Vigilância em saúde pública e o paradigma de dados, informações, conhecimento, inteligência e sabedoria

ABSTRACT This article points out deficiencies in present-day definitions of public health surveillance, which include data collection, analysis, interpretation and dissemination, but not public health action. Controlling a public health problem of concern requires a public health response that goes beyond information dissemination. It is undesirable to have public health divided into data generation processes (public health surveillance) and data use processes (public health response), managed by two separate groups (surveillance experts and policy-makers). It is time to rethink the need to modernize the definition of public health surveillance, inspired by the authors' enhanced Data, Information, Knowledge, Intelligence and Wisdom model. Our recommendations include expanding the scope of public health surveillance beyond information dissemination to comprise actionable knowledge (intelligence); mandating surveillance experts to assist policy-makers in making evidence-informed decisions; encouraging surveillance experts to become policy-makers; and incorporating public health literacy training - from data to knowledge to wisdom - into the curricula for all public health professionals. Work on modernizing the scope and definition of public health surveillance will be a good starting point.

RESUMEN En este artículo se señalan las deficiencias de las definiciones actuales de la vigilancia de salud pública, que incluyen la recopilación, el análisis, la interpretación y la difusión de los datos, pero no las medidas de salud pública. El control de un problema de salud pública de interés exige una respuesta de salud pública que vaya más allá de la difusión de información. No es deseable que la salud pública esté dividida por un lado en procesos de generación de datos (vigilancia de salud pública) y por otro en procesos de uso de datos (respuesta de salud pública), gestionados por dos grupos diferentes (expertos en vigilancia y responsables de la formulación de políticas). Ha llegado el momento de replantear la necesidad de modernizar la definición de la vigilancia de salud pública tomando como referencia el modelo mejorado de Datos, Información, Conocimiento, Inteligencia y Sabiduría de los autores. Entre las recomendaciones que se proponen se encuentran las de ampliar el alcance de la vigilancia de salud pública más allá de la difusión de información para que incluya también el conocimiento aplicable (inteligencia); instar a los expertos en vigilancia a que presten ayuda a los responsables de la formulación de políticas en la toma de decisiones basadas en la evidencia; alentar a los expertos en vigilancia a que se conviertan en responsables de la formulación de políticas; e incorporar la formación en conocimientos básicos de salud pública (desde los datos hasta los conocimientos y la sabiduría) en los planes de estudio de todos los profesionales de la salud pública. Un buen punto de partida será trabajar en la modernización del alcance y la definición de la vigilancia de salud pública.

RESUMO Este artigo aponta deficiências nas definições atuais de vigilância em saúde pública, que incluem coleta, análise, interpretação e disseminação de dados, mas não ações de saúde pública. O controle de um problema preocupante de saúde pública exige uma resposta de saúde pública que vá além da disseminação de informações. A saúde pública não deve ser dividida em processos de geração de dados (vigilância em saúde pública) e processos de uso de dados (resposta de saúde pública) gerenciados por dois grupos distintos (especialistas em vigilância e formuladores de políticas). É hora de repensar a necessidade de modernizar a definição de vigilância em saúde pública, inspirada no modelo aprimorado de Dados, Informações, Conhecimento, Inteligência e Sabedoria dos autores. Nossas recomendações incluem: expansão do escopo da vigilância em saúde pública para além da disseminação de informações, de modo a abranger conhecimentos acionáveis (inteligência); obrigatoriedade de que os especialistas em vigilância auxiliem os formuladores de políticas na tomada de decisões baseadas em evidências; incentivo para que os especialistas em vigilância se tornem formuladores de políticas; e incorporação de capacitação em letramento em saúde pública (partindo dos dados para o conhecimento e em seguida para a sabedoria) nos currículos de todos os profissionais de saúde pública. O trabalho de modernizar o escopo e a definição de vigilância em saúde pública será um bom ponto de partida.

Predictors and Management of Relapse to Axicabtagene Ciloleucel in Patients with Aggressive B-cell Lymphoma.

OBJECTIVE/BACKGROUND: Despite the success of chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive non-Hodgkin lymphoma (aNHL), some patients still fail treatment, and their prognosis is dismal. METHODS: We performed a retrospective study of aNHL patients treated with axicabtagene ciloleucel (axi-cel) at two Mayo Clinic centers between 2018 and 2020. We evaluated predictive factors, toxicities, and responses to salvage regimens after CAR T-cell therapy. RESULTS: Thirty-four patients received axi-cel with a median length of hospitalization of 14 days. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome of any grade occurred in 91% and 41% of patients, respectively. Furthermore, 71% of patients responded to therapy, with 53% achieving a complete response (CR). The CRS grade and absolute lymphocyte count at leukapheresis (ALCLeuk) correlated with CR and overall survival (OS), respectively. After a median follow-up of 6.8 months (interquartile range [IQR] 4.6-14.9), 15 patients (44%) showed progressive disease (PD). Most patients (60%) progressed during the first 3 months and had persistent CD19 tumor expression. Elevated C-reactive protein at baseline increased the risk of PD, whereas elevated ferritin increased PD and mortality risk. Twelve patients received salvage therapy, but only three responded. Median OS of relapsed/refractory patients to axi-cel was 3 months (IQR 1.3-5.1). CONCLUSION: The grade of CRS and ALCLeuk correlated with better outcomes to axi-cel therapy. In addition, elevated inflammatory markers at baseline were associated with PD and shorter survival. Relapses after treatment frequently occur within months after axi-cel infusion; they confer a poor prognosis and create an urgent need for novel and effective treatment options in this patient population.

Ibrutinib plus Obinutuzumab as Frontline Therapy for Chronic Lymphocytic Leukemia Is Associated with a Lower Rate of Infusion-Related Reactions and with Sustained Remissions after Ibrutinib Discontinuation: A Single-Arm, Open-Label, Phase 1b/2 Clinical Trial NCT0231576.

Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

Validation of VIRSTA and Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT) Scores to Determine the Priority of Echocardiography in Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: Infective endocarditis (IE) secondary to Staphylococcus aureus bacteremia (SAB) has high morbidity and mortality. The systematic use of echocardiography in SAB is controversial. We aimed to validate VIRSTA and Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT) scores for predicting the risk of IE in Colombian patients with SAB and, consequently, to determine the need for echocardiography. METHODS: Cohort of patients hospitalized with SAB in 2 high complexity institutions in Medellin, Colombia, between 2012 and 2018. The diagnosis of IE was established based on the modified Duke criteria. The VIRSTA and PREDICT scores were calculated from the clinical records, and their operational performance was calculated. RESULTS: The final analysis included 922 patients, 62 (6.7%) of whom were diagnosed with IE. The frequency of IE in patients with a negative VIRSTA scale was 0.44% (2/454). The frequency of IE in patients with a negative PREDICT scale on day 5 was 4.8% (30/622). The sensitivity and negative predictive value (NPV) of the VIRSTA scale was 96.7% and 99.5%, respectively. For the PREDICT scale on day 5, the sensitivity and NPV were 51.6% and 95.1%, respectively. The discrimination, given by the area under the receiver operating characteristic curve, was 0.86 for VIRSTA and 0.64 for PREDICT. CONCLUSIONS: In patients with negative VIRSTA, screening echocardiography may be unnecessary because of the low frequency of IE. In PREDICT-negative patients, despite the low frequency of IE, it is not safe to omit echocardiography.

Smartphone based on-chip fluorescence imaging and capillary flow velocity measurement for detecting ROR1+ cancer cells from buffy coat blood samples on dual-layer paper microfluidic chip.

Diagnosis of hematological cancer requires complete white blood cell count, followed by flow cytometry with multiple markers, and cytology. It requires substantial time and specialized training. A dual-layer paper microfluidic chip was developed as a quicker, low-cost, and field-deployable alternative to detect ROR1+ (receptor tyrosine-like orphan receptor one) cancer cells from the undiluted and untreated buffy coat blood samples. The first capture layer consisted of a GF/D glass fiber substrate, preloaded with cancer specific anti-ROR1 conjugated fluorescent particles to its center for cancer cell capture and direct smartphone fluorescence imaging. The second flow layer was comprised of a grade 1 cellulose chromatography paper with wax-printed four channels for wicking and capillary flow-based detection. The flow velocity was used as measure of antigen concentration in the buffy coat sample. In this manner, intact cells and their antigens were separated and independently analyzed by both imaging and flow velocity analyses. A custom-made smartphone-based fluorescence microscope and automated image processing and particle counter software were developed to enumerate particles on paper, with the limit of detection of 1 cell/µL. Flow velocity analysis showed even greater sensitivity, with the limit of detection of 0.1 cells/µL in the first 6 s of assay. Comparison with capillary flow model revealed great alignment with experimental data and greater correlation to viscosity than interfacial tension. Our proposed device is able to capture and on-chip image ROR1+ cancer cells within a complex sample matrix (buffy coat) while simultaneously quantifying cell concentration in a point-of-care manner.