Interpersonal school violence and mother-child communication about violence in relation to empathy in early adolescence.

INTRODUCTION: Exposure to interpersonal violence at school has been linked with lower empathy, but less is known about factors that may moderate this relationship. Positive parent-child communication has been associated with higher empathy during adolescence and children of parents that communicate their disapproval of violent behavior respond more peacefully in situations involving violence. Mother-child communication about violence may therefore reduce the risk of desensitization to violent behavior and promote empathy in youth that are frequently exposed to violence. Thus, this study examines whether mother-child communication about violence mitigates the association between exposure to interpersonal school violence and adolescents' empathy. METHODS: This study addressed this question using a diverse sample of early adolescents from the Southeastern United States in 2003 (N = 642; mean age 11.3 years; 52% male; 76% Black, 22% non-Hispanic White). Adolescents reported on how often they witness or experience interpersonal violence at school and how often they communicate with their mother about violence and how to avoid it. Adolescents also self-reported on their level of empathy. RESULTS: Results from a hierarchical regression model showed that exposure to interpersonal school violence and lower mother-child communication about violence were uniquely associated with lower empathy, but communication about violence did not moderate the link between interpersonal school violence exposure and empathy. There were no sex differences in these relationships. CONCLUSIONS: Contrary to the hypothesis, youth who experience and witness interpersonal violence at school show lower empathy independent of whether youth communicate with their mother about violence and responding to violent situations.

WITHDRAWN: Oncogenic KRAS G12D extrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.

Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-to-mesenchymal transition (EMT), and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis lung carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, preexisting fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of EMT. IMPLICATIONS: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.

Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.

Disclosure of Exposure to Violence in Urban Adolescents.

Research has documented high rates of exposure to violence in urban African American adolescents together with their negative effects on psychosocial adjustment. Coping with violence exposure may be facilitated by disclosure of these experiences to others, but little is known about the extent to which youth disclose their various experiences with violence. This study examined the prevalence of disclosure of violence experienced as a witness or victim in different contexts or locations to parents, friends, siblings, teachers, counselors, and relatives. Urban African American adolescents from Southeastern U.S. were interviewed at three time points (N = 81; average ages 13.3, 16.1, and 17.8). Across the three time points, 90% to 91% witnessed violence and 64% to 81% were victimized in the last year. Of these youth, 40% to 53% disclosed experiences of witnessing violence and 29% to 52% disclosed experiences of victimization. The results showed that disclosure of violence most often involved parents and friends, with fewer youth disclosing to teachers and counselors. Disclosure of violence victimization increased from early to late adolescence. Experiences of dating violence victimization were less likely to be disclosed by adolescents, especially among males. These findings support the need for more research on adolescents' disclosure of violence exposure and its links to adjustment, with implications for interventions aimed at improving coping in youth exposed to violence.

KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. EXPERIMENTAL DESIGN: We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. RESULTS: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. CONCLUSIONS: Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.

Coumel tachycardia in children.

BACKGROUND: Coumel tachycardia is an infrequent form of supraventricular tachycardia (SVT) that usually occurs in infants and children. It is a tachycardia mediated by an accessory pathway with retrograde slow conduction that explains the classic ECG pattern with long RP' interval and negative P waves in leads II, III, and aVF. In this study, we describe the clinical course and management of Coumel tachycardia in children. CASE REPORT: We conducted a retrospective review of five consecutive pediatric patients, mean age 11 ± 3 years (range 6 to 14). The first episode of SVT was at a mean age of 10.4 ± 4.8 years (range 2 to 14) with a mean evolution of 7.4 ± 9.4 months (range 1 to 24). Pharmacological therapy was unsuccessful despite the combination of antiarrhythmic drugs. The tachycardia was incessant with a density > 85% by 24-hour Holter monitoring; one patient developed tachycardia-induced cardiomyopathy. All children underwent successful radiofrequency catheter ablation, mean 5 ± 3 applications (range 1 to 8) with a single session and with no complications. After a mean follow-up of 24 ± 16 months, all patients were asymptomatic and recurrence-free without antiarrhythmic treatment. CONCLUSIONS: Coumel tachycardia is clinically persistent and usually refractory to antiarrhythmic treatment with substantial risk of tachycardia-mediated cardiomyopathy. Catheter ablation is effective and safe in children; thus, it should be indicated promptly and based on individual selection.

INTRODUCCIÓN: La taquicardia de Coumel es una forma poco frecuente de taquicardia supraventricular que suele presentarse en lactantes. Es una taquicardia mediada por una vía accesoria de conducción lenta retrógrada que explica el patrón ECG clásico con intervalo RP' largo y ondas P negativas en las derivaciones II, III y aVF. En este trabajo se describe el curso clínico y el manejo de la taquicardia de Coumel en niños. CASO CLÍNICO: Se llevó a cabo una revisión retrospectiva de cinco pacientes pediátricos consecutivos, con una media de edad de 11 ± 3 años (intervalos 6 a 14). El primer episodio de taquicardia 10.4 ± 4.8 años con evolución de 7.4 ± 9.4 meses. El tratamiento farmacológico fue ineficaz a pesar de la combinación de antiarrítmicos. La taquicardia era incesante con una densidad > 85% por Holter-24h; un paciente desarrolló miocardiopatía inducida por taquicardia. Todos los niños fueron sometidos a ablación con catéter y radiofrecuencia con éxito, y un promedio de 5 ± 3 aplicaciones en una sola sesión y sin complicaciones. Después de un seguimiento de 24 ± 16 meses, todos los pacientes fueron asintomáticos y libres de recurrencia sin tratamiento antiarrítmico. CONCLUSIONES: La taquicardia de Coumel es clínicamente persistente y generalmente refractaria al tratamiento antiarrítmico con un riesgo sustancial de miocardiopatía mediada por taquicardia. La ablación con catéter es eficaz y segura en niños, por lo que debe indicarse de forma temprana y en lactantes de una selección individual.

Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. SIGNIFICANCE: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275.

Arginase 1 is a key driver of immune suppression in pancreatic cancer.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions.

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significance: The causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

Coumel tachycardia in children / Taquicardia de Coumel en niños

Abstract Background: Coumel tachycardia is an infrequent form of supraventricular tachycardia (SVT) that usually occurs in infants and children. It is a tachycardia mediated by an accessory pathway with retrograde slow conduction that explains the classic ECG pattern with long RP' interval and negative P waves in leads II, III, and aVF. In this study, we describe the clinical course and management of Coumel tachycardia in children. Case report: We conducted a retrospective review of five consecutive pediatric patients, mean age 11 ± 3 years (range 6 to 14). The first episode of SVT was at a mean age of 10.4 ± 4.8 years (range 2 to 14) with a mean evolution of 7.4 ± 9.4 months (range 1 to 24). Pharmacological therapy was unsuccessful despite the combination of antiarrhythmic drugs. The tachycardia was incessant with a density > 85% by 24-hour Holter monitoring; one patient developed tachycardia-induced cardiomyopathy. All children underwent successful radiofrequency catheter ablation, mean 5 ± 3 applications (range 1 to 8) with a single session and with no complications. After a mean follow-up of 24 ± 16 months, all patients were asymptomatic and recurrence-free without antiarrhythmic treatment. Conclusions: Coumel tachycardia is clinically persistent and usually refractory to antiarrhythmic treatment with substantial risk of tachycardia-mediated cardiomyopathy. Catheter ablation is effective and safe in children; thus, it should be indicated promptly and based on individual selection.

Resumen Introducción: La taquicardia de Coumel es una forma poco frecuente de taquicardia supraventricular que suele presentarse en lactantes. Es una taquicardia mediada por una vía accesoria de conducción lenta retrógrada que explica el patrón ECG clásico con intervalo RP' largo y ondas P negativas en las derivaciones II, III y aVF. En este trabajo se describe el curso clínico y el manejo de la taquicardia de Coumel en niños. Caso clínico: Se llevó a cabo una revisión retrospectiva de cinco pacientes pediátricos consecutivos, con una media de edad de 11 ± 3 años (intervalos 6 a 14). El primer episodio de taquicardia 10.4 ± 4.8 años con evolución de 7.4 ± 9.4 meses. El tratamiento farmacológico fue ineficaz a pesar de la combinación de antiarrítmicos. La taquicardia era incesante con una densidad > 85% por Holter-24h; un paciente desarrolló miocardiopatía inducida por taquicardia. Todos los niños fueron sometidos a ablación con catéter y radiofrecuencia con éxito, y un promedio de 5 ± 3 aplicaciones en una sola sesión y sin complicaciones. Después de un seguimiento de 24 ± 16 meses, todos los pacientes fueron asintomáticos y libres de recurrencia sin tratamiento antiarrítmico. Conclusiones: La taquicardia de Coumel es clínicamente persistente y generalmente refractaria al tratamiento antiarrítmico con un riesgo sustancial de miocardiopatía mediada por taquicardia. La ablación con catéter es eficaz y segura en niños, por lo que debe indicarse de forma temprana y en lactantes de una selección individual.

COVID-19 and drivers of excess death rate in Peru: A longitudinal ecological study.

Background: Peru has experienced unprecedented mortality and economic toll due to the COVID-19 (Coronavirus disease 2019) pandemic in 2020. We aimed to assess the association between socioeconomic factors and excess death rate, and to explore the relative contribution of these factors to the differences in excess death rate during January-December 2020. Methods: Different national secondary data sources were used to describe excess death rates and different determinants, from distal to proximal. A confounding-adjusted multilevel mixed-effects linear regression was used to assess the association between these variables and excess death rates. Their relative contributions to the differences in excess death rate between the periods with the highest and lowest excess death rates were analyzed through regression-based Oaxaca-Blinder decomposition methods. Findings: The excess death rate showed an increasing trend in all regions, with different slopes. The confounding-adjusted multilevel analysis showed that higher healthcare access was associated with lower excess death rates (difference (95%CI) -0.004 (-0.005, -0.002)), whereas COVID-19 incidence was associated with higher excess death rates (difference (95%CI) 0.052 (0.042, 0.063)). The decomposition analysis showed COVID-19 incidence (41.9%), per capita income (19.4%) and unemployment rate (14.6%) as the main risk factors, while the main protective factors included per capita health expenditure (44.7%), healthcare access (33.2%) and health insurance (12.1%). Interpretation: Our study suggests that the excess death rate during the COVID-19 pandemic in Peru may have been influenced by other factors besides COVID-19 incidence, from distal to proximal drivers, including socioeconomic determinants, factors outside and within the health sector, and susceptibility factors. Further studies at individual level are needed to corroborate our findings.

Idiopathic left fascicular ventricular tachycardia in children and adolescents.

BACKGROUND: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. METHODS: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. RESULTS: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. CONCLUSIONS: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

INTRODUCCIÓN: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. MÉTODOS: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. RESULTADOS: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. CONCLUSIONES: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

Idiopathic left fascicular ventricular tachycardia in children and adolescents / Taquicardia ventricular fascicular izquierda idiopática en niños y adolescentes

Abstract Background: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. Methods: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. Results: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. Conclusions: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

Resumen Introducción: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. Métodos: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. Resultados: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. Conclusiones: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

Using digital photographs as a tool to assess the clinical color stability of lithium disilicate veneers: A clinical trial.

STATEMENT OF PROBLEM: Clinical information regarding the color stability of lithium disilicate veneers by using different methods of evaluation is scarce. PURPOSE: This clinical trial aimed to evaluate whether digital photographs are a reliable method of clinically assessing the color stability of lithium disilicate veneers. Standardized digital photographs (ELAB) were compared with the VITA Easyshade spectrophotometer (ES) at baseline and at a 6-month follow-up. MATERIAL AND METHODS: A split-mouth model was used in this randomized clinical trial to assess the performance of ceramic veneers (N=162), which were produced by either the CAD (IPS e.max CAD; n=81) or PRESS technique by heat pressing (IPS e.max PRESS; n=81), including the color dimension assessment. The ELAB evaluation was performed by making digital photographs with polarized light and a white balance (WhiBal) card. These data were transferred to the Adobe Lightroom CC2015 software program in RAW extension. The Digital Color Meter App (Apple) was used to measure L∗, a∗, and b∗ coordinates in this method. The ES color evaluation was performed with a spectrophotometer (Easy Shade) (control group) in the CIELab system. Measurements were performed 1 week after cementation (baseline) and at a 6-month follow-up. Data collected by the ELAB and ES methods were analyzed by a blinded calibrated operator to calculate ΔE by using the Mann-Whitney-Wilcoxon test (α=.05). RESULTS: For all periods, the comparison among ELAB and ES methods (P=.331), CAD×PRESS by ELAB (P=.658), and CAD×PRESS by ES (P=.833) showed no statistically significant differences. CONCLUSIONS: Standardized digital photographs (ELAB) were shown to be a straightforward and available resource for evaluating the color stability of lithium disilicate veneers, manufactured by CAD or PRESS.

Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB-Mediated Production of CXCL1.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in ApoE-/- mice showed reduced tumor growth in ApoE-/- mice. Histologic and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8+ T cells in tumors in ApoE-/- mice. Mechanistically, ApoE induced pancreatic tumor cell expression of Cxcl1 and Cxcl5, known immunosuppressive factors, through LDL receptor and NF-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment. SIGNIFICANCE: This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival.See related commentary by Sherman, p. 4186.

Reducción de eventos cardiovasculares de Lomitapida versus Estatinas en pacientes con diagnóstico de hipercolesterolemia fa-miliar. Protocolo de revisión sistemática / Reduction of cardiovascular events of Lomitapida versus Statins in patients with a diagnosis of familial hypercholesterolemia: A systematic review protocol

Introducción: La hipercolesterolemia familiar (HF) un trastorno genético autosómico domi-nante que produce un desarrollo prematuro de enfermedades cardiovasculares. Las estati-nas han sido el medicamento de elección en estos pacientes, sin embargo, un buen por-centaje de pacientes no pueden alcanzar sus objetivos terapéuticas con las dosis máximas por lo que la Lomitapida se podría establecer como una nueva alternativa de tratamiento. Objetivo: El objetivo de esta revisión sistemática es determinar si la Lomitapida reduce los eventos cardiovasculares en pacientes con diagnóstico de Hipercolesterolemia familiar comparado con estatinas. Métodos: Se incluirán ensayos controlados aleatorios (ECA) y cuasialeatorios de pacientes con diagnóstico de HF. Las medidas de resultado los niveles de LDL, HDL pos tratamiento y eventos cardiovasculares. Las búsquedas electrónicas se realizarán en PUBMED, The Coch-rane Central Register of Controlled Trials (CENTRAL), EMBASE y Scientific electronic library (Scielo). En la evaluación del riesgo de sesgo se utilizará la herramienta de Cochrane. Las medidas del efecto del tratamiento serán las diferencias de medias (DM) y los intervalos de confianza (IC) del 95%. La evaluación de heterogeneidad se realizará mediante la inspec-ción visual del diagrama de embudo. La evaluación de la calidad de la evidencia se reali-zará usando la evaluación GRADE.

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disor-der that produces hypercholesterolemia and premature development of cardiovascular diseas-es. Statins are the drug of choice in these patients; however, a high percentage of patients cannot achieve their therapeutic goals with the maximum recommended doses, so Lo-mitapide may prove to be useful as a new treatment alternative to traditional statins. Objective: The objective of this systematic review is to determine if Lomitapide is better than statins at reducing cardiovascular events in patients with a diagnosis of FH. Methods: Randomized controlled trials (RCTs) and quasi-randomized trials of patients di-agnosed with FH will be included. Primary outcome measures included several parameters: 1. Post-treatment low- and high-density lipoprotein (LDL and HDL, respectively) levels and 2. Presence of cardiovascular events. Electronic searches will be conducted in PUBMED, The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and the scientific elec-tronic library (Scielo). The assessment of the risk of bias will be used by the Cochrane tool. The measures of the treatment effect will be considered the mean differences (MD) and the 95% confidence intervals (CI). The evaluation of heterogeneity will be done by visual inspec-tion of the funnel diagram. The evaluation of the quality of the evidence will be done using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) ap-proach.