Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Adenosine-related small molecules show utility of recall antigen assay to screen compounds for off-target effects on memory T cells.

Extracellular adenosine suppresses T cell immunity in the tumor microenvironment and in vitro treatment of memory T cells with adenosine can suppress antigen-mediated memory T cell expansion. We describe utilizing the recall antigen assay platform to screen small molecule drug off-target effects on memory T cell expansion/function using a dosing regimen based on adenosine treatment. As a proof of principle, we show low dose GS-5734, a monophosphoramidate prodrug of an adenosine analog, does not alter memory T cell recall at lower doses whereas toxicity observed at high dose favors antigen-specific memory T cell survival/proliferation over non-specific CD8+ T cells. Conversely, parent nucleoside GS-441524 at high dosage does not result in cellular toxicity and reduces antigen-specific T cell recall in most donors. Despite similar chemical structure, these drugs displayed opposing effects on memory T cell expansion and viability highlighting the sensitivity of this assay setup in screening compounds for off-target effects.

Intranasal Therapeutic Peptide Vaccine Promotes Efficient Induction and Trafficking of Cytotoxic T Cell Response for the Clearance of HPV Vaginal Tumors.

Human papillomavirus (HPV)-induced cancers continue to affect millions of women around the world, and the five year survival rate under the current standard of care for these cancers is less than 60% in some demographics. Therefore there is still an unmet need to develop an effective therapy that can be easily administered to treat established HPV cervical cancer lesions. We sought to investigate the potential of an intranasal HPV peptide therapeutic vaccine incorporating the combination of α-Galactosylceramide (α-GalCer) and CpG-ODN adjuvants (TVAC) against established HPV genital tumors in a syngeneic C57BL/6J mouse model. We obtained evidence to show that TVAC, delivered by the mucosal intranasal route, induced high frequencies of antigen-specific CD8 T cells concurrent with significant reduction in the immunosuppressive regulatory T cells and myeloid derived suppressor cells in the tumor microenvironment (TME), correlating with sustained elimination of established HPV genital tumors in over 85% of mice. Inclusion of both the adjuvants in the vaccine was necessary for significant increase of antigen-specific CD8 T cells to the tumor and antitumor efficacy because vaccination incorporating either adjuvant alone was inefficient. These results strongly support the utility of the TVAC administered by needle-free intranasal route as a safe and effective strategy for the treatment of established genital HPV tumors.

Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV+ oral cancer.

BACKGROUND: The US is experiencing an epidemic of HPV+ oropharyngeal cancers (OPC), the rates and burden of which now exceed that for cervical cancer. Immunotherapy targeting programmed death 1 (PD-1) on tumor-infiltrating lymphocytes and/or its ligand PD-L1 on tumor cells, which was effective in several cancers has however, showed efficacy in only less than 15% of patients. METHODS: We used a preclinical HPV+ oral tumor model, mEER, consisting of mouse tonsil derived epithelial cells expressing HPV-16 E6 and E7 genes, along with the H-ras oncogene to test strategies for enhancing the efficacy of anti-PD-1 therapy. RESULTS: Monotherapy with PD-1 blocking antibody was ineffective against flank-implanted tumors, but induced regression in 54% of mice bearing orthotopic tongue tumors that correlated with higher CD8 T cell responses. Since the CD8+ T cells derived from tongue tumors also showed high levels of the immune checkpoint inhibitory receptor CTLA-4, we tested combination immunotherapy targeting both CTLA-4 and PD-1 together and observed 93.3% survival of mice bearing tumors in the tongue for the duration of our 100-day study. Protective immunity correlated with a significant decrease in immunosuppressive lymphoid and myeloid populations within the tumor microenvironment. Consistent with the reported capacity of interferon-driven PD-L1/PD-1 pathway induction to serve as a biomarker of response to PD-1 blockade, we observed elevated interferon signaling and significantly higher levels of PD-1/PD-L1 in tongue-implanted mEER tumors compared to those growing on the flank correlating with their preferential responsiveness to PD-1 blockade. More importantly, in a pseudometastasic mouse model bearing both flank and tongue tumors to represent metastatic disease, delivery of Stimulator of Interferon Induced Genes (STING) agonist into the flank tumors combined with systemic treatment with α-PD-1 and α-CTLA-4 antibodies resulted in sustained tumor regression in 71% of mice. In this case, productive abscopal anti-tumor immunity was associated with robust increases in the ratios of cytotoxic CD8+ T cells (CTL) versus regulatory T cells (Treg) and versus functional myeloid-derived suppressor cells (MDSC). CONCLUSIONS: These results support combining α-PD-1 therapy with induction of IFN-α/ß signaling via provision of STING agonist and/or through CTLA-4 blockade as potential treatment option for HNSCC patients, especially, those not responding to α-PD-1 monotherapy.

Relación entre antecedente de maltrato en la niñez y comportamiento maltratador hacia los hijos. Itagüí, Colombia, 2012-2013 / Relationship Between the History of Abuse in the Childhood and Abusive Behaviour Towards Children. Itagüí, Colombia, 2012-2013

RESUMEN Introducción: Una de las experiencias que representan mayor riesgo para el desarrollo de cualquier sociedad es el maltrato infantil. A pesar de las graves consecuencias que derivan de esta forma de violencia, tiende a ser un fenómeno oculto y poco comprendido. La razón que los padres maltraten a sus hijos es una de las cuestiones que mayor interés ha suscitado en la investigación de este fenómeno. Objetivo: Determinar cómo se relaciona el antecedente de maltrato en la niñez de los adultos con el comportamiento maltratador dirigido a sus propios hijos. Métodos: Estudio transversal, a partir de fuente de información secundaria. Se incluyeron variables sociodemográficas, relacionadas con comportamientos violentos dirigidos a otras personas, factores prosociales y el uso de sustancias psicoactivas. A partir de esta población, se seleccionaron 2 grupos, padres maltratadores y no maltratadores de sus propios hijos. En ambos grupos se evaluó la frecuencia de diferentes factores que pudieran explicar la probabilidad de comportamiento maltratador de los adultos hacia sus hijos. Se analizó la asociación entre el comportamiento agresivo contra los propios hijos y el hecho de tener el antecedente de haber sufrido maltrato en la niñez. Como medida de asociación, se utilizó la odds ratio (OR) con su respectivo intervalo de confianza del 95% (IC95%) y un umbral de significación p < 0,05. Resultados: Se incluyó a 187 adultos; el 63,1% eran mujeres. La mediana [intervalo intercuartílico] de edad fue 38 [24-52] años. El comportamiento maltratador de los padres hacia sus hijos se asoció con: sexo femenino (OR = 2,23; IC95%, 1,13-4,40), agresión a la pareja (OR = 3,28; IC95%, 1,58-6,80), agresión a otras personas fuera de la familia (OR = 2,66; IC95%, 1,05-6,74), comportamiento prosocial (OR = 0,32; IC95%, 0,14-0,73) y rasgos de conducta disfuncionales (OR = 2,23; IC95%, 1,11-4,52). No se encontró asociación con el antecedente de maltrato infantil en la niñez (OR = 1,54; IC95%, 0,59-4,04). Conclusiones: El antecedente de los padres de maltrato en la niñez no se asoció con el comportamiento maltratador hacia sus hijos. Sí se asociaron otras formas de violencia dirigida a la pareja y agresión a personas no familiares, lo que indica que el maltrato de la niñez en la población estudiada se relaciona con otras expresiones de violencia familiar y social.

ABSTRACT Introduction: One of the experiences that represent the biggest risk for any society is child abuse. Despite the consequences of this form of violence, it tends to be a hidden and little understood phenomenon. The reason why parents mistreat their children has been one of the issues that has raised the most interest in the investigation of this phenomenon. Objective: To determine how the history of child abuse in adults is related to abusive behaviour directed at their own children. Methodology: A cross-sectional study, based on a source of secondary information. The study included sociodemographic variables, variables related to violent behaviours directed to other people, pro-social factors and the use of psychoactive substances. From this population, 2 groups were selected, parents who were abusive and parents who were not abusive towards their own children. In both groups the frequency of different factors that could explain the probability of abusive behaviour of the adults towards their children was evaluated. We analysed the association between aggressive behaviour against one's own children and having a history of child abuse. As a measure of association, the OR was used with its respective 95% confidence interval and P-value<.05. Results: 187 adults were included, 63.1% were women. The median [IQR] age was 38 [2452] years. The abusive behaviour of the parents towards their children was associated with: the female sex (OR = 2.23; 95%CI, 1.13-4.40), partner's aggression (OR = 3.28; 95%CI, 1.58-6.80), aggression towards other people outside the family (OR = 2.66; 95%CI, 1.05-6.74), pro-social behaviour (OR = 0.32; 95%CI, 0.14-0.73), and dysfunctional behavioural traits (OR = 2.23; 95%CI, 1.11-4.52). There was no association with the history of child abuse (OR= 1.54; 95%CI, 0.59-4.04). Conclusions: The history of abuse in the parents' childhood was not associated with abusive behaviour towards their children. Other forms of partner's violence and non-family violence were associated, suggesting that child abuse in the study population was related to other expressions of family and social violence.

Relationship Between the History of Abuse in the Childhood and Abusive Behaviour Towards Children. Itagüí, Colombia, 2012-2013. / Relación entre antecedente de maltrato en la niñez y comportamiento maltratador hacia los hijos. Itagüí, Colombia, 2012-2013.

INTRODUCTION: One of the experiences that represent the biggest risk for any society is child abuse. Despite the consequences of this form of violence, it tends to be a hidden and little understood phenomenon. The reason why parents mistreat their children has been one of the issues that has raised the most interest in the investigation of this phenomenon. OBJECTIVE: To determine how the history of child abuse in adults is related to abusive behaviour directed at their own children. METHODOLOGY: A cross-sectional study, based on a source of secondary information. The study included sociodemographic variables, variables related to violent behaviours directed to other people, pro-social factors and the use of psychoactive substances. From this population, 2 groups were selected, parents who were abusive and parents who were not abusive towards their own children. In both groups the frequency of different factors that could explain the probability of abusive behaviour of the adults towards their children was evaluated. We analysed the association between aggressive behaviour against one's own children and having a history of child abuse. As a measure of association, the OR was used with its respective 95% confidence interval and P-value<.05. RESULTS: 187 adults were included, 63.1% were women. The median [IQR] age was 38 [24-52] years. The abusive behaviour of the parents towards their children was associated with: the female sex (OR=2.23; 95%CI, 1.13-4.40), partner's aggression (OR=3.28; 95%CI, 1.58-6.80), aggression towards other people outside the family (OR=2.66; 95%CI, 1.05-6.74), pro-social behaviour (OR=0.32; 95%CI, 0.14-0.73), and dysfunctional behavioural traits (OR=2.23; 95%CI, 1.11-4.52). There was no association with the history of child abuse (OR=1.54; 95%CI, 0.59-4.04). CONCLUSIONS: The history of abuse in the parents' childhood was not associated with abusive behaviour towards their children. Other forms of partner's violence and non-family violence were associated, suggesting that child abuse in the study population was related to other expressions of family and social violence.

Mucosal HPV E6/E7 Peptide Vaccination in Combination with Immune Checkpoint Modulation Induces Regression of HPV+ Oral Cancers.

High-risk human papillomavirus (HPV)-associated squamous cell carcinomas of the oropharynx (SCCOP) are among the fastest growing cancers. After standard-of-care treatment, however, patients with HPV+ SCCOP have better overall and disease-specific survival than patients with HPV- SCCOP, suggesting the importance of HPV-specific immunity. We reasoned that therapeutic vaccination targeting the HPV-16 E6 and E7 oncogenes could elicit high-affinity, high-frequency tumor antigen-specific T-cell responses, which could then be augmented and shielded from suppression in the tumor microenvironment by immune checkpoint modulation. In this study, we used a preclinical syngeneic mouse model of oral cancer comprised of mouse tonsil-derived epithelial cells stably expressing HPV-16 E6 and E7 genes along with H-ras oncogene (mEER) to identify combinations of vaccination and checkpoint antibodies capable of promoting tumor regression. Intranasal HPV E6/E7 peptide vaccination and single checkpoint antibodies failed to elicit responses in more than half of animals; however, 4-1BB agonist antibody along with either CD40 agonist antibody or CTLA-4 blockade eliminated the majority of established mEER tumors. The combination of intranasal HPV peptide vaccine and α4-1BB and αCTLA-4 antibodies produced curative efficacy and a better safety profile against orally implanted mEER tumors. Correlates of protective immunity included enhanced intratumoral levels of CD8 T cells relative to immunosuppressive regulatory T cells and myeloid-derived suppressor cells. Overall, our results demonstrate combination vaccine-immunotherapy modalities as novel treatment options for HPV+ SCCOP.Significance: Combinations of vaccine and checkpoint modulation are effective and safe treatment options for HPV+ oral cancers. Cancer Res; 78(18); 5327-39. ©2018 AACR.

Mental disorders and drug use in victims of the armed conflict in three cities in Colombia

Introduction: Violence in its different forms increases the risk of mental disorders and the use of drugs. Objectives: To assess the prevalence of mental disorders, and the use and abuse of drugs, as well as associated factors in victims of forced displacement in three cities in Colombia. Materials and methods: We conducted a prevalence study with 1.026 participants between 13 and 65 years old. Participants completed four surveys: the World Health Organization World Mental Composite International Diagnostic Interview, the World Health Organization Alcohol Use and Disorders Identification Test, a survey on drug use based on the Inter-American System of Uniform Drug-Use Data under the Inter-American Drug Abuse Commission of the Organization of American States, and a survey on aspects related to forced displacement. Data were analyzed using the SPSS™, version 21, software. Results: Lifetime prevalence of mental disorders was 17.7% for specific phobia, 16.4% for major depression, 9.9% for post-traumatic stress disorder, 8.9% for oppositional defiant disorder, 7.2% for separation anxiety disorder, 5.8% for conduct disorder, and 5.6% for attention deficit disorder. The lifetime prevalence of alcohol use was 68.7%; 31,3% for tobacco; 11,2% for marihuana; 3.5% for cocaine; 2.0% for coca paste (basuco); 2.5% for non-prescription anxiolytic drugs, 2.3% for inhalants, and 0.7% of participants had injected drugs. Presenting any mental disorder was associated with being female (OR=1,61 IC95%: 1,21-2,14) and experiencing more than one forced displacement (OR=1,47 IC95%: 1,05-2,05). The use of any drug was associated with being male (OR=5,38 IC95%: 2,35-12,34). Conclusions: Compared to the general population, our study population exhibited high prevalence of mental disorders and drug use, emerging as a public health issue that calls for the design of plans and the implementation of programs aimed at recovering the mental health and well-being of this population.

Trastornos mentales y consumo de drogas en la población víctima del conflicto armado en tres ciudades de Colombia / Mental disorders and drug use in victims of the armed conflict in three cities in Colombia

Resumen Introducción. La violencia en sus diferentes modalidades incrementa el riesgo de trastornos mentales y de consumo de drogas. Objetivos. Estimar la prevalencia de los trastornos mentales, del uso y abuso de drogas, así como los factores asociados en víctimas de desplazamiento forzado en tres ciudades colombianas. Materiales y métodos. Se hizo un estudio de prevalencia en una muestrade 1.026 personas entre los 13 y los 65 años de edad, a quienes se entrevistó utilizando el instrumento Composite International Diagnostic Interview y el Alcohol Use Disorders Identification Test de la Organización Mundial de la Salud, así como un cuestionario sobre el consumo de drogas modificado a partir de la encuesta del Sistema Interamericano de Datos Uniformes sobre Drogas de la Comisión Interamericana para el Control del Abuso de Drogas de la Organización de Estados Americanos, y otro sobre aspectos relacionados con el desplazamiento forzado. El análisis se hizo mediante el programa estadístico SPSS™, versión 21. Resultados. La prevalencia de vida de los trastornos mentales fue la siguiente: fobia específica, 17,7 %; depresión mayor, 16,4 %; estrés postraumático, 9,9 %; trastorno oposicionista desafiante, 8,9 %; ansiedad por separación, 7,2 %; trastornos de conducta, 5,8 %, y déficit de atención, 5,6 %. La prevalencia de vida del consumo de alcohol fue de 68,7 %; de tabaco, 31,3 %, de marihuana, 11,2 %, de cocaína, 3,5 %, de basuco, 2,0 %, de inhalables, 2,3 %, y de medicamentos ansiolíticos sin receta, 2,5 %, en tanto que 0,7 % de los entrevistados se había inyectado drogas. Elpresentar cualquiera de los trastornos mentales se asoció con el sexo femenino (odds ratio, OR=1,61; IC95% 1,21-2,14), así como el haber sido sometido a más de un desplazamiento forzado (OR=1,47; IC951,05-2,05). El consumo de cualquiera de las drogas se asoció con ser hombre (OR=5,38; IC95% 2,35-12,34). Conclusiones. La alta prevalencia de trastornos mentales y de consumo de drogas en la población estudiada, comparada con la población general, constituye un problema de salud pública que justifica el diseño de planes y la implementación de programas orientados a la recuperación de su bienestar y salud mental.

Abstract Introduction: Violence in its different forms increases the risk of mental disorders and the use of drugs. Objectives: To assess the prevalence of mental disorders, and the use and abuse of drugs, as well as associated factors in victims of forced displacement in three cities in Colombia. Materials and methods: We conducted a prevalence study with 1.026 participants between 13 and 65 years old. Participants completed four surveys: the World Health Organization World Mental Composite International Diagnostic Interview, the World Health Organization Alcohol Use and Disorders Identification Test, a survey on drug use based on the Inter-American System of Uniform Drug-Use Data under the Inter-American Drug Abuse Commission of the Organization of American States, and a survey on aspects related to forced displacement. Data were analyzed using the SPSS™, version 21, software. Results: Lifetime prevalence of mental disorders was 17.7% for specific phobia, 16.4% for major depression, 9.9% for post-traumatic stress disorder, 8.9% for oppositional defiant disorder, 7.2% for separation anxiety disorder, 5.8% for conduct disorder, and 5.6% for attention deficit disorder. The lifetime prevalence of alcohol use was 68.7%; 31,3% for tobacco; 11,2% for marihuana; 3.5% for cocaine; 2.0% for coca paste (basuco); 2.5% for non-prescription anxiolytic drugs, 2.3% for inhalants, and 0.7% of participants had injected drugs. Presenting any mental disorder was associated with being female (OR=1,61 IC95%: 1,21-2,14) and experiencing more than one forced displacement (OR=1,47 IC95%: 1,05-2,05). The use of any drug was associated with being male (OR=5,38 IC95%: 2,35-12,34). Conclusions: Compared to the general population, our study population exhibited high prevalence of mental disorders and drug use, emerging as a public health issue that calls for the design of plans and the implementation of programs aimed at recovering the mental health and well-being of this population.

Sexual abuse and neglect situations as risk factors for adolescent pregnancy / Abuso sexual y situaciones de negligencia como factores de riesgo de embarazo adolescente

Abstract Background: In Colombia, one out of five women between the ages of 15 and 19 years have been pregnant. Almost two-thirds (64%) of these pregnancies were unplanned. Objectives: To examine the socio-demographic, psychosocial and clinical risk factors associated with adolescent pregnancy. Methods: An analytical prevalence study was performed using secondary data from the First Demographic Study of Mental Health in Medellin, Colombia. Female adolescents between 13 and 19 years of age were included in the study. The population was evaluated using the Composite International Diagnosis Interview, a structured interview developed by the World Health Organization, which establishes diagnoses according to the DSM-IV and ICD-10 criteria. Results: A sample of 499 female adolescents was obtained, in which 135 adolescent pregnancies were identified, representing a prevalence of 21.5%. The large majority (84.4%) were between 16 and 19 years old. The median age was 17 years, with an interquartile range of 2 years. Almost two-thirds (61.2%) of female adolescents had initiated sexual activity at the age of 15 or later. Almost one-third (31.9%) reported being physically abused during childhood, and 6.7% sexually abused. Of those who were pregnant, 66.7% reported previous sexual abuse. A bivariate analysis showed that sexual abuse (OR = 7.68), childhood negligence (OR = 4.33), and having a partner (OR = 6.31) were factors associated with an adolescent pregnancy. Conclusions: Negligence and sexual abuse in childhood and adolescence can be prevented, and adolescent pregnancies can be decreased. This finding has important implications for clinical management and prognosis, and requires public preventive policies.

Resumen Introducción: En Colombia, 1 de cada 5 mujeres de 15-19 años ha estado embarazada. El 64% de estos embarazos no fueron planeados. Objetivo : Explorar los factores sociodemográficos, psicosociales y clínicos asociados con el embarazo adolescente. Métodos: Estudio de prevalencia analítica, de fuente secundaria (Primer Estudio Poblacional de Salud Mental Medellín). La muestra fue evaluada usando el Compositum International Diagnosis Interview, instrumento desarrollado por la Organización Mundial de la Salud para realizar diagnósticos con base en criterios diagnósticos del DSM-IV y el CIE-10. Resultados Se obtuvo una muestra de 499 adolescentes. Se identificaron 135 embarazos adolescentes, lo que lleva a una prevalencia de embarazo adolescente del 21,5%. El 84,4% de las adolescentes embarazadas tenían entre 16 y 19 años, y la edad mediana era 17 [intervalo intercuartílico, 2] anos. El 61,2% de ellas iniciaron la vida sexual a los 15 años. Del total de adolescentes, el 31,9% afirmaba haber sufrido maltrato físico y el 6,7%, haber sido violadas en la niñez. Del subgrupo de embarazadas, el 66,7% reportó haber sufrido violación. En el modelo bivariable, las variables que mostraron asociación con el embarazo adolescente fueron ser víctima de violación (odds ratio [OR] = 7,68), negligencia en la niñez (OR = 4,33) y tener pareja (OR = 6,31). Conclusiones: La negligencia y el abuso sexual en la infancia pueden evitarse buscando impactar positivamente el embarazo adolescente.

[Sexual Abuse and Neglect Situations as Risk Factors for Adolescent Pregnancy]. / Abuso sexual y situaciones de negligencia como factores de riesgo de embarazo adolescente.

BACKGROUND: In Colombia, one out of five women between the ages of 15 and 19 years have been pregnant. Almost two-thirds (64%) of these pregnancies were unplanned. OBJECTIVES: To examine the socio-demographic, psychosocial and clinical risk factors associated with adolescent pregnancy. METHODS: An analytical prevalence study was performed using secondary data from the First Demographic Study of Mental Health in Medellin, Colombia. Female adolescents between 13 and 19 years of age were included in the study. The population was evaluated using the Composite International Diagnosis Interview, a structured interview developed by the World Health Organization, which establishes diagnoses according to the DSM-IV and ICD-10 criteria. RESULTS: A sample of 499 female adolescents was obtained, in which 135 adolescent pregnancies were identified, representing a prevalence of 21.5%. The large majority (84.4%) were between 16 and 19 years old. The median age was 17 years, with an interquartile range of 2 years. Almost two-thirds (61.2%) of female adolescents had initiated sexual activity at the age of 15 or later. Almost one-third (31.9%) reported being physically abused during childhood, and 6.7% sexually abused. Of those who were pregnant, 66.7% reported previous sexual abuse. A bivariate analysis showed that sexual abuse (OR=7.68), childhood negligence (OR=4.33), and having a partner (OR=6.31) were factors associated with an adolescent pregnancy. CONCLUSIONS: Negligence and sexual abuse in childhood and adolescence can be prevented, and adolescent pregnancies can be decreased. This finding has important implications for clinical management and prognosis, and requires public preventive policies.

Spatial Analysis of Dengue Seroprevalence and Modeling of Transmission Risk Factors in a Dengue Hyperendemic City of Venezuela.

BACKGROUND: Dengue virus (DENV) transmission is spatially heterogeneous. Hence, to stratify dengue prevalence in space may be an efficacious strategy to target surveillance and control efforts in a cost-effective manner particularly in Venezuela where dengue is hyperendemic and public health resources are scarce. Here, we determine hot spots of dengue seroprevalence and the risk factors associated with these clusters using local spatial statistics and a regression modeling approach. METHODOLOGY/PRINCIPAL FINDINGS: From August 2010 to January 2011, a community-based cross-sectional study of 2012 individuals in 840 households was performed in high incidence neighborhoods of a dengue hyperendemic city in Venezuela. Local spatial statistics conducted at household- and block-level identified clusters of recent dengue seroprevalence (39 hot spot households and 9 hot spot blocks) in all neighborhoods. However, no clusters were found for past dengue seroprevalence. Clustering of infection was detected at a very small scale (20-110m) suggesting a high disease focal aggregation. Factors associated with living in a hot spot household were occupation (being a domestic worker/housewife (P = 0.002), lower socio-economic status (living in a shack (P<0.001), sharing a household with <7 people (P = 0.004), promoting potential vector breeding sites (storing water in containers (P = 0.024), having litter outdoors (P = 0.002) and mosquito preventive measures (such as using repellent, P = 0.011). Similarly, low socio-economic status (living in crowded conditions, P<0.001), having an occupation of domestic worker/housewife (P = 0.012) and not using certain preventive measures against mosquitoes (P<0.05) were directly associated with living in a hot spot block. CONCLUSIONS/SIGNIFICANCE: Our findings contribute to a better comprehension of the spatial dynamics of dengue by assessing the relationship between disease clusters and their risk factors. These results can inform health authorities in the design of surveillance and control activities. Focalizing dengue control measures during epidemic and inter-epidemic periods to disease high risk zones at household and neighborhood-level may significantly reduce virus transmission in comparison to random interventions.

Socio-demographic patterns of posttraumatic stress disorder in Medellin, Colombia and the context of lifetime trauma exposure.

Colombia, South America is currently transitioning to post-conflict status following 6 decades of armed conflict. The population has experienced extensive exposures to potentially traumatic events throughout the lifespan. Sources of trauma exposure include the prolonged armed insurgency, narco-trafficking violence, urban gang violence, violent actions of criminal bands, intra-familial violence, gender-based violence, and sex trafficking. Exposure to potentially traumatic events is related to a variety of psychiatric outcomes, in particular, posttraumatic stress disorder. Given this context of lifetime trauma exposure, socio-demographic patterns of posttraumatic stress disorder were explored in a sample of residents of Medellin, Colombia, the nation's second largest city and a nexus for multiple types of trauma exposure.

Multicountry prospective clinical evaluation of two enzyme-linked immunosorbent assays and two rapid diagnostic tests for diagnosing dengue fever.

We evaluated four dengue diagnostic devices from Alere, including the SD Bioline Dengue Duo (nonstructural [NS] 1 Ag and IgG/IgM), the Panbio Dengue Duo Cassette (IgM/IgG) rapid diagnostic tests (RDTs), and the Panbio dengue IgM and IgG capture enzyme-linked immunosorbent assays (ELISAs) in a prospective, controlled, multicenter study in Peru, Venezuela, Cambodia, and the United States, using samples from 1,021 febrile individuals. Archived, well-characterized samples from an additional 135 febrile individuals from Thailand were also used. Reference testing was performed on all samples using an algorithm involving virus isolation, in-house IgM and IgG capture ELISAs, and plaque reduction neutralization tests (PRNT) to determine the infection status of the individual. The primary endpoints were the clinical sensitivities and specificities of these devices. The SD Bioline Dengue Duo had an overall sensitivity of 87.3% (95% confidence interval [CI], 84.1 to 90.2%) and specificity of 86.8% (95% CI, 83.9 to 89.3%) during the first 14 days post-symptom onset (p.s.o.). The Panbio Dengue Duo Cassette demonstrated a sensitivity of 92.1% (87.8 to 95.2%) and specificity of 62.2% (54.5 to 69.5%) during days 4 to 14 p.s.o. The Panbio IgM capture ELISA had a sensitivity of 87.6% (82.7 to 91.4%) and specificity of 88.1% (82.2 to 92.6%) during days 4 to 14 p.s.o. Finally, the Panbio IgG capture ELISA had a sensitivity of 69.6% (62.1 to 76.4%) and a specificity of 88.4% (82.6 to 92.8%) during days 4 to 14 p.s.o. for identification of secondary dengue infections. This multicountry prospective study resulted in reliable real-world performance data that will facilitate data-driven laboratory test choices for managing patient care during dengue outbreaks.

Dengue seroprevalence and risk factors for past and recent viral transmission in Venezuela: a comprehensive community-based study.

Dengue transmission in Venezuela has become perennial and a major public health problem. The increase in frequency and magnitude of recent epidemics prompted a comprehensive community-based cross-sectional study of 2,014 individuals in high-incidence neighborhoods of Maracay, Venezuela. We found a high seroprevalence (77.4%), with 10% of people experiencing recent infections. Multivariate logistic regression analysis showed that poverty-related socioeconomic factors (place and duration of residence, crowding, household size, and living in a shack) and factors/constraints related to intradomiciliary potential mosquito breeding sites (storing water and used tires) were linked with a greater risk of acquiring a dengue infection. Our results also suggest that transmission occurs mainly at home. The combination of increasingly crowded living conditions, growing population density, precarious homes, and water storage issues caused by enduring problems in public services in Maracay are the most likely factors that determine the permanent dengue transmission and the failure of vector control programs.

Sequential waves of gene expression in patients with clinically defined dengue illnesses reveal subtle disease phases and predict disease severity.

BACKGROUND: Dengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the "early" group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0-1 and declined on day 3-4; the second "late" group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5-6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0-3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1. CONCLUSIONS/SIGNIFICANCE: Our study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1-3 may have applications in developing early molecular diagnostics for DHF.

Sentinel surveillance of influenza-like illness in two hospitals in Maracay, Venezuela: 2006-2010.

BACKGROUND: Limited information exists on the epidemiology of acute febrile respiratory illnesses in tropical South American countries such as Venezuela. The objective of the present study was to examine the epidemiology of influenza-like illness (ILI) in two hospitals in Maracay, Venezuela. METHODOLOGY/PRINCIPAL FINDINGS: We performed a prospective surveillance study of persons with ILI who presented for care at two hospitals in Maracay, Venezuela, from October 2006 to December 2010. A respiratory specimen and clinical information were obtained from each participant. Viral isolation and identification with immunofluorescent antibodies and molecular methods were employed to detect respiratory viruses such as adenovirus, influenza A and B, parainfluenza, and respiratory sincytial virus, among others. There were 916 participants in the study (median age: 17 years; range: 1 month--86 years). Viruses were identified in 143 (15.6%) subjects, and one participant was found to have a co-infection with more than one virus. Influenza viruses, including pandemic H1N1 2009, were the most frequently detected pathogens, accounting for 67.4% (97/144) of the viruses detected. Adenovirus (15/144), parainfluenza virus (13/144), and respiratory syncytial virus (11/144) were also important causes of ILI in this study. Pandemic H1N1 2009 virus became the most commonly isolated influenza virus during its initial appearance in 2009. Two waves of the pandemic were observed: the first which peaked in August 2009 and the second--higher than the preceding - that peaked in October 2009. In 2010, influenza A/H3N2 re-emerged as the most predominant respiratory virus detected. CONCLUSIONS/SIGNIFICANCE: Influenza viruses were the most commonly detected viral organisms among patients with acute febrile respiratory illnesses presenting at two hospitals in Maracay, Venezuela. Pandemic H1N1 2009 influenza virus did not completely replace other circulating influenza viruses during its initial appearance in 2009. Seasonal influenza A/H3N2 was the most common influenza virus in the post-pandemic phase.

A three-component biomarker panel for prediction of dengue hemorrhagic fever.

Dengue virus infections are a major cause of morbidity in tropical countries. Early detection of dengue hemorrhagic fever (DHF) may help identify individuals that would benefit from intensive therapy. Predictive modeling was performed using 11 laboratory values of 51 individuals (38 DF and 13 DHF) obtained on initial presentation using logistic regression. We produced a robust model with an area under the curve of 0.9615 that retained IL-10 levels, platelets, and lymphocytes as the major predictive features. A classification and regression tree was developed on these features that were 86% accurate on cross-validation. The IL-10 levels and platelet counts were also identified as the most informative features associated with DHF using a Random Forest classifier. In the presence of polymerase chain reaction-proven acute dengue infections, we suggest a complete blood count and rapid measurement of IL-10 can assist in the triage of potential DHF cases for close follow-up or clinical intervention improving clinical outcome.

Incidencia de infecciones sintomáticas y asintomáticas por virus dengue en Maracay, Venezuela: 2006-2007 / Incidence of symptomatic and asymptomatic dengue virus infections in Maracay, Venezuela: 2006-2007

Con el objetivo de estimar las tasas de incidencia de infecciones sintomáticas y asintomáticas por virus dengue (DENV) durante un año (octubre 2006-septiembre 2007) en cuatro barrios de Maracay (Venezuela) se realizó un estudio prospectivo consistente de visitas domiciliarias, tres veces por semana, para detectar casos de dengue y de encuestas serológicas semestrales para determinar infecciones asintomáticas probables por DENV. Los sujetos de estudio pertenecían a una cohorte de 2663 personas ≥5 años de edad. El diagnóstico confirmatorio de DENV se realizó mediante la reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR). Las pruebas serológicas se realizaron mediante el ensayo inmunoenzimático de captura de IgM anti-dengue (MAC-ELISA). Los resultados determinaron tasas de incidencia de 5,7 y 18,6 por 100 000 personas/día (p/d) para las infecciones sintomáticas y asintomáticas, respectivamente. La tasa de incidencia de las infecciones sintomáticas observada en las personas <15 años de edad fue significativamente mayor que la encontrada en los sujetos ≥15 años (15,8 versus 2,9 por 100 000 p/d). Por otro lado, las tasas de incidencia de las infecciones asintomáticas en ambos grupos de edad fueron similares (17,3 y 18,9 por 100 000 p/d, respectivamente). Se detectaron los cuatro serotipos del DENV en tres de los barrios estudiados. Se observó que la edad y la hiperendemicidad fueron probablemente los factores que más contribuyeron a la incidencia del dengue en los cuatro barrios investigados. Seguramente, las infecciones asintomáticas contribuyeron a incrementar la transmisión viral en el área de estudio.

The incidence rates of symptomatic and asymptomatic dengue virus (DENV) infections in four "barrios" of Maracay, Venezuela, during one-year (October 2006-September 2007) were estimated. A prospective study consisting of house visits three-times a week to detect dengue cases, and semiannual serological surveys to determine probable asymptomatic dengue virus (DENV) infections was conducted. The study subjects belonged to a cohort of 2,663 people ≥5 year-old. Confirmatory diagnosis of DENV infections was carried out by reverse-transcriptase polymerase chain reaction (RT-PCR). Serological surveys were performed by anti-dengue IgM-capture immunoassay (MAC-ELISA). The results showed that the incidence rates for symptomatic and asymptomatic infections were determined to be 5.7 and 18.6 per 100,000 persons/day (p/d), respectively. The incidence rate of symptomatic infections was significantly higher in persons <15 year-old than that found in subjects ≥15 years (15.8 versus 2.9 per 100,000 p/d). On the other hand, the incidence rates of asymptomatic infections in both age groups were similar (17.3 and 18.9 per 100,000 p/d, respectively). All four DENV serotypes were detected in three of the four "barrios" studied. Finally, age and hyperendemicity were probably the contributing factors to the incidence of dengue in the four "barrios" investigated. Surely, the asymptomatic infections contributed to increase the viral transmission in the study area.

Dengue virus infections in a cohort of schoolchildren from Maracay, Venezuela: a 2-year prospective study.

In 2001, we began a prospective longitudinal study in a cohort of schoolchildren 5-13 years of age residing in Maracay, Venezuela, to determine the cumulative incidence of dengue virus (DENV) infections by virus serotype. This report presents serological data from 710 schoolchildren who were tested during the first 2 years of the study. Serological evaluations were conducted by plaque reduction neutralization test (PRNT). At study initiation, 51% of children had PRNT antibody titers against one (30.1% = 13.4% DENV-1, 14.2% DENV-2, 0.6% DENV-3, and 2% DENV-4) or multiple DENV serotypes (20.9%). By the end of the first year, 89 of 348 (25.6%) PRNT-negative children seroconverted, and 94 of 362 (26%) who were PRNT-positive in their baseline sera tested positive for additional serotypes, for an overall cumulative incidence of DENV infections of 25.8%. By serotype, the percentages found were 1.4% DENV-1, 1.4% DENV-2, 19% DENV-3, and 1.2% DENV-4. In the second year, 37 of 259 (14.3%) PRNT-negative children seroconverted, and 83 of 451 (18.4%) who had monotypic and multitypic PRNT patterns in their baseline sera exhibited additional serotype seroconversions, for an overall cumulative incidence of DENV infections of 16.9%. By serotype, the percentages found were 0.8% DENV-1, 1.5% DENV-2, 8.5% DENV-3, and 2.3% DENV-4. Overall, these results suggest a high cumulative incidence of DENV infections among 5-13-year-old school children in Maracay, Venezuela.