Cynomolgus macaques as a translational model of human immune responses to yellow fever 17D vaccination.

The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed the evaluation of the safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a systems biology approach to compare hematological, biochemical, transcriptomic, and innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans but with a slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques [by Day 7[(D7)], but titers > 10 were reached in both species by D14 post-vaccination and were not significantly different by D28 [plaque reduction neutralization assay (PRNT)50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; P = 0.821]. Changes in neutrophils, NK cells, monocytes, and T- and B-cell frequencies were higher in cynomolgus macaques and persisted for 4 weeks versus less than 2 weeks in humans. Low levels of systemic inflammatory cytokines (IL-1RA, IL-8, MIP-1α, IP-10, MCP-1, or VEGF) were detected in either or both species but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3-D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low-level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques [28% (5/18)] but generally absent in humans [except one participant (5%; 1/20)].IMPORTANCECynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans and suggest a key role for type I IFN.

Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have shown remarkable results against B-cell malignancies, but only a minority of patients have long-term remission. The metabolic requirements of both tumor cells and activated T cells result in production of lactate. The export of lactate is facilitated by expression of monocarboxylate transporter (MCTs). CAR T cells express high levels of MCT-1 and MCT-4 on activation, while certain tumors predominantly express MCT-1. METHODS: Here, we studied the combination of CD19-specific CAR T-cell therapy with pharmacological blockade of MCT-1 against B-cell lymphoma. RESULTS: MCT-1 inhibition with small molecules AZD3965 or AR-C155858 induced CAR T-cell metabolic rewiring but their effector function and phenotype remained unchanged, suggesting CAR T cells are insensitive to MCT-1 inhibition. Moreover, improved cytotoxicity in vitro and antitumoral control on mouse models was found with the combination of CAR T cells and MCT-1 blockade. CONCLUSION: This work highlights the potential of selective targeting of lactate metabolism via MCT-1 in combination with CAR T cells therapies against B-cell malignancies.

Hydrogen Sulfide Ameliorates SARS-CoV-2-Associated Lung Endothelial Barrier Disruption.

Recent studies have confirmed that lung microvascular endothelial injury plays a critical role in the pathophysiology of COVID-19. Our group and others have demonstrated the beneficial effects of H2S in several pathological processes and provided a rationale for considering the therapeutic implications of H2S in COVID-19 therapy. Here, we evaluated the effect of the slow-releasing H2S donor, GYY4137, on the barrier function of a lung endothelial cell monolayer in vitro, after challenging the cells with plasma samples from COVID-19 patients or inactivated SARS-CoV-2 virus. We also assessed how the cytokine/chemokine profile of patients' plasma, endothelial barrier permeability, and disease severity correlated with each other. Alterations in barrier permeability after treatments with patient plasma, inactivated virus, and GYY4137 were monitored and assessed by electrical impedance measurements in real time. We present evidence that GYY4137 treatment reduced endothelial barrier permeability after plasma challenge and completely reversed the endothelial barrier disruption caused by inactivated SARS-CoV-2 virus. We also showed that disease severity correlated with the cytokine/chemokine profile of the plasma but not with barrier permeability changes in our assay. Overall, these data demonstrate that treatment with H2S-releasing compounds has the potential to ameliorate SARS-CoV-2-associated lung endothelial barrier disruption.

Preclinical evaluation of chimeric antigen receptor T cells targeting the carcinoembryonic antigen as a potential immunotherapy for gallbladder cancer.

Gallbladder cancer (GBC) is commonly diagnosed at late stages when conventional treatments achieve only modest clinical benefit. Therefore, effective treatments for advanced GBC are needed. In this context, the administration of T cells genetically engineered with chimeric antigen receptors (CAR) has shown remarkable results in hematological cancers and is being extensively studied for solid tumors. Interestingly, GBC tumors express canonical tumor-associated antigens, including the carcinoembryonic antigen (CEA). However, the potential of CEA as a relevant antigen in GBC to be targeted by CAR-T cell-based immunotherapy has not been addressed. Here we show that CEA was expressed in 88% of GBC tumors, with higher levels associated with advanced disease stages. CAR-T cells specifically recognized plate-bound CEA as evidenced by up-regulation of 4-1BB, CD69 and PD-1, and production of effector cytokines IFN-γ and TNF-α. In addition, CD8+ CAR-T cells up-regulated the cytotoxic molecules granzyme B and perforin. Interestingly, CAR-T cell activation occurred even in the presence of PD-L1. Consistent with these results, CAR-T cells efficiently recognized GBC cell lines expressing CEA and PD-L1, but not a CEA-negative cell line. Furthermore, CAR-T cells exhibited in vitro cytotoxicity and reduced in vivo tumor growth of GB-d1 cells. In summary, we demonstrate that CEA represents a relevant antigen for GBC that can be targeted by CAR-T cells at the preclinical level. This study warrants further development of the adoptive transfer of CEA-specific CAR-T cells as a potential immunotherapy for GBC.

Comportamiento de indicadores relacionados con la asistencia a pacientes con hemorragia subaracnoidea espontánea en la provincia de Cienfuegos

Fundamento: la importancia sanitaria de la hemorragia subaracnoidea espontánea, como problema de salud, es un hecho reconocido. Objetivo determinar el comportamiento de algunos indicadores relacionados con la asistencia médica a pacientes con hemorragia subaracnoidea espontánea, en el contexto provincial. Métodos estudio observacional, descriptivo-correlacional y retrospectivo, de 96 pacientes con hemorragia subaracnoidea espontánea entre 2016 y 2021. Se analizó el comportamiento de indicadores seleccionados, en su relación con diversas variables. En el análisis estadístico se utilizó como estadígrafo el Odds Ratio y su intervalo de confianza. Resultados el 22 % de los pacientes fue diagnosticado pasadas las primeras 48 horas del inicio de los síntomas, mientras que 13 enfermos (14 %) requirieron más de una asistencia para el diagnóstico. La ocurrencia de diagnóstico tardío cuando no se identificó el sangramiento en la primera consulta fue significativa (OR 21,8[5,1;91,8]). Doce pacientes fueron admitidos fuera de unidades especializadas; esta situación se observó más en pacientes menores de 60 años (21% vs 4 %; OR 5,7[1,1;27,9]), y en quienes el diagnóstico se realizó después de las 48 horas del inicio de las manifestaciones (29 % vs 8 %; OR 4,6[1,3;16,2]). De los 35 pacientes trasladados a otra institución para tratamiento neuroquirúrgico solo cuatro (12 %) fueron evacuados en las primeras 72 horas. Conclusiones se identifican brechas en la atención al paciente con hemorragia subaracnoidea en el contexto provincial; se destacan el ingreso de enfermos fuera de unidades especializadas y el traslado tardío a instituciones con servicio de cirugía neurovascular.

Background: the spontaneous subarachnoid hemorrhage's health importance, it's recognized as a health problem. Objective: to determine the behavior of some indicators related to medical care for patients with spontaneous subarachnoid hemorrhage, in the provincial context. Methods: Observational, descriptive-correlational and retrospective study of 96 patients with spontaneous subarachnoid hemorrhage between 2016 and 2021. The behavior of selected indicators was analyzed in relation to various variables. In the statistical analysis, the Odds Ratio and its confidence interval were used as statisticians. Results: 22% of the patients were diagnosed after the first 48 hours after the onset of symptoms, while 13 patients (14%) required more than one assistance for diagnosis. The occurrence of late diagnosis when bleeding was not identified at the first visit was significant (OR 21.8[5.1;91.8]). Twelve patients were admitted outside of specialized units; this situation was observed more in patients under 60 years of age (21% vs 4%; OR 5.7[1.1;27.9]), and in whom the diagnosis was made 48 hours after the onset of manifestations (29% vs 8%; OR 4.6[1.3;16.2]). Of the 35 patients transferred to another institution for neurosurgical treatment, only four (12%) were evacuated in the first 72 hours. Conclusions: gaps are identified in the patients' care with subarachnoid hemorrhage in the provincial context; The admission of patients outside specialized units and the late transfer to institutions with neurovascular surgery service stand out.

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis-van Creveld Syndrome.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. METHODS: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. RESULTS: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. CONCLUSION: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.

Dopaminergic Signalling Enhances IL-2 Production and Strengthens Anti-Tumour Response Exerted by Cytotoxic T Lymphocytes in a Melanoma Mouse Model.

Dopamine has emerged as an important regulator of immunity. Recent evidence has shown that signalling through low-affinity dopamine receptors exerts anti-inflammatory effects, whilst stimulation of high-affinity dopamine receptors potentiates immunity in different models. However, the dopaminergic regulation of CD8+ T-cells in anti-tumour immunity remains poorly explored. Here, we studied the role of dopamine receptor D3 (DRD3), which displays the highest affinity for dopamine, in the function of CD8+ T-cells and its consequences in the anti-tumour immune response. We observed that the deficiency of Drd3 (the gene encoding DRD3) in CD8+ T-cells limits their in vivo expansion, leading to an impaired anti-tumour response in a mouse melanoma model. Mechanistic analyses suggest that DRD3 stimulation favours the production of interleukin 2 (IL-2) and the surface expression of CD25, the α-chain IL-2 receptor, which are required for expansion and effector differentiation of CD8+ T-cells. Thus, our results provide genetic and pharmacologic evidence indicating that DRD3 favours the production of IL-2 by CD8+ T-cells, which is associated with higher expansion and acquisition of effector function of these cells, promoting a more potent anti-tumour response in a melanoma mouse model. These findings contribute to understanding how dopaminergic signalling affects the cellular immune response and represent an opportunity to improve melanoma therapy.

Linfangiomatosis esplénica en un paciente adulto: Reporte de caso

Los linfangiomas son malformaciones benignas del sistema linfático que afectan con mayor frecuencia a los niños y en raras ocasiones a adultos. Presentamos el caso de una mujer de 36 años, con cuadro clínico de 6 meses de dolor abdominal difuso sin irritación peritoneal, y asociado a adinamia. Como parte de los estudios, se solicitó una tomografía axial computarizada con contraste de abdomen, que reveló múltiples lesiones esplénicas hipodensas hipovasculares, con sospecha diagnóstica de lesiones linfoproliferativas. Por tal motivo se solicitó una esplenectomía diagnóstica, que finalmente mostró hallazgos macroscópicos, microscópicos y de inmunohistoquímica (positividad de las lesiones quísticas para CD31 y D2-40) compatibles con linfagiomatosis esplénica difusa.

Lymphangiomas are benign malformations of the lymphatic system. They most often affect children and rarely adults. We present the case of a 36-year-old woman with a 6-month clinical picture of diffuse abdominal pain without peritoneal irritation associated with adynamia. As part of the studies, a computerized axial tomography with abdominal contrast was requested, which revealed multiple hypovascular hypodense splenic lesions with suspected diagnosis of lymphoproliferative lesions. For this reason, a diagnostic splenectomy was requested, which showed macroscopic, microscopic and immunohistochemical findings (positivity of cystic lesions for CD31 and D2-40) compatible with diffuse splenic lymphagiomatosis

Innate cell markers that predict anti-HIV neutralizing antibody titers in vaccinated macaques.

Given the time and resources invested in clinical trials, innovative prediction methods are needed to decrease late-stage failure in vaccine development. We identify combinations of early innate responses that predict neutralizing antibody (nAb) responses induced in HIV-Env SOSIP immunized cynomolgus macaques using various routes of vaccine injection and adjuvants. We analyze blood myeloid cells before and 24 h after each immunization by mass cytometry using a three-step clustering, and we discriminate unique vaccine signatures based on HLA-DR, CD39, CD86, CD11b, CD45, CD64, CD14, CD32, CD11c, CD123, CD4, CD16, and CADM1 surface expression. Various combinations of these markers characterize cell families positively associated with nAb production, whereas CADM1-expressing cells are negatively associated (p < 0.05). Our results demonstrate that monitoring immune signatures during early vaccine development could assist in identifying biomarkers that predict vaccine immunogenicity.

Nanostructured mesoporous silica materials induce hormesis on chili pepper (Capsicum annuum L.) under greenhouse conditions.

Current agricultural practices for vegetable production are unsustainable, and the use of certain nanomaterials has shown significant potential for either plant growth promotion or defense induction in crop species. The aim of the present work was to evaluate the possible effects of two SBA nano-structured silica materials differing in morphology; SBA-15, with porous structure in parallel and with a highly ordered hexagonal array and SBA-16, with spheric nano-cages located in cubic arrays, as plant growth promoters/eustressors on chili pepper (Capsicum annuum L.) during cultivation under greenhouse conditions. The study was carried out at three foliarly applied concentrations (20, 50 and 100 ppm) of either SBA materials to determine effects on seed germination, seedling growth, plant performance and cold tolerance under greenhouse. Phytotoxicity tests were carried out using higher concentrations (100, 1000 and 200 ppm) applied by dipping or spraying onto chili pepper plants. Deionized water controls were included. The results showed that the SBA materials did not affect seed germination; however, SBA-15 at 50 ppm and 100 ppm applied by imbibition significantly increased seedling height (up to 8-fold) and provided enhanced growth performance in comparison with controls under select treatment regimes. Weekly application of SBA-15 at 20 ppm significantly increased stem diameter and cold tolerance; however, SBA-16 showed significant decreases in plant height (20 ppm biweekly applied) and stem diameter (20, 50 and 100 ppm biweekly applied). The results demonstrate that both SBA materials provided hormetic effects in a dose dependent manner on chili pepper production and protection to cold stress. No phytotoxic response was evident. These findings suggested the nanostructured mesoporous silica have potential as a sustainable amendment strategy to increase crop production under stress-inducing cultivation conditions.

Anti-carbamylated protein antibodies positivity and disease activity in Hispanic patients with established rheumatoid arthritis: An observational study.

OBJECTIVES: We aimed to determine the prevalence of anti-carbamylated protein (anti-CarP) antibodies in Mexican Hispanics with established rheumatoid arthritis (RA) and to assess their relationship with disease activity. METHODS: A cohort study was conducted in 278 patients with established RA during an 18-month follow-up. We measured IgG/IgM/IgA rheumatoid factor (RF), IgG anticitrullinated protein antibodies (ACPA) and IgG/IgM/IgA anti-CarP antibodies using enzyme-linked immunosorbent assay (ELISA). For disease activity, we performed the 28-joint disease activity score with erythrocyte sedimentation rate (DAS28-ESR). Repeated measures one-way ANOVA was used to test the association between anti-CarP IgG antibody status and longitudinal DAS28-ESR scores. Patients were evaluated at baseline and at 6, 12, and 18 months during follow-up. RESULTS: Anti-CarP IgG antibodies were positive in 47.8% of patients and, accounting for all isotypes, in 9.5% of patients with negative RF and ACPA. Triple antibody positivity was present in 42.6% of patients in our sample. Anti-CarP IgG antibody positivity did not show statistically significant differences in mean DAS28-ESR when compared to anti-CarP IgG antibody negative patients at baseline, 6, 12 or 18 months. CONCLUSION: Anti-CarP IgG antibodies are not associated to a higher disease activity in Hispanic patients with established RA. Our findings suggest that the clinical value of measuring anti-CarP antibodies in RA diminishes over time.

Comportamiento y manejo actual de la infección por virus de la hepatitis B / Behavior and current management of hepatitis B virus infection

RESUMEN Introducción: Las hepatitis virales son un problema de salud a nivel mundial, provocan elevada mortalidad y morbilidad. A pesar de los avances en la prevención, diagnóstico y tratamiento de la hepatitis B, esta enfermedad es todavía preocupación de las autoridades sanitarias. Objetivo: Realizar una actualización acerca del comportamiento y manejo actual de la infección por el virus de la hepatitis B. Métodos: Se realizó una revisión bibliográfica durante abril y mayo de 2021, se consultaron 211 artículos en idioma inglés y español en las bases de datos como SciELO, PubMed, Lilacs y Medigraphic, de ellos se utilizaron 30 citas. Se empleó la combinación de términos y operadores booleanos y métodos teóricos como: análisis-síntesis, inducción-deducción e histórico-lógico. Resultados: Se abordó el comportamiento de la infección causada por el virus de la hepatitis B, se hizo hincapié en su epidemiología, características morfológicas y funcionales que permiten su infectividad, evolución y manifestaciones clínicas, complicaciones, tratamiento y perspectivas actuales. Conclusiones: La historia natural de la infección es dinámica y las manifestaciones clínicas dependen de diversos factores. La infección por el virus de la hepatitis B puede causar complicaciones como: la cirrosis hepática y el carcinoma hepatocelular y su principal vía de transmisión es la parenteral. El diagnóstico se realiza a través de técnicas serológicas. Es imprescindible la atención diferenciada a los grupos con riesgo y, aunque se cuenta con una vacuna eficaz, aún existen casos y se han desarrollado tratamientos con resultados positivos.

ABSTRACT Introduction: Viral hepatitis is a global health problem, causing high mortality and morbidity. Despite advances in the prevention, diagnosis and treatment of hepatitis B, this disease is still a concern of health authorities. Objective: Toupdate on current behavior and management of hepatitis B virus infection. Methods: A bibliographic review was carried out during April and May 2021, consulting 211 articles in English and Spanish from databases such as SciELO, PubMed, Lilacs and Medigraphic, of which 30 citations were used. The combination of Boolean terms and operators and theoretical methods such as: analysis-synthesis, induction-deduction and historical-logical were used. Results: The behavior of the infection caused by the hepatitis B virus was addressed, emphasizing its epidemiology, morphological and functional characteristics that allow its infectivity, evolution and clinical manifestations, complications, treatment and current perspectives. Conclusions: The natural history of infection is dynamic, and clinical manifestations depend on various factors. Hepatitis B virus infection can cause complications such as liver cirrhosis and hepatocellular carcinoma, and its main route of transmission is parenterally. The diagnosis is made mainly through serological techniques. Differentiated care for groups at risk is essential and, although there is an effective vaccine, there are still cases and treatments have been developed with positive results.

Actualización sobre hepatitis A

Introducción: La hepatitis es una enfermedad inflamatoria que afecta al hígado. El virus de la hepatitis A produce un cuadro infeccioso agudo por lo general autolimitado en el ser humano, para el cual no existe tratamiento específico. Objetivo: Realizar una actualización acerca del comportamiento y manejo actual de la infección por el virus de la hepatitis A. Métodos: Se realizó una revisión bibliográfica durante septiembre y octubre de 2021, se consultaron 156 artículos en idioma inglés y español de bases de datos como SciELO, PubMed, LILACS y Medigraphic, de ellos se utilizaron 30 citas. Se empleó la combinación de términos y operadores booleanos y métodos teóricos como: análisis-síntesis, inducción-deducción e histórico-lógico. Resultados: Se abordó el comportamiento de la infección causada por el virus de la hepatitis A, se hizo hincapié en su epidemiología, características morfológicas y funcionales que permiten su infectividad, evolución y manifestaciones clínicas, complicaciones, tratamiento y perspectivas actuales. Conclusiones: El virus de la hepatitis A produce un cuadro infeccioso agudo. Se presenta tanto de forma esporádica como epidémica. Es la forma más común de hepatitis viral aguda. La transmisión es de persona a persona por vía fecal oral. Los síntomas relacionados con las hepatitis virales agudas son variables e inespecíficos. El diagnóstico de certeza se realiza mediante las pruebas serológicas y técnicas de biología molecular para la identificación del virus. No existe tratamiento específico para esta infección.

Introduction: Hepatitis is an inflammatory disease that affects the liver. The hepatitis A virus produces a generally self-limited acute infectious picture in humans, for which there is no specific treatment. Objective: To update on current behavior and management of hepatitis A virus infection. Methods: A bibliographic review was carried out during September and October 2021, consulting 156 articles in English and Spanish from databases such as SciELO, PubMed, Lilacs and Medigraphic, of which 30 citations were used. The combination of Boolean terms and operators and theoretical methods such as: analysis-synthesis, induction-deduction and historical-logical was used. Results: The behavior of the infection caused by the hepatitis A virus was addressed, emphasizing its epidemiology, morphological and functional characteristics that allow its infectivity, evolution and clinical manifestations, complications, treatment and current perspectives. Conclusions: The hepatitis A virus produces an acute infectious picture. It occurs both sporadically and epidemically. It is the most common form of acute viral hepatitis. Transmission is person-to-person by the fecal oral route. Symptoms related to acute viral hepatitis are variable and nonspecific. The diagnosis of certainty is carried out by means of serological tests and molecular biology techniques for the identification of the virus. There is no specific treatment for this infection.

El HeberNasvac®, una opción en el tratamiento de la hepatitis B crónica

Introducción: En Cuba se produce la vacuna HeberNasvac® para el tratamiento de la hepatitis B crónica. Su relevancia radica en lograr resultados de control virológico sostenido en una mayor proporción de pacientes. Objetivo: Evaluar seguridad y efectividad de la vacuna terapéutica HeberNasvac® en el tratamiento de la hepatitis B crónica, en la provincia Camagüey en el periodo comprendido de enero de 2019 a diciembre de 2020. Métodos: Se realizó un estudio cuasi experimental de intervención terapéutica, en pacientes atendidos en la Consulta Provincial de hepatitis virales crónicas. El universo estuvo constituido por 24 pacientes adultos, con carga viral detectable al inicio del estudio. La fuente primaria de la investigación estuvo dada por la historia clínica. Resultados: En el primer ciclo fueron más frecuentes la cefalea y los estornudos; y en el segundo ciclo la fiebre y el malestar general. Al concluir el tratamiento la mayoría mostraron mejoría de resultados de las pruebas de función hepática. Antes del tratamiento el mayor número de pacientes presentó una carga viral detectable por encima de 250 copias/mL y después de haber recibido tratamiento varios de los casos resultaron carga no detectable. El tratamiento se consideró con mediana seguridad en el mayor número de pacientes y la efectividad fue alta. Conclusiones: Se presentaron más eventos adversos en el segundo ciclo del tratamiento. Las pruebas de función hepática mostraron mejoría al concluir tratamiento. La carga viral después del tratamiento presentó un descenso. El tratamiento mostró mediana seguridad y efectividad alta.

Introduction: Cuba produces the HeberNasvac® vaccine for the treatment of chronic hepatitis B. Its relevance lies in achieving sustained virological control results in a greater proportion of patients. Objective: To evaluate the safety and effectiveness of the therapeutic vaccine HeberNasvac® in the treatment of chronic hepatitis B, in the province of Camagüey in the period from January 2019 to December 2020. Methods: A quasi-experimental study of therapeutic intervention was carried out in patients treated at the Provincial Consultation of Chronic Viral Hepatitis. The universe consisted of 24 adult patients, with detectable viral load at the beginning of the study. The primary source of the investigation was given by the medical history. Results: In the first cycle, headache and sneezing were more prevalent; and in the second cycle, fever and general malaise were more prevalent. At the end of the treatment, the majority showed improvement in the results of liver function tests. Before treatment, the largest number of patients had a detectable viral load above 250 copies / mL and after receiving treatment, several of the cases resulted in an undetectable load. The treatment was considered to be of medium safety in the largest number of patients and the effectiveness was high. Conclusions: There were more adverse events in the second cycle of treatment. Liver function tests showed improvement at the end of treatment. The viral load after treatment showed a decrease. The treatment showed medium safety and high effectiveness.

Crime, quarantine, and the U.S. coronavirus pandemic.

RESEARCH SUMMARY: Priorresearch has produced varied results regarding the impact of the coronavirus pandemic on crime rates, depending on the offenses and time periods under investigation. The current study of weekly offense rates in large U.S. cities is based on a longer time period, a greater number of offenses than prior research, and a varying number of cities for each offense (max = 28, min = 13, md = 20). We find that weekly property crime and drug offense rates, averaged across the cities, fell during the pandemic. An exception is motor vehicle theft, which trended upward after pandemic-related population restrictions were instituted in March 2020. Robbery rates also declined immediately after the pandemic began. Average weekly homicide, aggravated assault, and gun assault rates did not exhibit statistically significant increases after March. Beginning in June 2020, however, significant increases in these offenses were detected, followed by declines in the late summer and fall. Fixed-effects regression analyses disclose significant decreases in aggravated assault, robbery, and larceny rates associated with reduced residential mobility during the pandemic. These results support the routine activity hypothesis that the dispersion of activity away from households increases crime rates. The results for the other offenses are less supportive. POLICY IMPLICATIONS: Quarantines and lockdowns, although necessary to reduce contagious illness, are not desirable crime-control devices. An object lesson of the coronavirus pandemic is to redouble effective crime reduction strategies and improve police-community relations without confining people to their homes.

Comportamiento de las enfermedades inflamatorias del intestino en el Servicio Provincial de Coloproctología de Camagüey / Behavior of the inflammatory diseases of the intestine in Camagüey's provincial Colon-proctology service

RESUMEN Fundamento: la enfermedad inflamatoria del intestino se define como una afectación inflamatoria crónica del tubo digestivo de causa desconocida que evoluciona de modo recurrente con brotes, remisiones que pueden presentar diversas complicaciones y manifestaciones extra digestivas. Objetivo: describir el comportamiento de las enfermedades inflamatorias del intestino en el Servicio Provincial de Coloproctología del Hospital Universitario Manuel Ascunce Domenech. Métodos: se realizó un estudio descriptivo y transversal, desde abril de 2016 hasta abril de 2018. El universo de estudio estuvo constituido por los 100 pacientes diagnosticados por estudios de endoscopía y biopsia de enfermedad inflamatoria del intestino en el servicio ya mencionado. La fuente primaria de la investigación estuvo dada por un formulario diseñado por los autores. Resultados: los pacientes diagnosticados de colitis ulcerosa ocuparon el primer lugar con predominio de la edad de diagnóstico entre 30-39 años; casi la mitad de los pacientes estudiados presentaron antecedentes familiares positivos de enfermedad inflamatoria intestinal, la localización distal fue la más frecuente para la colitis ulcerosa, mientras que para el Crohn solo fue la perineal reportado con un solo caso; las manifestaciones clínicas intestinales más frecuentes correspondieron a las diarreas. Conclusiones: la colitis ulcerativa resultó ser más frecuente que la enfermedad de Crohn y que la colitis inespecífica con la edad de diagnóstico entre 30-39 años, con predominio de antecedentes familiares de primer orden de la enfermedad, en la colitis ulcerosa prevaleció la localización distal y en el Crohn fue perineal donde la diarrea fue el síntoma más frecuente en ambas.

ABSTRACT Background: the inflammatory disease of the intestine defines like an inflammatory chronic affectation of the alimentary canal of unknown etiology that evolves of recurrent mode with sprouts and remissions and can present various complications and extra digestive manifestations. Objective: to describe the behavior of the inflammatory diseases of the intestine in Provincial Colon-proctology Service of the Teaching Hospital Manuel Ascunce Domenech. Methods: a descriptive cross-sectional study was carried out from April, 2016 to April, 2018. The universe of study was constituted for the 100 patients diagnosed by endoscopy's studies and biopsy of inflammatory disease of the intestine in the aforementioned service. The investigation's primary source was given for a fill-out form designed by the authors. Results: the patients diagnosed of ulcerous colitis occupied the first place with a predominance of age diagnosis between 30-39 years old, almost half of the studied patients presented familiar background of intestinal inflammatory disease, the distal localization showed the most frequent for the ulcerative idiopathic colitis, while for Crohn the most frequent localization was perinea localization with just a case; the clinical intestinal manifestation more frequent corresponded to the diarrheas. Conclusions: the ulcerative colitis turned out to be more frequent than the disease of Crohn and then unspecified colitis with an age diagnosis between 30-39 years old; and with predominance of first-rate family record of the disease; in the ulcerative colitis prevailed the location distal and in the Crohn it was perineal being the diarrhea the most frequent symptom in both.

Predictive Markers of Immunogenicity and Efficacy for Human Vaccines.

Vaccines represent one of the major advances of modern medicine. Despite the many successes of vaccination, continuous efforts to design new vaccines are needed to fight "old" pandemics, such as tuberculosis and malaria, as well as emerging pathogens, such as Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination aims at reaching sterilizing immunity, however assessing vaccine efficacy is still challenging and underscores the need for a better understanding of immune protective responses. Identifying reliable predictive markers of immunogenicity can help to select and develop promising vaccine candidates during early preclinical studies and can lead to improved, personalized, vaccination strategies. A systems biology approach is increasingly being adopted to address these major challenges using multiple high-dimensional technologies combined with in silico models. Although the goal is to develop predictive models of vaccine efficacy in humans, applying this approach to animal models empowers basic and translational vaccine research. In this review, we provide an overview of vaccine immune signatures in preclinical models, as well as in target human populations. We also discuss high-throughput technologies used to probe vaccine-induced responses, along with data analysis and computational methodologies applied to the predictive modeling of vaccine efficacy.

The Heteromeric Complex Formed by Dopamine Receptor D5 and CCR9 Leads the Gut Homing of CD4+ T Cells Upon Inflammation.

BACKGROUND AND AIMS: CD4+ T cells constitute central players in inflammatory bowel diseases (IBDs), driving inflammation in the gut mucosa. Current evidence indicates that CCR9 and the integrin α4ß7 are necessary and sufficient to imprint colonic homing on CD4+ T cells upon inflammation. Interestingly, dopaminergic signaling has been previously involved in leukocyte homing. Despite dopamine levels are strongly reduced in the inflamed gut mucosa, the role of dopamine in the gut homing of T cells remains unknown. Here, we study how dopaminergic signaling affects T cells upon gut inflammation. METHODS: Gut inflammation was induced by transfer of naïve T cells into Rag1-/- mice or by administration of dextran sodium sulfate. T cell migration and differentiation were evaluated by adoptive transfer of congenic lymphocytes followed by flow cytometry analysis. Protein interaction was studied by bioluminescence resonance energy transfer analysis, bimolecular fluorescence complementation, and in situ proximity ligation assays. RESULTS: We show the surface receptor providing colonic tropism to effector CD4+ T cells upon inflammation is not CCR9 but the complex formed by CCR9 and the dopamine receptor D5 (DRD5). Assembly of the heteromeric complex was demonstrated in vitro and in vivo using samples from mouse and human origin. The CCR9:DRD5 heteroreceptor was upregulated in the intestinal mucosa of IBD patients. Signaling assays confirmed that complexes behave differently than individual receptors. Remarkably, the disruption of CCR9:DRD5 assembly attenuated the recruitment of CD4+ T cells into the colonic mucosa. CONCLUSIONS: Our findings describe a key homing receptor involved in gut inflammation and introduce a new cell surface module in immune cells: macromolecular complexes formed by G protein-coupled receptors integrating the sensing of multiple molecular cues.

The Route of Vaccine Administration Determines Whether Blood Neutrophils Undergo Long-Term Phenotypic Modifications.

Innate immunity modulates adaptive immunity and defines the magnitude, quality, and longevity of antigen-specific T- and B- cell immune memory. Various vaccine and administration factors influence the immune response to vaccination, including the route of vaccine delivery. We studied the dynamics of innate cell responses in blood using a preclinical model of non-human primates immunized with a live attenuated vaccinia virus, a recombinant Modified vaccinia virus Ankara (MVA) expressing a gag-pol-nef fusion of HIV-1, and mass cytometry. We previously showed that it induces a strong, early, and transient innate response, but also late phenotypic modifications of blood myeloid cells after two months when injected subcutaneously. Here, we show that the early innate effector cell responses and plasma inflammatory cytokine profiles differ between subcutaneous and intradermal vaccine injection. Additionally, we show that the intradermal administration fails to induce more highly activated/mature neutrophils long after immunization, in contrast to subcutaneous administration. Different batches of antibodies, staining protocols and generations of mass cytometers were used to generate the two datasets. Mass cytometry data were analyzed in parallel using the same analytical pipeline based on three successive clustering steps, including SPADE, and categorical heatmaps were compared using the Manhattan distance to measure the similarity between cell cluster phenotypes. Overall, we show that the vaccine per se is not sufficient for the late phenotypic modifications of innate myeloid cells, which are evocative of innate immune training. Its route of administration is also crucial, likely by influencing the early innate response, and systemic inflammation, and vaccine biodistribution.

Perinatal morbidity and mortality of children born to mothers with chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) associated with pregnancy increases the risk of maternal and fetal complications. OBJECTIVE: To determine perinatal morbidity and mortality of children born to mothers with mild and moderate CKD during pregnancy. METHODS: Retrospective study of medical records of women with mild and moderate CKD during pregnancy cared for at La Raza National Medical Center between 2010 and 2016. RESULTS: There were 142 patients, 99 (69.72%) with mild CKD and 43 (30.28%) with moderate CKD; 79 neonates (55.63%) reached full term, 28 (19.71%) had growth restriction; 44 (30.98%), low birth weight and 54 (38.02%) were admitted to the neonatal intensive care unit (NICU); and four women (4.04%) had an abortion; in four (2.81%), their children had intrauterine death, and in 10 (7.04%), neonatal death. High blood pressure (odds ratio [OR] = 6.93) and hemoglobin < 11 g/dL (OR = 2.48) were risk factors for prematurity. CONCLUSION: A relationship was found between anemia and blood pressure levels and risk for prematurity, low Apgar, and NICU admission.

INTRODUCCIÓN: La enfermedad renal (ER) crónica asociada al embarazo incrementa el riesgo de complicaciones maternas y fetales. OBJETIVO: Determinar la morbilidad y mortalidad perinatal del hijo de madre con enfermedad renal leve y moderada del embarazo. MÉTODOS: Estudio retrospectivo de expedientes de mujeres con ER leve y moderada del embarazo atendidas en el Centro Médico Nacional La Raza entre 2010 y 2016. RESULTADOS: Se trató de 142 pacientes, 99 (69.72 %) con ER leve y 43 (30.28 %) con ER moderada; 79 (55.63 %) neonatos llegaron a término, 28 (19.71 %) presentaron restricción de crecimiento; 44 (30.98 %), peso bajo al nacimiento y 54 (38.02 %) ingresaron a la unidad de cuidados intensivos neonatales; cuatro (4.04 %) mujeres presentaron aborto, en cuatro (2.81 %) sus hijos presentaron muerte intrauterina y en 10 (7.04 %), muerte neonatal. La presión arterial alta (RM = 6.93) y la hemoglobina < 11g/dL (RM = 2.48) constituyeron factores de riesgo para prematurez. CONCLUSIÓN: Se encontró relación entre la anemia y las cifras de tensión arterial como riesgo para prematurez, Apgar bajo e ingreso a unidad de cuidados intensivos neonatales.