Zeolitic imidazolate frameworks activate endosomal Toll-like receptors and potentiate immunogenicity of SARS-CoV-2 spike protein trimer.

Nanomaterials offer unique opportunities to engineer immunomodulatory activity. In this work, we report the Toll-like receptor agonist activity of a nanoscale adjuvant zeolitic imidazolate framework-8 (ZIF-8). The accumulation of ZIF-8 in endosomes and the pH-responsive release of its subunits enable selective engagement with endosomal Toll-like receptors, minimizing the risk of off-target activation. The intrinsic adjuvant properties of ZIF-8, along with the efficient delivery and biomimetic presentation of a severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain trimer, primed rapid humoral and cell-mediated immunity in a dose-sparing manner. Our study offers insights for next-generation adjuvants that can potentially impact future vaccine development.

A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines.

Decentralized manufacture of thermostable mRNA vaccines in a microneedle patch (MNP) format could enhance vaccine access in low-resource communities by eliminating the need for a cold chain and trained healthcare personnel. Here we describe an automated process for printing MNP Coronavirus Disease 2019 (COVID-19) mRNA vaccines in a standalone device. The vaccine ink is composed of lipid nanoparticles loaded with mRNA and a dissolvable polymer blend that was optimized for high bioactivity by screening formulations in vitro. We demonstrate that the resulting MNPs are shelf stable for at least 6 months at room temperature when assessed using a model mRNA construct. Vaccine loading efficiency and microneedle dissolution suggest that efficacious, microgram-scale doses of mRNA encapsulated in lipid nanoparticles could be delivered with a single patch. Immunizations in mice using manually produced MNPs with mRNA encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain stimulate long-term immune responses similar to those of intramuscular administration.

Genomic alterations in a cohort of pediatric acute myeloid leukemia patients at two cancer centers in Colombia.

Few studies identifying genomic aspects in pediatric acute myeloid leukemia patients in Latin American countries have been reported. The aim of this study was to identify genomic alterations, clinical characteristics and outcomes in a cohort of pediatric AML patients. This descriptive observational cohort study included patients with confirmed de novo acute myeloid leukemia up to 18 years of age. Cytogenetics and conventional FISH analysis, next-generation sequencing and PCR testing were performed. The correlation of genomic data with treatment response and outcomes were analyzed. Of the 51 patients analyzed, 67.4% had a cytogenetic abnormality and 74.5% had a genetic variant. FLT3 variants (ITD or TKD D835) were found in 27.4%, followed by NRAS (21.6%), KRAS (13.7%) and WT1 and KIT (11.8%). Patients were stratified by risk (66.6% high-risk) after the end of induction. FLT3-ITD was associated with relapse (OR 11.25; CI 1.89-66.72, p 0.006) and NRAS with death during induction (OR 16.71; CI 1.51-184.59, p 0.022). Our study highlights the importance of rapid incorporation of genetic testing in pediatric AML in Colombia, as it directly affects treatment decisions and outcomes. Incorporation of targeted therapies with conventional chemotherapy is an increasingly urgent need in pediatric patients.

Pharmacogenetics of ABCB1, CDA, DCK, GSTT1, GSTM1 and outcomes in a cohort of pediatric acute myeloid leukemia patients from Colombia.

BACKGROUND AND AIM: Different studies have shown pharmacogenetic variants related to drug toxicity in acute myeloid leukemia (AML) patients. Our aim was to identify the association between ABCB1, CDA, DCK, GSTT1, and GSTM1 variants with clinical outcomes and toxicity in pediatric patients with AML. METHODS: Fifty-one confirmed de novo AML pediatric patients were included. A SNaPshot™ assay and conventional PCR were used to evaluate ABCB1, CDA, DCK, GSTT1, and GSTM1 variants. Clinical outcomes and toxicity associations were evaluated using odds ratios and Chi-square analysis. RESULTS: Patients carrying ABCB1 (1236C > T, rs1128503) GG genotype in had a 6.8 OR (CI 95% 1.08-42.73, p = .044) for cardiotoxicity as compared to patients carrying either AA or GA genotypes 0.14 OR (CI 95% 0.023-0.92, p = .044). For ABCB1 (1236G > A rs1128503/2677C > A/T rs2032582/3435G > A rs1045642) AA/AA/AA combined genotypes had a strong association with death after HSTC OR 13.73 (CI 95% 1.94-97.17, p = .009). Combined genotypes GG/CC/GG with CDA (79A > C, rs2072671) CA genotype or CDA (-451G > A, rs532545) CT genotype, had a 4.11 OR (CI 95% 2.32-725, p = .007) and 3.8 OR (CI 95% 2.23-6.47, p = .027) with MRD >0.1% after first chemotherapy cycle, respectively. CONCLUSION: Our results highlight the importance of pharmacogenetic analysis in pediatric AML, particularly in populations with a high degree of admixture, and might be useful as a future tool for patient stratification for treatment.

Philadelphia-like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia.

BACKGROUND: Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America. AIM: This study evaluated the frequency and clinical and biological characteristics of Ph-like ALL in a pediatric cancer center in Colombia. METHODS: The Ph-like genetic profile was analyzed by a low-density array (LDA). Samples from patients with Ph-like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification. RESULTS: Data from 121 patients were analyzed. Fifteen patients (12.4%) had Ph-like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph-like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%). CONCLUSIONS: Ph-like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.

Eficacia de racecadotrilo en el tratamien-to de la enfermedad diarreica aguda, en niños de 3 a 36 meses, en el servicio de emer-gencia del Hospital Vicente Corral Mos-coso. Ensayo clínico controlado ciego. 2014 / Racecadotril effectiveness in the treatment of acute diarrhea in chil-dren from 3 to 36 months. Emergency department, Hospital Vicente Corral Mosocoso. Blind clinical controlled trial. 2014

Objetivo:Determinar la eficacia del tratamiento combinado de sales de rehidratación oral (SRO) y racecadotrilo frente al uso de SRO y placebo en los niños de 3 a 36 meses con enfermedad diarreica aguda (EDA), en el Servicio de Emergencia del Hospital Vicente Corral Moscoso (HVCM). Método:Ensayo clínico controlado ciego, en niños de 3 a 36 meses del servicio de emergencia del HVCM, con cuadro de enfermedad diarreica aguda, sin deshidratación o con deshidratación leve o moderada, que no necesiten hos-pitalización, sin tratamiento antidiarreico o antibiótico previo, cuyos padres o representantes legales firmen el consentimiento informado. Se reclutaron 79 pacientes, 45 en el grupo SRO más racecadotrilo y 34 grupo SRO más placebo. Resultados:Los grupos fueron comparables clínicamente, los pacientes del grupo SRO más racecadotrilo mostraron una diferencia significativa en el número de diarreas por día a partir de las 48 horas [2.7 (DS: ±1.5), grupo SRO más pla-cebo 4.1 (DS: ±2,6)] con una p: 0.012; a las 72 horas, el grupo racecadotrilo [2.2 (DS: ±1.7), y grupo placebo 3.3 (DS: ±2,5)] con p: 0.027. No se encontró diferencia significativa en las primeras 24 horas (p: 0.27). Conclusiones:Racecadotrilo es un medicamento eficaz en disminuir el número de diar-reas a partir de las 48 horas, en el tratamiento inicial de niños con EDA, acompañando a la terapia con SRO en un grupo de pacientes atendidos en el Hospital Vicente Corral Moscoso.

Objective:To determine the efficacy of the combined treatment of oral rehydration salts (ORS) and racecadotril against the use of ORS and placebo in children aged between 3 and 36 months with acute diarrhea disease (ADD), in the Vicente Corral Moscoso Hospital (VCMH) emergency service. Method:It is a blind controlled clinical trial in children from 3 to 36 months of the VCMH emergency service, with acute diarrheic disease, without dehydration or mild or moderate dehydration; they do not need hospitalization, without previous antidiarrheal treatment or antibiotic, if their parents or legal representatives sign the informed consent. A total of 79 patients were recruited, 45 in the ORS plus racecadotril group and 34 ORS plus placebo group. Results:The groups were clinically comparable, the patients in the ORS plus racecadotril group showed a significant difference in the number of diarrheas per day from 48 hours [2.7 (DS: ± 1.5), the ORS plus placebo group 4.1 (DS: ± 2.6)] with a p: 0.012; at 72 hours, the racecadotril group [2.2 (DS: ± 1.7), and placebo group [3.3 (DS: ± 2.5)] with p: 0.027. No significant difference was found in the first 24 hours (p: 0.27). Conclusions:Racecadotril is an effective medication to reduce the number of diarrhea after 48 hours, in the initial treatment of children with ADD accompanying ORS therapy in a group of patients treated at the Vicente Corral Moscoso Hospital.

A survey of particulate matter on california dairy farms.

Over the past 30 yr, individual California dairy operations have grown in size; however, little is known about the distribution and determinants of particulate matter (PM) concentrations on these dairies. Elevated exposure to PM is associated with respiratory and cardiovascular health effects, particularly in occupational settings. The purpose of this study was to quantify the concentrations of PM and all inhalable PM (0-100 µm) on California dairies. Samplers were placed at various locations (e.g., milking parlor, grain storage area, drylot corral, and freestall barns) on 13 different dairies to collect PM and all inhalable PM during the 2008 summer months. The PM and all inhalable PM concentrations varied between different areas on a dairy and from dairy to dairy. Geometric mean concentrations for PM and inhalable PM were 24 µg m (range, 2-116 µg m) and 332 µg m (range, 74-1690 µg m). A key variable for explaining variation in PM concentrations with a mixed effects model was regional background ambient concentrations of PM No significant differences were observed in mean concentrations between upwind and downwind fence line concentrations (adjusted geometric mean ratio [AGMR] = 0.7; 95% CI, 0.4-1.3), although significant differences were found between upwind and central location mean values (AGMR = 0.5; 95% CI, 0.3-0.8; < 0.01). These results indicate dairy PM sources and, thus, elevated occupational exposure. Covariates, such as the age of the dairy and number of cows in the freestall barn and drylot corral, were important variables in explaining PM concentration variability. Levels of PM were lower compared with dairies in other U.S. states and other countries.

Occupational exposure to particulate matter and endotoxin for California dairy workers.

Occupational exposure of dairy workers to particulate matter (PM) and endotoxin has been considered by some to be of potential concern. This paper reports personal exposure concentrations of PM (µg/m3) and endotoxin (EU/m3) for 226 workers from 13 California dairies. Arithmetic mean personal concentrations for PM2.5, inhalable PM and endotoxin were 48 µg/m3 (N = 222), 987 µg/m3 (N = 225) and 453 EU/m3 (N = 225), respectively. Using mixed effects models, time spent re-bedding of freestall barns versus any other job conducted on a dairy led to the highest exposure for PM2.5, inhalable PM, and endotoxin. Personal exposure concentrations were found to be greater than those reported for ambient area based concentrations at the same dairies. A pseudo R-square approach revealed that one area based measure combined with time spent performing tasks explained a significant portion of variation in personal exposure concentrations.

Activation of inflammatory responses in human U937 macrophages by particulate matter collected from dairy farms: an in vitro expression analysis of pro-inflammatory markers.

BACKGROUND: The purpose of the present study was to investigate activation of inflammatory markers in human macrophages derived from the U937 cell line after exposure to particulate matter (PM) collected on dairy farms in California and to identify the most potent components of the PM. METHODS: PM from different dairies were collected and tested to induce an inflammatory response determined by the expression of various pro-inflammatory genes, such as Interleukin (IL)-8, in U937 derived macrophages. Gel shift and luciferase reporter assays were performed to examine the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like-receptor 4 (TLR4). RESULTS: Macrophage exposure to PM derived from dairy farms significantly activated expression of pro-inflammatory genes, including IL-8, cyclooxygenase 2 and Tumor necrosis factor-alpha, which are hallmarks of inflammation. Acute phase proteins, such as serum amyloid A and IL-6, were also significantly upregulated in macrophages treated with PM from dairies. Coarse PM fractions demonstrated more pro-inflammatory activity on an equal-dose basis than fine PM. Urban PM collected from the same region as the dairy farms was associated with a lower concentration of endotoxin and produced significantly less IL-8 expression compared to PM collected on the dairy farms. CONCLUSION: The present study provides evidence that the endotoxin components of the particles collected on dairies play a major role in mediating an inflammatory response through activation of TLR4 and NF-κB signaling.

Screening for addictive disorders within a workers' compensation clinic: an exploratory study.

We conducted a cross-sectional study investigating the extent of addictive disorders within a workers' compensation (WC) clinic. We also examined the feasibility of substance abuse screening within the same clinic. In 2009 , 100 patients were asked to complete the World Health Organization's Alcohol, Smoking, Substance Involvement Screening Test (WHO-ASSIST) and the Current Opioid Misuse Measure (COMM). According to the WHO-ASSIST, we found that 46% of WC patients required intervention for at least one substance-related disorder (25% tobacco, 23% sedatives, 8% opioids), and according to the COMM, 46% screened positive for prescription opioid misuse. Importantly, the addition of this screening was brief, economical, and well accepted by patients. Further research should analyze the costs and benefits of detection and intervention of substance-related disorders in this setting.

Factores epidemiológicos e incidencia del cáncer gástrico en población hospitalaria rural de Manabí / Factors epidemiologists and incidence of the gastric cancer in rural hospitable population in Manabí

Motivados por la alta incidencia y mortalidad del cáncer gástrico en el Ecuador, patología que se constituye en la principal causa de muerte de los ecuatorianos dentro de todos los tumores, especialmente en la Provincia de Manabí, que en esta última década se ha constituido en un grave problema de centros de diagnósticos. Después de haber constatado en 1987 que el 19,3xciento de los cánceres procedían de un área rural ubicada en la zona central de la provincia, iniciamos nuestro primer trabajo de despistaje poblacional en la parroquia Alajuela y posteriormente en San Plácido y Calderón. La encuesta epidemiológica detreminó el consumo de manera importante de alimentos orgánicos de origen animal (carne y/o pescado), conservados en sal en un 75,5xciento de la población y, el análisis de la concentración de nitritos en 30 pozos que reportó 2 con elevada concentración y 8 con un ligero aumento...

Cáncer gástrico diminuto: reporte de caso clínico / Tiny gastric cancer: report of clinical case

Existe un incremento de las afecciones gástricas en nuestro país, especialmente de la úlcera y el cáncer gástrico, constituyéndose este último como la primera causa de mortalidad dentro de todos los tumores, por motivo de su diagnóstico tardío. Nosotros reportamos un caso de cáncer gástrico incipiente-diminuto, con seguimiento clínico y endoscópico de 3 años y medio con intervalos asintomáticos y constatación macroscópica de cicatrizzación y reactivación después del tratamiento médico, compatible con la historia natural que puede presentar en su evolución el cáncer gástrico, de acuerdo a trabajos publicados por autores japoneses. La presencia de helicobacter pylori fue evidenciada al inicio del estudio por test de ureasa y anatomía patológica. El diagnóstico endoscópico fue el de un cáncer gástrico diminuto (8mm. de diámetro), de tipo IIa+IIc con estudio histológico de adenocarcinoma diferenciado de tipo tubular intramucuso asociado a gastritis crónica atrófica y metaplasia intestinal...