Expanding the chemical space of enol silyl ethers: catalytic dicarbofunctionalization enabled by iron catalysis.

Enol silyl ethers are versatile, robust, and readily accessible substrates widely used in chemical synthesis. However, the conventional reactivity of these motifs has been limited to classical two electron (2-e) enolate-type chemistry with electrophilic partners or as radical acceptors in one electron (1-e) reactivity leading, in both cases, to exclusive α-monofunctionalization of carbonyls. Herein we describe a mild, fast, and operationally simple one-step protocol that combines readily available fluoroalkyl halides, silyl enol ethers, and, for the first time, hetero(aryl) Grignard reagents to promote selective dicarbofunctionalization of enol silyl ethers. From a broader perspective, this work expands the synthetic utility of enol silyl ethers and establishes bisphosphine-iron catalysis as enabling technology capable of orchestrating selective C-C bond formations with short-lived α-silyloxy radicals with practical implications towards sustainable chemical synthesis.

Evaluation of oral telmisartan administration as a suppression test for diagnosis of primary hyperaldosteronism in cats.

BACKGROUND: Development of a telmisartan-based suppression test may facilitate the diagnosis of primary hyperaldosteronism (PHA) in cats, which remains difficult today. OBJECTIVES: To develop a telmisartan suppression test (TST) that is safe, and able to suppress aldosterone secretion in healthy cats but not in cats with PHA. ANIMALS: Ten healthy cats and 6 cats with PHA. METHODS: Prospective study using a placebo-controlled crossover design to investigate a TST in healthy cats, and evaluation of TST in cats with PHA. Plasma aldosterone concentration, potassium concentration, and systolic blood pressure (SBP) were measured before (T0), and 1 hour (T1) and 1.5 hours after (T1.5) PO administration of 1 mg/kg of telmisartan, 2 mg/kg of telmisartan or placebo. RESULTS: Median age in healthy cats was 3 years old (range, 1-7). In healthy cats, a telmisartan dose of 2 mg/kg significantly decreased aldosterone concentration at T1 and T1.5 compared with T0. Placebo had no significant effect on aldosterone concentration. In cats diagnosed with PHA, a 2-mg/kg dose of telmisartan did not induce any significant change in aldosterone concentration at T1 or T1.5 compared with T0. No adverse effects of telmisartan (e.g., hyperkalemia, systemic hypotension) were observed in any cats. CONCLUSIONS AND CLINICAL IMPORTANCE: The oral TST shows promise as a diagnostic test for the diagnosis of PHA in cats.

Pathogenicity of Avibacterium paragallinarum Strains from Peru and the Selection of Candidate Strains for an Inactivated Vaccine.

Worldwide, Avibacterium paragallinarum is the aetiological agent of infectious coryza in poultry. Vaccines are the best means of control, helping reduce clinical signs and colonization of this bacterium. Most vaccines are based on international reference strains, or, lately, regional strains, but, generally, without any information regarding their virulence. The characterization of the pathogenicity of 24 Av. paragallinarum strains of the three Page serogroups, including four variant strains of serogroup B, all isolated from infectious coryza outbreaks in Peru, was performed. After experimental inoculation into the infraorbital sinuses, information regarding their capacity to induce infectious coryza typical clinical signs, spreading, and colonization was recorded. Furthermore, after intraperitoneal inoculation, septicaemia and death were registered. Differences among strains in these parameters were observed, even within strains from the same serogroup. Finally, the four most pathogenic strains, one from each serogroup, were chosen to formulate an experimental vaccine that was tested successfully against homologous challenges in reducing clinical signs and colonization in vaccinated birds compared to unvaccinated ones. This is the first time that Av. paragallinarum strains from Peru were studied thoroughly for their virulence in a search for improving vaccine formulation.

The Efficacy of a Trivalent Inactivated Salmonella Vaccine Combined with the Live S. Gallinarum 9R Vaccine in Young Layers after Experimental Infections with S. Enteritidis, S. Typhimurium, and S. Infantis.

Worldwide, poultry infections by Salmonella are the cause of significant economic losses, not only due to reduced production (due to fowl typhoid disease), but also considering the efforts and control measures that must be constantly applied, especially due to zoonotic serovars. Poultry is a common reservoir of Salmonella and its transmission into the food chain is a risk for humans. The vaccination of layers plays an important role in the overall efforts to prevent Salmonella infections. An inactivated trivalent vaccine was prepared with S. Enteritidis, S. Typhimurium, and S. Infantis strains. Infection trials were performed to evaluate the efficacy of three vaccination schedules using inactivated and live S. Gallinarum 9R vaccines. For this purpose, at week 5 of life, one subcutaneous dose of live S. Gallinarum 9R vaccine (1-5 × 107 CFU) was given to Groups 1 and 2. At weeks 8 and 11 of life, chickens were also vaccinated with one (Group 1) or two (Groups 2 and 3) intramuscular doses of the inactivated oil-adjuvant trivalent vaccine (1 × 108 CFU/dose of each antigen). Group 4 consisted of chickens that remained unvaccinated (control). At week 14 of life, the efficacy of the vaccination plans was evaluated in three separate inoculation trials with S. Enteritidis, S. Typhimurium, or S. Infantis. After vaccination with the inactivated vaccine, homologous antibody production was observed, and after challenge, a significant reduction in the faecal shedding, invasion, and colonization of S. Typhimurium and S. Infantis was achieved by all vaccination schedules, while the vaccination with at least one dose of the live S. Gallinarum 9R vaccine was necessary to obtain such a significant protection against S. Enteritidis infection.

Adherencia al tratamiento y nivel de control en pacientes asmáticos en un hospital de Lima

Objetivo: Describir la asociación entre el control del asma y la adherencia al tratamiento en los pacientes del Hospital Nacional Dos de Mayo en los años 2019-2020. Materiales y métodos: Se realizó un estudio cuantitativo, descriptivo y retrospectivo, de tipo clínico, durante el periodo 2019-2020, en pacientes asmáticos del Hospital Nacional Dos de Mayo (HNDM) para evaluar la relación entre control del asma y adherencia al tratamiento en los pacientes atendidos en el Consultorio de Asma del Servicio de Neumología. La información fue recolectada de las historias clínicas y los datos registrados fueron los siguientes: test de adherencia a los inhaladores (TAI), test de control de asma (ACT), edad, sexo, tratamiento instaurado, tiempo de enfermedad y la valoración nutricional, a través de la revisión de historias clínicas. El análisis estadístico se realizó con el software IBM SPSS Statistics versión 22, y para determinar la asociación se realizó la prueba estadística X2. Resultados: Se evaluaron 187 pacientes mediante historias clínicas, 84 hombres (44,92 %) y 103 mujeres (55,08 %). El promedio de edad fue de 59,42 ± 15,08 años (solo los mayores de edad fueron considerados en el estudio). Mediante el análisis de los datos de las historias clínicas, se determinó que había 86 pacientes controlados (45,99 %) y que 48 pacientes eran adherentes (25,67 %). El corticoide inhalado (CSI) fue el tratamiento más usado (50,80 %). El tipo inconsciente fue la modalidad más frecuente de paciente incumplidor (64,17 %). El promedio de tiempo de enfermedad, en años, estuvo en 21,78 ± 16,75. Conclusiones: El 75% de los pacientes asmáticos con adherencia al tratamiento controlan la enfermedad.

Objective: To describe the association between asthma control and adherence to treatment among patients of the Hospital Nacional Dos de Mayo from 2019 to 2020. Materials and methods: A quantitative, descriptive and retrospective clinical study was carried out in asthma patients treated at the asthma office of the Pneumology Service from the Hospital Nacional Dos de Mayo (HNDM) from 2019 to 2020 to assess the relationship between asthma control and adherence to treatment. The following data was collected from the medical records: test of adherence to inhalers (TAI) results, asthma control test (ACT) results, age, sex, treatment, disease period and nutritional assessment. The statistical analysis was performed using IBM SPSS Statistics statistical software version 22 and the association between both variables was determined by the chi-square test. Results: One hundred eighty-seven (187) patients were evaluated through their medical records, out of which 84 were men (44.92 %) and 103 were women (55.08 %). The mean age was 59.42 ± 15.08 years (only adults participated in the study). Data from the medical records determined that 86 patients (45.99 %) had their asthma under control and 48 showed adherence to treatment (25.67 %). Inhaled corticosteroid (ICS) was the most widely used treatment (50.80 %). Irresponsible people were the most frequent noncompliant patients (64.17 %). The mean disease period was 21.78 ± 16.75. Conclusions: Seventy-five percent (75 %) of asthma patients who adhere to treatment are able to control their condition.

Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients.

INTRODUCTION: Using mathematical modelling allows to select a treatment's regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. RESULTS: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1-32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine's AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). MATERIALS AND METHODS: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. CONCLUSIONS: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγ(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12(-)IL-10(-)CCL1(-)CD163(-)CD14(+) cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.