A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.

Adaptación transcultural al español de los instrumentos de tamizaje auditivo para escolares TEAP y ABEL / Transcultural adaptation to Spanish of the hearing screening questionnaires TEAP and ABEL

Introducción: La hipoacusia es una condición prevalente que tiene consecuencias en el desarrollo de los individuos. Cada vez cobran mayor importancia los programas de tamizaje de hipoacusia. Una estrategia involucra la utilización de cuestionarios de tamizaje de hipoacusia. Objetivos: Realizar la adaptación transcultural al español de los instrumentos de tamizaje auditivos ABEL y TEAP. Material y método: Se realizó un estudio de corte transversal de validación de cuestionario en escolares de cuarto básico. Se utilizó la teoría clásica de tests, que incluye validez de criterio, confiabilidad test-retest y consistencia interna. Resultados: Fueron evaluados 100 escolares de San Bernardo. Cincuenta y dos por ciento de la muestra fueron mujeres. El promedio (DE) de edad fue 9,75 (± 0,78) años. Hubo tres casos de hipoacusia bilateral y dos de hipoacusia unilateral. La consistencia interna del test ABEL fue de 0,73. La consistencia interna del test TEAP fue de 0,82. La confiabilidad test-retest del ABEL fue 0,86 y del TEAP fue 0,86. No hubo diferencia entre los puntajes del ABEL ni del TEAP entre niños con hipoacusia y sin hipoacusia. Conclusión: Sería de utilidad utilizar cuestionarios para el tamizaje de hipoacusia en escolares. Estos resultados permiten plantear un programa formal de tamizaje basado en cuestionarios de hipoacusia.

Introduction: Hearinglossis a prevalent condition that has consequences for children's development. As a result, screening programs for hearing loss are of increasing importance. One screening strategy involves the use of questionnaires for people with hearing loss. Aim: Transcultural adaptation to Spanish of the hearing screening in struments ABEL and the TEAP. Material and method: A cross-sectional questionnaire validation study in fourth grade school children was conducted. Classical test theory, including criterion validity, test-retest reliability and internal consistency was used. Results: A total of 100 school children in San Bernardo were evaluated. 52% of the sample were girls. The mean (SD) age was 9.75 (± 0.78) years. There were three cases of bilateral hearing loss and two cases of unilateral hearing loss. The internal consistency of the test was 0.73 for ABEL. The internal consistency was 0.82 for TEAP. The test-retest reliability was 0.86 for ABEL and for TEAP was 0.86. There was no difference between the scores of ABEL or TEAP between the children with hearing loss and those without hearing loss. Conclusions: It would be helpful to use questionnaires to screen for hearing loss in school. These results support a formal screening program based on questionnaires of hearing loss.

Antibody responses to respiratory coronavirus infections of cattle during shipping fever pathogenesis.

Antibody responses against respiratory bovine coronavirus (RBCV) infections were monitored in cattle from the onset of a naturally occurring severe shipping fever (SF) epizootic to complete recovery of affected cattle or fatal outcomes. The infection with RBCV was detected in nasal secretions of 86 cattle, and 81 of them developed acute respiratory tract disease, including fatal pneumonia. Cattle nasally shedding RBCV at the beginning of the epizootic experienced characteristic primary immune responses with specific antibodies for hemagglutinin-esterase (HE) and spike (S) glycoproteins. Virus shedding in nasal secretions of the majority of the cattle ceased between days 7 and 14 with the appearance of HE- and S-specific antibodies. Nasal samples and lung tissues from 9 of the 10 fatal cases had high titers of RBCV, but these cattle had only IgM responses to RBCV infections. Cattle remaining negative in RBCV isolation tests entered this epizootic with antibodies against HE and S. Protection against respiratory tract disease was apparently associated with high level of opsonic and virus-neutralizing IgG2. The HE and S glycoproteins were recognized earliest by the bovine immune system while the N protein induced antibody responses during the later stage of initial infection and the early stage of reinfection. The membrane (M) glycoprotein was the least immunogenic of the major viral structural proteins.

Pasteurella haemolytica ultraviolet-irradiated vaccine by parenteral and aerosol routes compared in the goat model.

Positive control 1 (PC1) (n = 9) goats were injected transthoracically into the left lung with live Pasteurella haemolytica biovar A, serovar 1 (PhA1) in polyacrylate (PA) beads on days 0 and 21. Positive control 2 (PC2) (n = 6) goats were nebulized with live PhA1 and PA beads on days 0 and 21. Negative control (NC) goats (n = 6) were each injected transthoracically into the left lung with PA beads alone on days 0 and 21. Four groups (n = 6) were administered PA beads mixed with ultraviolet (UV) killed PhA1 on days 0 and 21. The treatment doses of bacteria for these groups were principal group 1 (PR1) injected into the left lung (7.7 x 10(10) cfu); PR2, 7.7 x 10(10) UV-killed PhA1 injected subcutaneously (SC); PR3, 7.7 x 10(10) UV-killed PhA1 injected SC only on day 21; PR4, nebulized with PA beads mixed with 5.6 x 10(10) cfu of UV-killed PhA1; and PR5, nebulized with PA beads mixed with 5 x 10(8) cfu of UV-killed PhA1. All goats were challenged transthoracically in the right lung with 1 x 10(8) cfu of live PhA1 on day 42 and necropsied on day 46. The sizes of consolidated lung lesions at the challenge site were used as a measure of immunity. The data show that the introduction of live PhA1 into the lungs of goats, either by injection or aerosolization, offers excellent protection against a subsequent homologous challenge. The data also demonstrate that two transthoracic injections (21 days apart) of UV-killed PhA1 (PR1), and subcutaneous injection of UV-killed PhA1(PR2) also offer excellent protection against a subsequent homologous live PhA1 challenge. One SC injection of UV-killed PhA1 (PR3) appears to offer only partial protection against a subsequent homologous live PhA1 challenge. Inhalation of UV-killed PhA1 mixed with PA beads (PR4 and PR5) induced no protection in goats against a subsequent live PhA1 transthoracic challenge.

Efficacy of a subcutaneously administered, ultraviolet light-killed Pasteurella multocida A:3-containing bacterin against transthoracic challenge exposure in goats.

OBJECTIVE: To determine the effectiveness of Pasteurella multocida biovar A, serovar 3 (Pm A:3) killed by exposure to UV light and incorporated with a polyacrylate bead carrier as a vaccine. ANIMALS: 18 weanling male Spanish goats. PROCEDURE: Prospective, randomized controlled study with 3 treatment groups: positive-control (PC), negative-control (NC), and principal Pm A:3 bacterin (PA) groups. Six PC goats each received live Pm A:3 and polyacrylate beads twice, 22 days apart, by transthoracic injection into the left lung. Six NC goats each received only PA beads twice, 22 days apart, by transthoracic injection. Six principal goats each received Pm A:3 vaccine SC twice, 22 days apart. Fourteen days after the second vaccination, all goats were challenge exposed with live Pm A:3 by transthoracic injection into the right lung, and 4 days later they were euthanatized and necropsied. RESULTS: Mean volume of consolidated lung tissue at the challenge site was 1.75 cm3 for the PC group, 15.18 cm3 for the NC group, and 3.9 cm3 for the PA vaccine group. The NC group had a significantly (P < or = 0.002) larger mean volume of consolidated lung tissue than did the PC and PA groups after challenge exposure. CONCLUSIONS: The PA bacterin and the PC groups developed protective immunity against live Pm A:3 challenge exposure. An SC administered, UV light-killed, Pm A:3 bacterin induced protective immunity similar to that induced by virulent live Pm A:3 injected into the target organ, the lung.

Efficacy of a subcutaneously administered, ultraviolet light-killed Pasteurella haemolytica A1-containing vaccine against transthoracic challenge exposure in goats.

OBJECTIVE: To determine the effectiveness of Pasteurella haemolytica biovar A, serovar 1 (Ph A1) killed by UV light and incorporated with an oil adjuvant or carriers. ANIMALS: 40 weaning male Spanish goats. PROCEDURE: Goats were randomly allotted to 1 of 6 treatment groups: 4 Ph A1 bacterins (agar beads, polyacrylate beads [PA], phosphate-buffered saline solution, Freund's incomplete adjuvant), live Ph A1 with polyacrylate beads (LiPhPA), and polyacrylate beads (UnVac). Each of 4 Ph A1 vaccines was administered SC twice, 21 days apart, to 1 of 4 groups; another group received only PA beads SC, and the last group received live Ph A1 with PA beads by transthoracic injection into the left lung. 14 days after the second vaccination, all goats were challenge exposed with live Ph A1 by transthoracic injection into the right lung, and 4 days later, all goats were euthanatized and necropsied. RESULTS: Mean volume of consolidated right lung tissue was 1.02 cm3 for the LiPhPA group, 168.1 cm3 for the UnVac group, 2.3 cm3 for the Freund's incomplete adjuvant bacterin group, 5.53 cm3 for the PA bacterin group, 9.01 cm3 for the agar beads bacterin group, and 7.51 cm3 for the phosphate-buffered saline solution bacterin group. Mean volume of consolidated lung tissue was significantly different between the UnVac group and the other 5 groups. CONCLUSION: The LiPhPA group and 4 bacterin groups developed protective immunity against live Ph A1 challenge exposure. CLINICAL RELEVANCE: An s.c. administered, UV light-killed Ph A1 bacterin induced protective immunity equal to that induced by virulent live Ph A1 injected into the target organ, the lung.

Identification of Pasteurella haemolytica A1 isolates from market-stressed feeder calves by use of enzyme and antimicrobial susceptibility profiles.

An epidemiologic study of Pasteurella haemolytica serovar 1 (Ph1) in market-stressed feeder calves from 7 farms in eastern Tennessee was conducted. The nasal mucus of each calf was cultured sequentially at the farm of origin (day 0), at an auction market (day 133), and at a feedyard in Texas (days 141, 148, 155, and 169). Of the 103 calves tested, 77 were culture-positive, including 1 on day 0, 1 on day 133, 20 on day 141, 57 on day 148, 50 on day 155, and 14 on day 169. From the 143 Ph1 isolates, 20 enzyme profiles were determined by use of a commercial enzyme system that detects 19 enzymatic reactions; 4 antimicrobial susceptibility profiles were obtained, using the disk-diffusion method, which evaluated susceptibility to 11 antibacterial drugs. All isolates were positive for acid phosphatase and alkaline phosphatase, but were negative for alpha-galactosidase, alpha-mannosidase, beta-glucosidase, beta-glucuronidase, cystine aminopeptidase, N-acetyl-beta-glucosaminidase, and trypsin. Other positive enzyme reactions included: leucine aminopeptidase, 140 Ph1 isolates; phosphohydrolase, 90 isolates; alpha-fucosidase, 63 isolates; esterase (C4), 59 isolates; valine aminopeptidase, 30 isolates; esterase lipase (C8), 24 isolates; beta-galactosidase, 2 isolates; and alpha-glucosidase, chymotrypsin and lipase (C14), 1 isolate each. Thirty-four Ph1 profiles were identified, using combined enzyme and antimicrobial susceptibility profiles. The data indicate that the strains isolated during the feedyard period may have been determined more by farm of origin (P < or = 0.001) than by habitation with calves from other farms while in the feedyard.(ABSTRACT TRUNCATED AT 250 WORDS)