Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Enhanced passive surveillance for early detection of African and classical swine fevers.

African swine fever (ASF) and classical swine fever (CSF) are transboundary animal diseases (TADs) of pigs. Much effort and resources are regularly put into preventing these diseases' introduction in free areas. Passive surveillance activities bring the highest chances for the early detection of TAD incursions because they are routinely and widely conducted at farms, and because these activities focus on the time between introduction and when the first sample is sent for diagnostic testing. The authors proposed the implementation of an enhanced passive surveillance (EPS) protocol based on collecting data through participatory surveillance actions using an objective and adaptable scoring system to aid the early detection of ASF or CSF at the farm level. The protocol was applied in two commercial pig farms for ten weeks in the Dominican Republic, which is a CSF- and ASF-infected country. This study was a proof of concept, based on the EPS protocol to aid detection of substantial variations in the risk score triggering testing. One of the followed farms had score variation, which triggered testing of the animals, although the test results were negative. The study enables assessment of some of the weaknesses associated with passive surveillance and provides lessons applicable to the problem. Results demonstrate the potential for overcoming some issues preventing the broad application of EPS protocols and suggest that standardised approaches may contribute to the early detection of CSF and ASF introductions.

La peste porcine africaine (PPA) et la peste porcine classique (PPC) sont des maladies animales transfrontalières touchant les porcs. De nombreux efforts et ressources sont régulièrement alloués pour prévenir l'introduction de ces maladies dans des zones indemnes. Les activités de surveillance passive offrent les meilleures perspectives de détection précoce des incursions de maladies animales transfrontalières parce qu'elles sont menées de manière systématique et exhaustive dans les élevages, et parce qu'elles se concentrent sur la période entre l'introduction de la maladie et le moment où le premier échantillon est envoyé au laboratoire pour analyse. Les auteurs proposent la mise en oeuvre d'un protocole de surveillance passive renforcée fondé sur la collecte de données via des actions de surveillance participative utilisant un système de notation objectif et adaptable, en vue d'une détection précoce de la PPA et de la PPC dans les élevages. Ce protocole a été appliqué en République dominicaine, pays infecté par la PPA et la PPC, dans deux élevages porcins commerciaux pendant dix semaines. Cette étude était destinée à valider le principe de la méthode et se fondait sur le protocole de surveillance passive renforcée pour mieux détecter les variations substantielles de la note de risque qui conduisent à tester les animaux. L'un des élevages suivis a présenté une variation de cette note, ce qui a conduit à tester les animaux mais les tests se sont révélés négatifs. L'étude permet d'évaluer certaines des faiblesses associées à la surveillance passive et apporte des enseignements applicables à ce problème. Les résultats illustrent le potentiel de l'approche à surmonter certaines des problématiques empêchant l'application extensive des protocoles de surveillance passive renforcée. Ils suggèrent également que des approches normalisées pourraient contribuer à la détection précoce des cas d'introduction de la PPC et de la PPA.

La peste porcina africana (PPA) y la peste porcina clásica (PPC) son enfermedades animales transfronterizas que afectan al cerdo. Periódicamente se dedican grandes esfuerzos y cuantiosos recursos a evitar que estas enfermedades penetren en zonas que están exentas de ellas. Las actividades de vigilancia pasiva son las más eficaces para detectar con prontitud toda incursión de enfermedades animales transfronterizas, no solo por la regularidad y amplitud con que se llevan a cabo en las explotaciones, sino también porque inciden específicamente en el intervalo entre la penetración de una enfermedad y el momento en que se envía la primera muestra para que sea sometida a pruebas de diagnóstico. Los autores propusieron que se aplicara un protocolo de vigilancia pasiva reforzada que reposaba en la obtención de datos mediante actividades de vigilancia participativa, empleando para ello un sistema objetivo y adaptable de puntuación que ayudaba a detectar con prontitud la presencia en las explotaciones de PPA o PPC. Dicho protocolo fue aplicado a lo largo de diez semanas en dos explotaciones porcinas industriales de la República Dominicana, país en el que ambas infecciones están presentes. El estudio, que sirvió para poner a prueba la idea, pasaba por la aplicación del protocolo de vigilancia pasiva reforzada para ayudar a detectar variaciones sustanciales de la puntuación del nivel de riesgo que activa la realización de pruebas. En una de las explotaciones estudiadas se produjo una variación de la puntuación, cosa que activó la realización de pruebas en los animales, aunque estas arrojaron resultado negativo. El estudio aquí descrito permite evaluar algunos de los puntos débiles de la vigilancia pasiva y extraer enseñanzas aplicables al problema. Los resultados demuestran que es posible salvar algunas de las dificultades que impiden la aplicación generalizada de protocolos de vigilancia pasiva reforzada y dejan pensar que quizá el uso de planteamientos normalizados pueda ayudar a detectar con prontitud los casos de penetración de PPC o PPA.

Effect of Gammulin supplementation during the first 24 d of life on health, growth, and first-lactation performance of Holstein cows.

Development and health during calfhood are paramount for the success of dairy operations because they are associated with longevity and productivity later in life. Thus, provision of nutritional supplements has been explored as an alternative to improve growth of preweaned calves. Holstein calves (female = 472, male = 46) from 2 dairies located in the San Joaquin Valley were assigned randomly to receive 25 g/d of Gammulin (APC Inc.) from 2 to 24 d of age (GAM = 263) or to receive no supplementation (control = 255). Calves were fed a mixture of waste milk and milk replacer (3.79 L/d), and study personnel added the supplement to the bottles of calves in the GAM treatment daily. Study personnel monitored calves 6 d/wk and recorded starter intake, fecal score (1 = firm, 4 = watery), and attitude score (1 = alert and responsive, 4 = recumbent). Blood samples were collected (4, 7, 14, 26, 44, 56, and 68 d of age) to determine concentrations of total protein, glucose (n = 64), nonesterified fatty acids (n = 64), ß-hydroxybutyrate (n = 171), and hematocrit (n = 518). Calves (n = 64) were treated with 0.5 mg of ovalbumin at 3, 21, and 42 d of age, and concentration of anti-ovalbumin IgG was measured. The percentage of polymorphonuclear leukocytes positive for phagocytosis and oxidative burst after the ex vivo exposure to an enteropathogenic Escherichia coli was evaluated (n = 64). We followed the female calves through the end of the first lactation or until they left the herd to evaluate the effect of treatment on first-lactation performance. Treatment did not affect metabolic and immune responses. During the supplementation (1 to 24 d of age), starter intake did not differ between treatments, but the GAM treatment reduced starter intake (638.5 ± 1.1 vs. 696.6 ± 1.1 g/d; mean ± standard error of the mean) from 25 to 60 d of age and average daily gain (798.8 ± 15.4 and 749.5 ± 15.2) from 23 to 60 d of age, resulting in reduced body weight at 60 d of age (68.4 ± 0.4 vs. 69.8 ± 0.5 kg). From 1 to 24 d of age, GAM treatment reduced the number of days calves had fecal score = 4 (ratio of number of days = 0.92; 95% confidence interval = 0.84-1.00) and it reduced the number of electrolyte treatments calves received (ratio of number of treatments = 0.92; 95% confidence interval = 0.85-0.99). Treatment did not affect the hazard of first calving and first-lactation 305-d milk yield, but the adjusted hazard ratio (0.82; 95% confidence interval = 0.65, 1.04) of pregnancy in the first lactation tended to be reduced for the GAM treatment. In the conditions of this experiment, supplementation with 25 g/d of GAM to the liquid feed from 2 to 24 d of age did not improve calfhood health and performance.

The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC.

BACKGROUND: Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. DESIGN: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. RESULTS: We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were $155 605 and $187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was $215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183% and decreased the ICER by up to 65%. Pembrolizumab was studied only in patients whose tumors expressed PD-L1. The QALY gain was 0.346 and the ICER was $98 421. Patient selection also reduced the budget impact of immunotherapy. CONCLUSION: The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved.

Biochemical studies of amylase, lipase and protease in Callosobruchus maculatus (Coleoptera: Chrysomelidae) populations fed with Vigna unguiculata grain cultivated with diazotrophic bacteria strains.

The objective of this study was to evaluate the enzymatic activity of homogenates of insects fed on grain of cowpea, Vigna unguiculata (L.), cultivars grown with different nitrogen sources. For the experiment we used aliquots of the homogenate of 100 unsexed adult insects, emerged from 10 g of grain obtained from four cowpea cultivars: 'BRS Acauã', 'BRS Carijó', 'BRS Pujante', and 'BRS Tapaihum' grown under different regimes of nitrogen sources: mineral fertilizer, inoculation with strains of diazotrophs (BR 3267, BR 3262, BR 3299; INPA 03-11B, 03-84 UFLA, as well as the control (with soil nitrogen). The parameters evaluated were enzymatic activities of insect protease, amylase and lipase and the starch content of the grains. There were differences in the enzymatic activity of amylase, lipase and protease of insect homogenate according to the food source. A lower activity of the enzyme amylase from C. maculatus homogenate was observed when insects were fed grain of the cultivar BRS Carijó. A lower activity of lipase enzyme from C. maculatus homogenate was observed when the insects fed on grain from the interaction of the cultivar Tapaihum inoculated with BR 3262 diazotrophs. The lowest proteolytic activity was observed in homogenate of insects fed on interaction of 'BRS Carijó' inoculated with BR 3262 diazotrophs. Starch content correlated positively with the amylase activity of C. maculatus homogenate. The cultivar BRS Carijó had a different behavior from the other cultivars, according to the cluster analysis.

Listeria monocytogenes isolates from food and food environment harbouring tetM and ermB resistance genes.

UNLABELLED: Listeria monocytogenes is a foodborne pathogen that has become an important cause of human and animal diseases worldwide. The purpose of this study was to evaluate the serotypes, virulence potential, antimicrobial resistance profile, and genetic relationships of 50 L. monocytogenes isolates from food and food environment in southern Brazil. In this study, the majority of L. monocytogenes isolates belonged to the serotypes 1/2b (42%) and 4b (26%), which are the main serotypes associated with human listeriosis. In addition, all isolates harboured internalin genes (inlA, inlC, inlJ), indicating a virulence potential. The isolates were sensitive to most of the antimicrobial compounds analysed, and five isolates (10%) were multi-resistant. Two isolates harboured antimicrobial resistance genes (tetM and ermB) and in one of them, the gene was present in the plasmid. Moreover, according to the pulsed field gel electrophoresis assay, two multi-resistant isolates were a single clone isolated from food and the processing plant. The isolates were susceptible to the most frequently used antibiotics for listeriosis treatment. However, the presence of multidrug-resistant isolates and antimicrobial resistance genes including in the plasmid could even be transferred between bacterial species, suggesting a potential health risk to consumers and a potential risk of spreading multi-resistance genes to other bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Listeria monocytogenes is an important agent of foodborne diseases. The results of this study suggest a potential capacity of L. monocytogenes isolates from food and food environment to cause human infections. Antimicrobial multi-resistance profiles were detected in 10%, and two isolates harboured tetM and ermB resistance genes. Moreover, the present research can help to build up a better knowledge about antimicrobial resistance of L. monocytogenes. Additionally, we found one isolate carrying tetM resistance gene in a plasmid, that suggests a possible transmission between commensal and/or other pathogenic bacteria of food environment, thereby raising up concerns regarding bacterial resistance.

Beneficial use of industrial by-products for phytoremediation of an arsenic-rich soil from a gold mining area.

This study investigated two industrial by-products - red mud (RM) and its mixture with phosphogypsum (RMG), as amendments in an As((5+))-contaminated soil from a gold mining area in Brazil in order to grow three plant species: Brachiaria decumbens, Crotalaria spectabilis, and Stylosanthes cv. Campo Grande. These amendments were applied to reach a soil pH of 6.0. Using RM and RMG increased shoot dry matter (SDM) and root dry matter (RDM) of most plants, with RMG being more effective. Adding RMG increased the SDM of Brachiaria and Crotalaria by 18 and 25% and the RDM by 25 and 12%, respectively. Stylosanthes was sensitive to As toxicity and grew poorly in all treatments. Arsenic concentration in shoots of Brachiaria and Crotalaria decreased by 26% with the use of RMG while As in roots reduced by 11 and 30%, respectively. Also, the activities of the plant oxidative stress enzymes varied following treatments with the by-products. The plants grew in the As-contaminated soil from the gold mining area. Thus, they might be employed for phytoremediation purposes, especially with the use of RMG due to its potential advantage in terms of nutrient supply (Ca(2+) and SO4(2-) from phosphogypsum).

Co-Infestation and Spatial Distribution of Bactrocera carambolae and Anastrepha spp. (Diptera: Tephritidae) in Common Guava in the Eastern Amazon.

Field infestation and spatial distribution of introduced Bactrocera carambolae Drew and Hancock and native species of Anastrepha in common guavas [Psidium guajava (L.)] were investigated in the eastern Amazon. Fruit sampling was carried out in the municipalities of Calçoene and Oiapoque in the state of Amapá, Brazil. The frequency distribution of larvae in fruit was fitted to the negative binomial distribution. Anastrepha striata was more abundant in both sampled areas in comparison to Anastrepha fraterculus (Wiedemann) and B. carambolae The frequency distribution analysis of adults revealed an aggregated pattern for B. carambolae as well as for A. fraterculus and Anastrepha striata Schiner, described by the negative binomial distribution. Although the populations of Anastrepha spp. may have suffered some impact due to the presence of B. carambolae, the results are still not robust enough to indicate effective reduction in the abundance of Anastrepha spp. caused by B. carambolae in a general sense. The high degree of aggregation observed for both species suggests interspecific co-occurrence with the simultaneous presence of both species in the analysed fruit. Moreover, a significant fraction of uninfested guavas also indicated absence of competitive displacement.

Sino-Nasal Outcome Test-22: translation, cultural adaptation and validation in Portugal.

OBJECTIVES: Sino-Nasal Outcome Test-22 is a questionnaire that evaluates the specific quality of life in chronic rhinosinusitis and was widely used in scientific literature. The aim of our study was to translate and culturally adapt Sino-Nasal Outcome Test-22 for the Portuguese reality and validate the version obtained for use in Portugal. DESIGN: We translate Sino-Nasal Outcome Test-22 into European Portuguese according to the methodology recommended by the scientific literature. After translation, we proceeded with the evaluation of the questionnaire regarding its feasibility, reliability (internal consistency and test-retest reproducibility) and discriminant validity. Statistical analysis was performed using spss 22.0. SETTING: Patients treated at a single institute. PARTICIPANTS: We applied Sino-Nasal Outcome Test-22 questionnaire to 15 volunteers with no nasal or sinus disease and to 50 patients with chronic rhinosinusitis. MAIN OUTCOME MEASURES: Feasibility, reliability (internal consistency and test-retest reproducibility) and discriminant validity. RESULTS: We observed good internal consistency, with general Cronbach's α coefficient of 0.935, good test-retest reproducibility (32.5 versus 32, P < 0.001), with Pearson coefficient of 0.99 (P < 0.001) and Cohen Kappa coefficient of 0.898. The discriminant validity of the Portuguese version of Sino-Nasal Outcome Test-22 was confirmed by applying the Mann-Whitney U-test (P < 0.001). CONCLUSIONS: Until now, there were no validated questionnaires to evaluate quality of life in patients with chronic rhinosinusitis in Portugal. Translation and validation of Sino-Nasal Outcome Test-22 in Portugal will allow a more consistent assessment of the specific quality of life of these patients and the comparison with international data. Thus, we recommend this version for use with the Portuguese population with chronic rhinosinusitis.

Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079).

BACKGROUND: This study investigated the activity of MK-2206, an AKT inhibitor, in metastatic or recurrent nasopharyngeal carcinoma (NPC). METHOD: Oral MK-2206 at a dose of 200 mg was administered on days 1, 8, 15 and 22 of a 28-day cycle until progression. Plasma EBV DNA clearance during the first month of treatment was measured, and archived tumors were analyzed for the expression of AKT and PIK3CA mutation and PIK3CA amplification. The dual primary endpoint was objective response rate and 6-month progression-free survival (PFS) rate. RESULTS: 21 patients were enrolled and one patient achieved a partial response (5 %) and 11 had stable disease (52 %), with a median PFS of 3.5 months (95 % confidence interval, CI: 0.9-7.3). The 6-month PFS rate was 43 % (95 % CI: 22-66 %) and the median OS was 10 months (95 % CI: 5.9 months-not reached). Seven patients (33 %) experienced grade 3 toxicities which could be related to MK-2206. Macular-papular rash was the most common (n = 6), followed by hyperglycemia (n = 2) and fatigue (n = 1). In the 12 tumor samples analyzed, PIK3CA amplification was detected in one patient's primary NPC, who had SD lasting over 12 months. Patients with decreasing EBV DNA values over time were more likely to be alive and progression-free for at least 6 months than those without a decrease (p = 0.001). CONCLUSION: The study was terminated due to the limited activity observed in this heavily pre-treated group of patients. Further studies are needed to elucidate the optimal way of selecting patients for AKT inhibitors.

Tris-egg yolk-glycerol (TEY) extender developed for freezing dog semen is a good option to cryopreserve bovine epididymal sperm cells.

Cryopreservation of epididymal spermatozoa is often performed after shipping the excised testis-epididymis complexes, under refrigeration, to a specialized laboratory. However, epididymal spermatozoa can be collected immediately after excision of the epididymis and sent extended and refrigerated to a laboratory for cryopreservation. In this experiment, we evaluated the effect of both methods of cold storage bovine epididymal spermatozoa as well as of two different extenders on spermatozoa characteristics after freeze-thawing. For that, spermatozoa collected from the caudae epididymis of 19 bulls were extended and cryopreserved in either AndroMed(®) or a Tris-egg yolk (TEY)-based extender. Cryopreservation of sperm cells was performed immediately after castration (Group A, n = 9) or after cold storage for 24 h diluted in the two extenders and (Group B, n = 9) and also after cold storage for 24 h within the whole epididymis (Group C, n = 10). Sperm subjective progressive motility (light microscopy), plasma membrane integrity (hypoosmotic swelling test) and sperm viability (eosin-nigrosin) were evaluated. In vitro fertilization and culture (IVF) was performed to assess the blastocyst rate. No differences (p > 0.05) were observed on post-thaw sperm parameters between samples from Group A, B and C. TEY extended samples presented a higher (p < 0.01) percentage of progressive motile and live sperm, than those extended in AndroMed(®) . Blastocyst rate after IVF differed only (p < 0.05) between the reference group (IVF performed with frozen semen with known in vitro fertility) and Group A extended in AndroMed(®) . We conclude that when cryopreservation facilities are distant from the collection site, bovine epididymal sperm can be shipped chilled overnight either within the epididymal tail or after dilution without deleterious effect on post-thaw sperm quality. TEY extender was more suitable for cold storage and freezing bovine epididymal sperm, than the commercial extender AndroMed®.

Reproductive performance of lactating dairy cows managed for first service using timed artificial insemination with or without detection of estrus using an activity-monitoring system.

Lactating dairy cows (n=1,025) on a commercial dairy farm were randomly assigned at 10 ± 3 d in milk (DIM) to 1 of 3 treatments for submitting cows to first artificial insemination (AI) and were fitted with activity-monitoring tags (Heatime; SCR Engineers Ltd., Netanya, Israel) at 24 ± 3 DIM. Cows (n=339) in treatment 1 were inseminated based on increased activity from the end of the voluntary waiting period (50 DIM) until submission to an Ovsynch protocol; cows without increased activity from 21 to 65 DIM began an Ovsynch protocol at 65 ± 3 DIM, whereas cows without increased activity from 21 to 50 DIM but not from 51 to 79 DIM began an Ovsynch protocol at 79 ± 3 DIM. Cows (n=340) in treatment 2 were inseminated based on activity after the second PGF2α injection of a Presynch-Ovsynch protocol at 50 DIM, and cows without increased activity began an Ovsynch protocol at 65 ± 3 DIM. Cows (n=346) in treatment 3 were monitored for activity after the second PGF2α injection of a Presynch-Ovsynch protocol, but all cows received timed AI (TAI) at 75 ± 3 DIM after completing the Presynch-Ovsynch protocol. The activity-monitoring system detected increased activity in 56, 69, and 70% of cows in treatments 1, 2, and 3, respectively. Treatment-2 cows had the fewest average days to first AI (62.5), treatment-3 cows had the most average days to first AI (74.9), and treatment-1 cows had intermediate average days to first AI (67.4). Treatment-1 and -2 cows in which inseminations occurred as a combination between increased activity and TAI had fewer overall pregnancies per AI (P/AI) 35 d after AI (32% for both treatments) compared with treatment-3 cows, all of which received TAI after completing the Presynch-Ovsynch protocol (40%). Based on survival analysis, although the rate at which cows were inseminated differed among treatments, treatment did not affect the proportion of cows pregnant by 300 DIM. Thus, use of an activity-monitoring system to inseminate cows based on activity reduced days to first AI, whereas cows receiving 100% TAI after completing a Presynch-Ovsynch protocol had more P/AI. The trade-off between AI service rate and P/AI in the rate at which cows became pregnant was supported by an economic analysis in which the net present value ($/cow per year) differed by only $4 to $8 among treatments. We conclude that a variety of strategies using a combination of AI based on increased activity using an activity-monitoring system and synchronization of ovulation and TAI can be used to submit cows for first AI.

Evaluation of castor bean genotypes sown in winter and summer at a low altitude.

Current demands for the genetic breeding of castor bean include the adaptation of genotypes to low altitudes to expand the potential areas of cultivation. This study was conducted to evaluate the response of different genotypes of castor bean that were sown in winter and summer at a low altitude. The study was conducted in northwestern Rio de Janeiro State at an altitude of 60 m. The treatments consisted of genotypes IAC 80, AL Guarany 2002, BRS 149 Nordestina, BRS 188 Paraguaçu, Savana, Lyra, Mirante 10, IAC 226, Cafelista, G1, V1, and T1 with spaces of 2.0 m between rows, 1.0 m between plants, and one plant per hole. The plant height, number and length of racemes, number of fruits per raceme, seed yield, and incidence of gray mold were determined. The highest yields in both seasons were obtained by the genotypes BRS 149 Nordestina, G1, BRS 188 Paraguaçu, and IAC 226. The genotypes Savannah and Lyra had the lowest yields in both cultivation seasons. The genotypes responded differently to the environmental conditions depending on the growing season, and the spring-summer period was found to be more favorable at the low altitude of the study site.

Effect of breeding activity on the microflora of the external genitalia and in the semen of stallions, and the relationship between micro-organisms on the skin and on the external genitalia.

A possible role of breeding activities in the composition of the microbial population in stallions' external genitalia (EG) and the relationship between micro-organisms colonizing the skin of the abdomen and the ones colonizing the EG have not been studied. In experiment 1, EG microbiological samples were collected from 41 stallions used for both natural cover and semen collection (BST) and from 18 non-breeding stallions (NBST). A higher (p < 0.05) frequency of isolation of potentially pathogenic species was found for BST. Age did not influence number of micro-organism species isolated both in BST and NBST. In experiment 2, the microbial content of the EG and semen was compared in 23 BST. Most micro-organisms isolated from the EG were present in semen, albeit with a numerically lower prevalence. In 7 stallions, six microbial species isolated from semen were absent from the EG cultures, suggesting contamination by the operator. In experiment 3, a numerically higher number of micro-organism species was isolated from the EG of 31 stallions, than from their skin of the ventral abdomen in contact with the penis or from the skin of the thorax. With the sole exception of Escherichia coli, potentially pathogenic bacteria were only isolated from the EG but not from the skin. Results suggest that breeding activity increased the number of species colonizing the EG; most species isolated from the EG were also found in semen even if with a lower frequency, and additional semen contamination seemed to occur during its manipulation. Many micro-organism species of the skin were also isolated from the penis, but independently of being or not in contact with the penis, skin did not seem to provide an adequate environment for the growth of potentially pathogenic bacteria that were isolated from EG, with the sole exception for E. coli.

Influence of airborne particle abrasion on dentin bonding effectiveness of a 2-step universal adhesive.

OBJECTIVE: To determine the effect of airborne particle abrasion (APA) on micro-tensile bond strength (µTBS) to dentin using different air-abrasion/polishing powders. METHODS: The bonding effectiveness of G2 Bond Universal (G2B), used in etch-and-rinse (E&R) and self-etch mode (SE), was tested on bur-cut dentin and dentin air abraded/polished using six different powders (aluminum oxide 29 µm (AO29) and 53 µm (AO53), aluminum trihydroxide (AT), sodium bicarbonate (SB), sodium bicarbonate soft (SBsoft) and bioactive glass (BG); Velopex). Adhesive-composite resin specimens were immersed in distilled water at 37 °C for one week and cut into microspecimens. Half of the specimens were subjected to 50,000 thermocycles (aged). Immediate and aged µTBS to dentin were measured. Statistical analysis was performed using linear mixed-effects (LME) modeling (p < 0.05). RESULTS: Comparing the aged bond strengths to air-abraded/polished dentin with bur-cut dentin, pretreatment with SB and SBsoft in combination with G2B used in E&R mode, and BG air polishing in combination with both application modes (E&R, SE), resulted in a significantly higher bond strength. Dentin bond strength was only significantly lower when air abraded with AO29 and using G2B in SE mode. Aging did not significantly influence bond strength for both application modes (E&R, SE), except for AO29 and AT-treated dentin, where bond strengths decrea sed significantly using G2B in SE mode. In general, G2B reached significantly higher bond strengths on air-abraded/polished dentin in E&R mode than in SE mode. CONCLUSION: Air-abrasion/polishing did not impair dentin bond strength using G2B, except when dentin was air abraded with AO29 and using G2B in SE mode. Air polishing positively influenced the bond strength to dentin in specific groups. CLINICAL SIGNIFICANCE: APA is safe concerning bonding to dentin. The E&R application mode is preferred using G2B as adhesive on air-abraded/polished dentin. Air polishing with BG positively influenced dentin bond strength for both application methods.

Results of implementation of preventive recommendations for tuberculosis after renal transplantation in an endemic area.

This retrospective cohort study assessed the results of the implementation of preventive recommendations for tuberculosis (TB) among renal transplant recipients in an endemic area (Rio de Janeiro, Brazil). Subjects were defined as at high risk for TB if they had latent tuberculosis infection (LTBI), reported recent close contact with individuals with TB or received a graft from a donor with LTBI. A 6-month course of isoniazid preventive therapy (IPT) was targeted to high-risk subjects. The study end point was TB confirmed by culture. Altogether, 535 patients were included. Median follow-up was 59 months. The overall cumulative incidence of TB was 2.1% while among the 274 patients in whom the preventive protocol was fully implemented, the incidence was only 0.7%. The incidence of TB among 75 high-risk recipients not treated with isoniazid (7%) was significantly higher than that observed in 209 untreated low-risk patients (1%, p = 0.006) and in 65 high-risk subjects that received IPT (no case, p = 0.03). In conclusion, the implementation of preventive recommendations for TB in an endemic area allowed the appropriate discrimination between high- and low-risk renal transplant recipients and was associated with long-term reduction in the incidence of this complication among high-risk subjects.

Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India.

Cancer treatments have improved outcomes but access to medications is an issue around the world and especially so in low- and middle-income countries, such as India. Generic substitution may lead to significant cost savings. The author aimed to compare the cost and estimate potential cost savings per cycle, per patient, and for the country as a whole with generic substitution of frequently used chemotherapy drugs in the treatment of common cancers in India. Generic paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine, oxaliplatin and irinotecan cost from 8.9% to 36% of their equivalent branded originator drug, resulting in cost savings of ~ Indian Rupees (INR) 11,000 to >INR 90,000 (USD 200-1600, Euro 160-1300) per cycle; and ~INR 50,000 to >INR 240,000 (USD 900-4300, Euro 700-3400) per patient. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (~USD 843 million, Euro 670 million). In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to cancer treatments in India and other low- and middle-income countries.

Clinical and economic implications of the use of nanoparticle paclitaxel (Nanoxel) in India.

Paclitaxel (Taxol), one of the most commonly used chemotherapeutic agents, is poorly soluble in water and requires cremophor, which often causes infusion reactions, as a solvent. Nanoxel, a nanoparticle formulation of the taxane, has been approved by the Indian regulatory authority. In the present article, we aim to describe the experience with the use of Nanoxel in India and its clinical and economic implications. We present three retrospective series in a common practice environment and an economic model. The first series shows no reactions in 596 Nanoxel infusions; the second series shows comparable adverse events other than infusion reactions between 83 patients who received Nanoxel and 32 treated with conventional paclitaxel. The third reveals comparable clinical outcomes for 51 patients treated with Nanoxel or conventional paclitaxel for gastroesophageal tumors. Finally, we describe an economic model which estimates savings of 21 580 Indian rupees per cycle with Nanoxel vis-à-vis conventional paclitaxel in the treatment of solid tumors in India. In conclusion, in an era in which the greatest challenge we face as medical oncologists is how to conciliate hard-won and incremental--but small--improvements in survival with exponentially rising drugs costs, it is refreshing to see a potential new formulation of a commonly used drug that may actually generate cost-savings while improving clinical outcomes and patient well-being. Further studies are clearly warranted to determine the optimal dose and schedule for Nanoxel as well as its comparative effectiveness to cremophor-based paclitaxel.