Pharmacodynamic activity of BMS-986156, a glucocorticoid-induced TNF receptor-related protein agonist, alone or in combination with nivolumab in patients with advanced solid tumors.

BACKGROUND: The success of immune checkpoint inhibitors has revolutionized cancer treatment options and triggered development of new complementary immunotherapeutic strategies, including T-cell co-stimulatory molecules, such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). BMS-986156 is a fully agonistic human immunoglobulin G subclass 1 monoclonal antibody targeting GITR. We recently presented the clinical data for BMS-986156 with or without nivolumab, which demonstrated no compelling evidence of clinical activity in patients with advanced solid tumors. Here, we further report the pharmacodynamic (PD) biomarker data from this open-label, first-in-human, phase I/IIa study of BMS-986156 ± nivolumab in patients with advanced solid tumors (NCT02598960). MATERIALS AND METHODS: We analyzed PD changes of circulating immune cell subsets and cytokines in peripheral blood or serum samples collected from a dataset of 292 patients with solid tumors before and during treatment with BMS-986156 ± nivolumab. PD changes in the tumor immune microenvironment were measured by immunohistochemistry and a targeted gene expression panel. RESULTS: BMS-986156 + nivolumab induced a significant increase in peripheral T-cell and natural killer (NK) cell proliferation and activation, accompanied by production of proinflammatory cytokines. However, no significant changes in expression of CD8A, programmed death-ligand 1, tumor necrosis factor receptor superfamily members, or key genes linked with functional parameters of T and NK cells were observed in tumor tissue upon treatment with BMS-986156. CONCLUSIONS: Despite the robust evidence of peripheral PD activity of BMS-986156, with or without nivolumab, limited evidence of T- or NK cell activation in the tumor microenvironment was observed. The data therefore explain, at least in part, the lack of clinical activity of BMS-986156 with or without nivolumab in unselected populations of cancer patients.

Omics-Based Insights into Flavor Development and Microbial Succession within Surface-Ripened Cheese.

In this study, a young Cheddar curd was used to produce two types of surface-ripened cheese, using two commercial smear-culture mixes of yeasts and bacteria. Whole-metagenome shotgun sequencing was used to screen the microbial population within the smear-culture mixes and on the cheese surface, with comparisons of microorganisms at both the species and the strain level. The use of two smear mixes resulted in the development of distinct microbiotas on the surfaces of the two test cheeses. In one case, most of the species inoculated on the cheese established themselves successfully on the surface during ripening, while in the other, some of the species inoculated were not detected during ripening and the most dominant bacterial species, Glutamicibacter arilaitensis, was not a constituent of the culture mix. Generally, yeast species, such as Debaryomyces hansenii and Geotrichum candidum, were dominant during the first stage of ripening but were overtaken by bacterial species, such as Brevibacterium linens and G. arilaitensis, in the later stages. Using correlation analysis, it was possible to associate individual microorganisms with volatile compounds detected by gas chromatography-mass spectrometry in the cheese surface. Specifically, D. hansenii correlated with the production of alcohols and carboxylic acids, G. arilaitensis with alcohols, carboxylic acids and ketones, and B. linens and G. candidum with sulfur compounds. In addition, metagenomic sequencing was used to analyze the metabolic potential of the microbial populations on the surfaces of the test cheeses, revealing a high relative abundance of metagenomic clusters associated with the modification of color, variation of pH, and flavor development. IMPORTANCE Fermented foods, in particular, surface-ripened cheese, represent a model to explain the metabolic interactions which regulate microbial succession in complex environments. This study explains the role of individual species in a heterogeneous microbial environment, i.e., the exterior of surface-ripened cheese. Through whole-metagenome shotgun sequencing, it was possible to investigate the metabolic potential of the resident microorganisms and show how variations in the microbial populations influence important aspects of cheese ripening, especially flavor development. Overall, in addition to providing fundamental insights, this research has considerable industrial relevance relating to the production of fermented food with specific qualities.

A pilot study demonstrating the altered gut microbiota functionality in stable adults with Cystic Fibrosis.

Cystic Fibrosis (CF) and its treatment result in an altered gut microbiota composition compared to non-CF controls. However, the impact of this on gut microbiota functionality has not been extensively characterised. Our aim was to conduct a proof-of-principle study to investigate if measurable changes in gut microbiota functionality occur in adult CF patients compared to controls. Metagenomic DNA was extracted from faecal samples from six CF patients and six non-CF controls and shotgun metagenomic sequencing was performed on the MiSeq platform. Metabolomic analysis using gas chromatography-mass spectrometry was conducted on faecal water. The gut microbiota of the CF group was significantly different compared to the non-CF controls, with significantly increased Firmicutes and decreased Bacteroidetes. Functionality was altered, with higher pathway abundances and gene families involved in lipid (e.g. PWY 6284 unsaturated fatty acid biosynthesis (p = 0.016)) and xenobiotic metabolism (e.g. PWY-5430 meta-cleavage pathway of aromatic compounds (p = 0.004)) in CF patients compared to the controls. Significant differences in metabolites occurred between the two groups. This proof-of-principle study demonstrates that measurable changes in gut microbiota functionality occur in CF patients compared to controls. Larger studies are thus needed to interrogate this further.

Effect of seaweed-derived laminarin and fucoidan and zinc oxide on gut morphology, nutrient transporters, nutrient digestibility, growth performance and selected microbial populations in weaned pigs.

In the present study, two experiments were conducted to (1) evaluate the effect of laminarin and/or fucoidan on ileal morphology, nutrient transporter gene expression and coefficient of total tract apparent digestibility (CTTAD) of nutrients and (2) determine whether laminarin inclusion could be used as an alternative to ZnO supplementation in weaned pig diets. Expt 1 was designed as a 2 × 2 factorial arrangement, comprising four dietary treatments (n 7 replicates, weaning age 24 d, live weight 6·9 kg). The dietary treatments were as follows: (1) basal diet; (2) basal diet+300 ppm laminarin; (3) basal diet+240 ppm fucoidan; (4) basal diet+300 ppm laminarin and 240 ppm fucoidan. There was an interaction between laminarin and fucoidan on the CTTAD of gross energy (GE) (P< 0·05) and the expression of sodium-glucose-linked transporter 1 (SGLT1/SLC5A1) and GLUT1/SLC2A1 and GLUT2/SLC2A2 (P< 0·05) in the ileum. The laminarin diet increased the CTTAD of GE and increased the expression of SGLT1, GLUT1 and GLUT2 compared with the basal diet. However, there was no effect of laminarin supplementation on these variables when combined with fucoidan. Expt 2 was designed as a complete randomised design (n 8 replicates/treatment, weaning age 24 d, live weight 7·0 kg), and the treatments were (1) basal diet, (2) basal diet and laminarin (300 ppm), and (3) basal diet and ZnO (3100 ppm, 0-14 d, and 2600 ppm, 15-32 d post-weaning). The laminarin diet increased average daily gain and gain:feed ratio compared with the basal diet during days 0-32 post-weaning (P< 0·01) and had an effect similar to the ZnO diet. These results demonstrate that laminarin provides a dietary means to improve gut health and growth performance post-weaning.

Effect of dietary laminarin and fucoidan on selected microbiota, intestinal morphology and immune status of the newly weaned pig.

A 2 × 2 factorial experiment was conducted to investigate the interactions between laminarin (LAM; 0 and 300 parts per million (ppm)) and fucoidan (FUC; 0 and 240 ppm) levels on intestinal morphology, selected microbiota and inflammatory cytokine gene expression in the weaned pig. There was an interaction between LAM and FUC supplementation on the Enterobacteriaceae population (P< 0·05) and the abundance of attaching and effacing Escherichia coli (AEEC) strains (P< 0·05) in the colon. Pigs offered the FUC diet had a reduced Enterobacteriaceae population compared with pigs offered the basal diet. However, the effect of FUC on the Enterobacteriaceae population was not observed when combined with LAM. Pigs offered the LAM diet had reduced abundance of AEEC strains compared with pigs offered the basal diet. However, there was no effect of LAM on the abundance of AEEC strains when combined with FUC. There was an interaction between LAM and FUC supplementation on villous height (P< 0·01) and the villous height:crypt depth ratio (P< 0·01) in the duodenum. Pigs offered the LAM or FUC diet had an increased villous height and villous height:crypt depth ratio compared with pigs offered the basal diet. However, there was no effect of the LAM and FUC combination diet on intestinal morphology. Pigs offered the LAM-supplemented diets had a lower IL-6 (P< 0·05), IL-17A (P< 0·01) and IL-1ß (P< 0·01) mRNA expression in the colon compared with pigs offered the diets without LAM. In conclusion, supplementation with either LAM or FUC alone modified intestinal morphology and selected intestinal microbiota, but these effects were lost when offered in combination.

The effects of supplementing varying molecular weights of chitooligosaccharide on performance, selected microbial populations and nutrient digestibility in the weaned pig.

An experiment (complete randomised design) was conducted to investigate the effects of supplementing different molecular weights (MW) of chitooligosaccharide (COS) on pig performance, selected microbial populations and nutrient digestibility post-weaning. A total of 396 weaned piglets (24 days of age, 7.3 kg ± (s.d.) 1.7 kg live weight) were assigned to one of six dietary treatments (22 replicates/treatment) for a 33-day experimental period. The dietary treatments were as follows (1) control diet (0 ppm COS), (2) control diet plus <1 kDa COS, (3) control diet plus 3 to 5 kDa COS, (4) control diet plus 5 to 10 kDa COS, (5) control diet plus 10 to 50 kDa COS and (6) control diet plus 50 to 100 kDa COS. The COS were included at 250 ppm in the diets. There was no significant effect of dietary treatment on piglet performance during the starter period (days 0 to 18; P > 0.05). However, there were quadratic responses in both daily gain (P < 0.05) and gain to feed ratio (P < 0.05) to the increased MW of COS inclusion during the weaner period (days 18 to 33) with all COS-supplemented treatments improving daily gain and gain to feed ratio compared with the control. There was a quadratic response in faecal scoring to the increased MW of COS inclusion from days 0 to 7 (P < 0.001), days 7 to 14 (P < 0.001) and during the overall experimental period (P < 0.01) with all the COS-supplemented treatments having an improved faecal score compared with the control. During the weaner period, there was a cubic response in lactic acid bacteria and Escherichia coli populations as the MW of COS increased (P < 0.05). The 5 to 10 kDa and 10 to 50 kDa COS increased lactic acid bacteria populations compared with the control, whereas lactic acid bacteria populations decreased at 50 to 100 kDa. The 5 to 10 kDa, 10 to 50 kDa and 50 to 100 kDa COS decreased E. coli populations compared with the control. There was a cubic response in the apparent total tract digestibility of dry matter (DM; P < 0.01), organic matter (OM; P < 0.01), ash (P < 0.01), nitrogen (N; P < 0.01) and gross energy (GE; P < 0.01) to the increased MW of COS inclusion during the weaner period. The 5 to 10 kDa COS had a higher apparent total tract digestibility of DM, OM, ash, N and GE in comparison to the control, whereas the apparent total tract nutrient digestibility of these nutrients decreased at 10 to 50 kDa. The current results indicate that the MW ranges of 5 to 10 kDa and 10 to 50 kDa COS decreased E. coli numbers while increasing nutrient digestibility of the diets.

The effect of chitooligosaccharide supplementation on intestinal morphology, selected microbial populations, volatile fatty acid concentrations and immune gene expression in the weaned pig.

An experiment (complete randomised design) was conducted to investigate the effects of supplementing different molecular weights (MW) of chitooligosaccharide (COS) on intestinal morphology, selected microbial populations, volatile fatty acid (VFA) concentrations and the immune status of the weaned pig. A total of 28 piglets (24 days of age, 9.1 kg (± s.d. 0.80) live weight) were assigned to one of four dietary treatments for 8 days and then sacrificed. The treatments were (1) control diet (0 ppm COS), (2) control diet plus 5 to 10 kDa COS, (3) control diet plus 10 to 50 kDa COS and (4) control diet plus 50 to 100 kDa COS. The COS was included in dietary treatments at a rate of 250 mg/kg. Tissue samples were taken from the duodenum, jejunum and ileum for morphological measurements. Digesta samples were taken from the proximal colon to measure lactobacilli and Escherichia coli populations and digesta samples were taken from the caecum and proximal colon for VFA analysis. Gene expression levels for specific cytokines were investigated in colonic tissue of the pig. Supplementation of different MW of COS had no significant effect on pig performance during the post-weaning period (days 0 to 8; P > 0.05). The inclusion of COS at all MW in the diet significantly reduced faecal scores compared with the control treatment (P < 0.01). Pigs fed the 10 to 50 kDa COS had a higher villous height (P < 0.05) and villous height : crypt depth ratio (P < 0.05) in the duodenum and the jejunum compared with the control treatment. Pigs fed the 5 to 10 kDa COS had a lower lactobacilli population (P < 0.05) and E. coli population (P < 0.05) in the colon compared with the control group. Pigs offered the 5 to 10 kDa COS had significantly lower levels of acetic acid and valeric acid compared with the control group (P < 0.05). The inclusion of different MW of COS had no significant effect on the expression of the cytokines tumour necrosis factor-α, Interleukin (IL)-6, IL-8 and IL-10 in the gastro-intestinal tract of the weaned pig. The current results indicate that a lower MW of 5 to 10 kDa COS possessed an antibacterial activity, while the higher MW of 10 to 50 kDa was optimum for enhancing the intestinal structure.

Effects of supplementing dietary laminarin and fucoidan on intestinal morphology and the immune gene expression in the weaned pig.

Previous studies have shown the benefit of combining seaweed extracts laminarin (LAM) and fucoidan (FUC) on improving growth in piglets' performance after weaning. A 2 × 2 factorial experiment was conducted to investigate the interaction between FUC (0 and 240 mg/kg) and LAM (0 and 300 mg/kg) levels on gut morphology and colonic cytokine gene expression in the weaned pig. Twenty-eight piglets (6.9 kg BW) were assigned to 1 of 4 dietary treatments for 8 d after weaning and then sacrificed. The dietary treatments were as follows: (i) basal diet, (ii) basal diet + 240 mg/kg FUC, (iii) basal diet + 300 mg/kg LAM, and (iv) basal diet + 300 mg/kg LAM and 240 mg/kg FUC. There was an interaction (P < 0.01) between LAM and FUC supplementation on duodenal villous height and the villus height to crypt depth ratio. Pigs offered the LAM or FUC diet singularly had an increased villus height and villus height to crypt depth ratio compared with pigs offered the basal diet. However, there was no effect of the LAM and FUC combination diet on morphology. Pigs offered the LAM-supplemented diets had a lower IL-6 (P < 0.05), IL-17 (P < 0.001), and IL-1ß (P < 0.001) mRNA expression in the colon compared with pigs offered diets without LAM supplementation. In conclusion, the enhancement in intestinal structure and downregulation of inflammatory cytokine gene expression obtained suggest that LAM may provide a dietary means to improve gut health in weaned pigs.

Effect of supplementing different ratios of laminarin and fucoidan in the diet of the weanling piglet on performance, nutrient digestibility, and fecal scoring.

A 3 × 2 factorial experiment was conducted to investigate the effects of different ratios of dietary laminarin (LAM) and fucoidan (FUC) on growth performance and nutrient digestibility in newly weaned piglets. At weaning, 168 piglets (24 d of age; 6.8 kg live weight) were assigned to 1 of 6 dietary treatments (n = 14/treatment): (i) basal diet, (ii) basal diet + 240 mg/kg FUC, (iii) basal diet + 150 mg/kg LAM, (iv) basal diet + 150 mg/kg LAM and 240 mg/kg FUC, (v) basal diet + 300 mg/kg LAM, and (vi) basal diet + 300 mg/kg LAM and 240 mg/kg FUC. Pigs offered 300 mg/kg LAM-supplemented diets had a higher ADG (P < 0.05) throughout the entire experimental period (days 0-35) compared with pigs offered diets with 0 and 150 mg/kg LAM supplementation. There was a significant interaction between LAM and FUC supplementation on G:F (P < 0.05) during the entire experimental period. Pigs offered the 300 mg/kg LAM-supplemented diet had a higher G:F than pigs offered the basal diet. However, there was no effect of the high level LAM on G:F when combined with FUC. There was a significant interaction between LAM and FUC supplementation on the apparent total tract digestibility (ATTD) of GE (P < 0.05). Pigs offered the 150 and 300 mg/kg LAM diet had an increased ATTD of GE compared with pigs offered the basal diet. However, there was no effect of LAM on ATTD of GE when combined with FUC. Pigs offered the 150 and 300 mg/kg LAM-supplemented diets had an improved fecal consistency (P < 0.05) from day 7 to day 14 compared to pigs offered diets without LAM supplementation. In conclusion, the inclusion of LAM improved growth performance of pigs after weaning partially due to an increased ATTD of GE.

High-throughput genotyping of KIR2DL2/L3, KIR3DL1/S1, and their HLA class I ligands using real-time PCR.

Killer immunoglobulin-like receptors (KIRs) expressed on natural killer cells are critical components of innate immunity. Interactions between KIRs and their human leukocyte antigen (HLA) ligands have been shown to influence autoimmune and infectious disease course in defined populations. However, the low throughput and high cost of current methods impede confirmation of the universality of these findings. To support large epidemiology surveys, we developed a high-throughput real-time polymerase chain reaction-based assay to identify carriers of KIR3DL1, KIR3DS1, KIR2DL2, and KIR2DL3 and their HLA ligands. The platform performed with 100% sensitivity and specificity in detection of carrier and non-carrier on reference samples. The application of this platform will further clarify the nature and impact of the KIR-HLA epistatic interaction on disease course in large global population-based studies.

HLA class I allele and haplotype diversity in Ugandans supports the presence of a major east African genetic cluster.

The objective of this study was to characterize the class I human leukocyte antigen (HLA) genetic composition of the Ugandan population to better define its relationship with other African groups. Samples from 175 individuals from Kampala (Uganda) were subjected to class I HLA-A, -B, and -C sequence-based typing. The high concordance between the major alleles and haplotypes found in the current and Kenyan populations and interpopulation genetic distance analysis strongly supported the presence of an East African cluster that contained the current Ugandan population along with Kenyan Luo and Nandi populations. The congruence of major alleles in different populations would permit consideration of East Africa as an integrated setting when designing and evaluating much needed malaria, tuberculosis, and AIDS vaccines.

Improving pain management by nurses: A pilot Peer Intervention Program.

Significant pain continues to be reported by many hospitalized patients despite the numerous and varied educational programs developed and implemented to improve pain management. A theoretically based Peer Intervention Program was designed from a predictive model to address nurses' beliefs, attitudes, subjective norms, self-efficacy, perceived control and intentions in the management of pain with p.r.n. (as required) narcotic analgesia. The pilot study of this program utilized a quasi-experimental pre-post test design with a patient intervention, nurse and patient intervention and control conditions consisting of 24, 18 and 19 nurses, respectively. One week after the intervention, significant differences were found between the nurse and patient condition and the two other conditions in beliefs, self-efficacy, perceived control, positive trend in attitudes, subjective norms and intentions. The most positive aspects of the program were supportive interactive discussions with peers and an awareness and understanding of beliefs and attitudes and their roles in behavior.

Fever management practises: what pediatric nurses say.

Pediatric nurses manage fevers in hospitalized children daily: a complex practise. The present study identified varied decision-making criteria and inconsistent practise influenced by many external variables. Nurses perform comprehensive assessments in order to make informed decisions. However, factors influencing their practise include medical orders, the temperament of the child, a history of febrile convulsions, parental requests, colleagues and ward norms. Nurses have a 'temperature' at which they consider a child febrile (37.2-39.0 degrees C) and many reported a 'temperature' at which they administered antipyretics (37.5-39.0 degrees C). Antipyretics were administered to febrile children for pain relief, irritability, at the request of parents and to settle a child for the night. Administration was reported to be higher during the day and evening shifts, at medication rounds and when the ward was busy. At night, nurses were reluctant to wake a sleeping febrile child, preferring to observe them instead. Recommendations to promote consistent fever management practises are included.

Determinants of nurses' intention to administer opioids for pain relief.

A statewide cross-sectional survey was conducted in Australia to identify the determinants of registered nurses' intention to administer opioids to patients with pain. Attitudes, subjective norms and perceived control, the key determinants of the Theory of Planned Behavior, were found to independently predict nurses' intention to administer opioids to these patients. Perceived control was the strongest predictor. Nurses reported positive overall attitudes towards opioids and their use in pain management. However, many negative attitudes were identified; for example, administering the least amount of opioid and encouraging patients to have non-opioids rather than opioids for pain relief. The findings related to specific attitudes and normative pressures provide insight into registered nurses' management of pain for hospitalized patients and the direction for educational interventions to improve registered nurses' administration of opioids for pain management.

Mentoring in health administration: the critical link in executive development.

Career development in the next century will be predicated on the ability to forge hierarchical as well as lateral relationships within diverse organizational environments. Mentoring relationships may provide the critical link for future health executives to remain involved in their organization and their profession. This national study of 540 healthcare managers examined the prevalence of mentoring relationships according to demographic, organizational, and professional variables. Mentors appeared to influence access to promotional opportunities for managers in the healthcare industry and provide a mechanism for executive development.

Cross-gender mentoring and career development in the health care industry.

Career development in the next century will be predicated upon the ability to forge hierarchical as well as lateral relationships. This study of 223 managers in the health care industry found that mentors influenced the career mobility of female executives and ensured access to promotions within the organization.

Managing environmental uncertainty: an analysis of executive behavior in the health and social service sector.

Executives who are involved in a variety of professional associations may be in a more favorable position to manage environmental uncertainty because of their ability to access information through the informal network. This study examined the professional involvement of 116 executives in the health and social service sector and found that leadership status within a professional association influenced contractual agreements between executives and a regional area agency on aging.

Quantitation of bacteria in blood of typhoid fever patients and relationship between counts and clinical features, transmissibility, and antibiotic resistance.

Salmonella typhi was isolated from 369 and Salmonella paratyphi A was isolated from 6 of 515 Vietnamese patients with suspected enteric fever. Compared with conventional broth culture of blood, direct plating of the buffy coat had a diagnostic sensitivity of 99.5% (95% confidence interval [CI], 97.1 to 100%). Blood bacterial counts were estimated by the pour plate method. The median S. typhi count in blood was 1 CFU/ml (range, <0.3 to 387 CFU/ml), of which a mean of 63% (95% CI, 58 to 67%) were intracellular. The mean number of bacteria per infected leukocyte was 1.3 (interquartile range [IQR], 0.7 to 2.4) CFU/cell (n = 81). Children (< 15 years old; n = 115) had higher median blood bacterial counts than adults (n = 262): 1.5 (range, <0.3 to 387) versus 0.6 (range, <0.3 to 17.7) CFU/ml (P = 0.008), and patients who excreted S. typhi in feces had higher bacteremias than those who did not: a median of 3 (range, <0.3 to 32) versus 1 (range, <0.3 to 68) CFU/ml (P = 0.02). Blood bacterial counts declined with increasing duration of illness (P = 0.002) and were higher in infections caused by multidrug-resistant S. typhi (1.3 [range, <0.3 to 387] CFU/ml; n = 313) than in infections caused by antibiotic-sensitive S. typhi (0.5 [range, <0.3 to 32] CFU/ml; n = 62) (P = 0.006). In a multivariate analysis this proved to be an independent association, suggesting a relationship between antibiotic resistance and virulence in S. typhi.

Positioning for capitation in long-term care: a profile of vertical integration strategies in health and social service organizations.

During the next decade, the population over age 65 is expected to increase by 11% while the population over age 85 is expected to increase by 42%. These projections suggest that many organizations which currently provide services to the aged will be required to design a range of new products and services for this diverse population. Vertically integrated services provide a viable opportunity to competitively position an organization to respond to the diverse needs of an aged market. Since vertical integration will be essential in negotiating capitate contracts for the aged in the future, this study examined the extent of vertical integration in 116 health and social service organizations in an urban market with an expanding geriatric population.