Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

Effect of replacing soybean meal protein with protein from upland cottonseed, Pima cottonseed, or extruded Pima cottonseed on production of lactating dairy cows.

Pima cotton production is increasing in the United States, but Pima cottonseed generally contains higher concentrations of the antinutritive pigment gossypol than conventional upland cottonseed. Heating promotes the reaction of gossypol with protein, reducing gossypol absorption and toxicity. The objective of this study was to assess the nutritional value for dairy cattle of Pima cottonseed cake (PCSC) that was heated and oil largely removed by an experimental extrusion process, compared with upland cottonseed (UCS) and Pima cottonseed (PCS). The PCS had greater crude protein (CP) and ether extract, less neutral detergent fiber (NDF) and acid detergent fiber (ADF), similar total gossypol, but higher (-)-gossypol isomer compared with UCS. Extrusion reduced lipid content by 73%, increased concentrations of CP, NDF, and ADF, and reduced total gossypol, (+)-gossypol, and (-)-gossypol in PCSC versus PCS. Forty lactating Holsteins (8 with ruminal cannulas) were blocked by days in milk into 5 squares in a replicated, incomplete 8 × 8 Latin square, and were fed diets containing, on a dry matter (DM) basis, 30% alfalfa silage, 31% corn silage, 21 to 25% high-moisture corn, and about 15% CP. Diets were fed as total mixed rations for ad libitum intake. Supplemental CP was from (1) solvent soybean meal (SSBM) only or 50% from SSBM plus 50% from (2) UCS, (3) PCS, (4) PCSC, (5) UCS plus PCS, and (6) UCS plus PCSC, or (7) 50% from expeller soybean meal (ESBM) plus 50% from PCS, and (8) 50% from ESBM plus 50% from PCSC. Periods were 4 wk long (total of 16 wk); production data were collected over the last 2 wk and blood and ruminal samples were taken on d 28 of each period. Data were analyzed using Proc Mixed of SAS (SAS Institute Inc., Cary, NC). Diet affected dry matter intake, with greatest intake on diet 6 and lowest intake on diets 1 and 3. The highest milk fat content was observed on diet 5 and the greatest fat yield on diet 7; fat content and yield were lowest on diet 1 (soybean meal control). Milk fat secretion was proportional to dietary fat content, indicating that cottonseed oil was used effectively for milk fat synthesis. We observed a trend for an effect on milk protein yield with the greatest protein secretion occurring on diet 7. Milk urea was lowest on diets 3, 7, and 8. Ruminal concentrations of branched-chain volatile fatty acids were lower, or tended to be lower, when PCSC replaced either UCS or PCS in the diet, suggesting reduced degradation and increased escape of PCSC protein. Among cottonseed-containing diets, total gossypol intake was lowest on PCSC, intermediate on PCS, and highest on UCS. Total gossypol and both (+)- and (-)-isomers of gossypol were higher in blood plasma on PCS and lower on PCSC than on the corresponding diets containing UCS, indicating that the extrusion process reduced gossypol absorption. In this trial, production on diets supplemented with UCS, PCS, or PCSC was comparable to that on diets containing soybean meal.

Ruminal fermentation and amino acid flow in Holstein steers fed whole cottonseed with elevated concentrations of free fatty acids in the oil.

The influence of feeding whole cottonseed (WCS) containing elevated concentrations of free fatty acids (FFA) in the oil on ruminal fermentation and amino acid (AA) flow to the abomasum was evaluated in a 4 x 4 Latin square trial. Four ruminally and abomasally cannulated Holstein steers were fed diets containing 12.5% of dry matter as WCS with concentrations of 8.0, 11.3, 14.7, or 18.0% FFA in the oil. Intake, ruminal digestibility, and flow to the abomasum of dry matter, organic matter, and acid detergent fiber were not affected by FFA level of WCS. Intake of neutral detergent fiber and total kilograms of neutral detergent fiber digested in the rumen were similar for all treatments. Ruminal neutral detergent fiber digestibility was lower for 8 and 14.7% FFA, resulting in a cubic effect on flow to the abomasum. Ruminal pH, molar proportions of isobutyrate, and total branched-chain volatile fatty acids (VFA) decreased linearly, whereas molar proportions of acetate and acetate:propionate ratio increased linearly as FFA in WCS increased. Total VFA were lower, and molar proportions of propionate were higher, for 8 and 14.7% FFA, resulting in a cubic effect. Intake of N, total N flow, and nonmicrobial N flow to the abomasum were similar among treatments. Flow of microbial N was lower for the 11.3% FFA treatment, resulting in a quadratic response. Only nonsignificant differences were observed in AA flow to the abomasum. Results of this trial indicate that WCS with FFA up to 18% may result in small changes in rumen fermentation.

Performance of lactating dairy cows fed whole cottonseed with elevated concentrations of free fatty acids in the oil.

Twenty-four multiparous cows were used in a 10-wk randomized block design trial to evaluate the effects of feeding whole cottonseed (WCS) containing increasing concentrations of free fatty acids (FFA) in the oil on nutrient intake and digestibility, milk yield and composition, and select plasma metabolites. Two lots of WCS containing either 3 or 12% FFA were blended to provide WCS with 3, 6, 9, and 12% FFA. Cottonseeds were included in the wheat silage-based total mixed ration at 12.5% of dry matter (DM). There was no difference in intakes of DM, crude protein (CP), or neutral detergent fiber; yield of milk; or percentages of milk protein, lactose, or SNF. Milk fat percentage was lowest for the diet containing WCS with 6% FFA. Concentrations of individual milk fatty acids C6:0 decreased and C16:1 increased linearly as FFA in WCS increased. A cubic response was observed for concentrations of C8:0, C10:0, and C12:0 because of higher concentrations when diets contained WCS with 6% FFA than 3 and 12% FFA, which were higher than 9% FFA. Intake and apparent total tract digestibility of acid detergent fiber increased linearly as FFA concentration in WCS increased. Apparent NDF digestibility was highest for diets containing WCS with 3 and 6% FFA; CP digestibility was highest with WCS containing 3 and 9% FFA. Differences in milk fatty acid concentration and nutrient digestibility suggest minor changes in rumen fermentation; however, feeding WCS with up to 12% FFA did not negatively impact nutrient intake and digestibility or milk yield or composition.

Herbal medicine on the rise: the case of 'awa.

There has been increasing interest in 'awa on several levels (e.g., cultural, medicinal, economic). The present article explores the issues surrounding 'awa use, highlights existing literature, places the discussion in its proper indigenous context, and sheds light on the tensions fueled by culturally inappropriate practice. In concluding the article, recommendations within a native context are put forth in four domains: (a) education, (b) research, (c) analysis and implementation of legal protections, and (d) economic development.

Effect of sugars and malate on ruminal microorganisms.

The objective of this study was to examine the effects of a commercial feed supplement that contains sugars and malate on lactate fermentation by Selenomonas ruminantium grown in batch culture. Experiments also were conducted to examine the effects of this feed supplement on the mixed ruminal microorganism fermentation of ground corn and soluble starch in the presence and absence of 5 mg/kg of monensin. When S. ruminantium strains HD4 and H18 were incubated in basal medium that contained DL-lactate, some DL-lactate was utilized by both strains after 24 h. In the presence of 1 g/L of sugars plus malate commercial feed supplement, both strains used most of the carbohydrate associated with the feed supplement between 6 and 8 h, and lactate was the main end product. In ground corn fermentations by mixed ruminal microorganisms, 2.25 and 3.25 g/L of sugars plus malate commercial feed supplement increased concentrations of acetate, propionate, and total volatile fatty acids, while 3.25 g/L increased lactate and decreased final pH and butyrate. Fermentation of soluble starch in the presence of both concentrations of sugars plus malate commercial feed supplement increased concentrations of acetate, propionate, and total volatile fatty acids and decreased the acetate:propionate ratio. In the presence of 5 mg/kg of monensin, sugars plus malate treatment increased concentrations of propionate and total volatile fatty acids in ground corn and soluble starch fermentations. Collectively, these results suggest that the sugars plus malate commercial feed supplement stimulates the ruminal fermentation.

Effects of a Saccharomyces cerevisiae culture on in vitro mixed ruminal microorganism fermentation.

Previous research has shown that Saccharomyces cerevisiae culture increases lactate utilization and cellulose digestion by pure cultures of ruminal bacteria. Based on these pure culture results, in vitro mixed ruminal microorganism fermentations were conducted to determine the effects of 0.35 and 0.73 g/L of Sacc. cerevisiae culture on the fermentation of ground corn, maltose, alfalfa hay, bermudagrass hay, and lactate. In addition, experiments were performed to evaluate the effects of Sacc. cerevisiae culture and monensin on the mixed ruminal microorganism fermentation. In the presence of ground corn, both concentrations of Sacc. cerevisiae culture had little effect on final pH or fermentation products, except the 0.35 g/L treatment increased valerate concentration. Saccharomyces cerevisiae culture had little effect on final pH or fermentation products in maltose or lactate fermentations. When alfalfa hay was the substrate, 0.73 g/L of Sacc. cerevisiae culture increased propionate concentration and both treatments decreased the acetate to propionate ratio. In the case of Coastal bermudagrass hay, 0.73 g/L Sacc. cerevisiae culture increased concentrations of acetate, propionate, CH4, butyrate, isovalerate, valerate, and decreased the acetate to propionate ratio, whereas both treatments increased total volatile fatty acid concentrations. Similar to alfalfa hay, in vitro dry matter disappearance of Coastal bermudagrass hay was numerically increased in the presence of Sacc. cerevisiae culture. Monensin altered the fermentation by decreasing concentrations of CH4 and lactate and increasing concentrations of propionate. There was no interaction between Sacc. cerevisiae culture and monensin. In conclusion, the incorporation of Sacc. cerevisiae culture into mixed ruminal microorganism fermentations of ground corn, maltose, or lactate had little effect on final pH and fermentation products. However, in the presence of alfalfa hay or Coastal bermudagrass hay Sacc. cerevisiae culture increased concentrations of several fermentation products and numerically increased in vitro dry matter disappearance of forage fiber.

Transdermal delivery of estradiol in postmenopausal women with a novel topical aerosol.

The objective of this study was to determine if a novel metered-dose topical aerosol (MDTA) formulation containing the new dermal penetration enhancer, padimate O, could enhance the transdermal delivery of estradiol to an extent that would result in clinically relevant plasma concentrations. The estradiol MDTA (with padimate O) was applied once daily at 0800 h to postmenopausal women for 9 days, and plasma estradiol and estrone was measured daily (24 h postapplication) by radioimmunoassay. The topical dose was administered as three 1 mg doses of estradiol, each applied as a single spray over 10 cm2 which were placed adjacent to each other on the subject's ventral forearm. None of the subjects tested showed any sign of skin irritation at the application site over the entire study period using the Draize irritation score. In four postmenopausal women (age 54-63 years, weight 67-93 kg) the mean estradiol level 24 h postapplication over the 9 day study period was 53 pg/mL. This result was significantly greater (p < 0.001) than the baseline value of 13 pg/mL. The mean estradiol/estrone ratio also rose significantly (p < 0.04) from a baseline value of 0.2 up to 0.8. We conclude that this novel MDTA formulation significantly enhances the transdermal delivery of estradiol to allow a clinically relevant dose of estradiol to be delivered in postmenopausal women with once daily dosing.