Milk was collected from eight Holstein cows four times before and four times after intramammary infection with Streptococcus agalactiae. Postinfection milk had significantly higher somatic cell count (SCC) (849,000 cells/ml) than preinfection milk (45,000 cells/ml). High SCC raw milk had more lipolysis and proteolysis than low SCC raw milk. Pasteurized, homogenized, 2% fat milks from pre- and postinfection periods were stored at 5 degrees C and analyzed for lipolysis, proteolysis, microbial quality, and sensory attributes at 1, 7, 14, and 21 d post processing. During refrigerated storage, the average rates of free fatty acid increase (i.e., lipolysis) and casein hydrolysis in high SCC milk were, respectively, three and two times faster than those in low SCC milk. In general, standard plate counts, coliform counts, and psychrotrophic bacterial counts of both the high and low SCC milks remained low (<100,000 cfu/ ml) during 5 degrees C storage. Low SCC milk maintained high organoleptic quality for the entire 21-d shelf-life period. However, for high SCC milk, between 14 and 21 d, sensory defects were detected, which resulted in low overall quality ratings. The sensory defects mainly included rancidity and bitterness and were consistent with higher levels of lipolysis and proteolysis. Hence, mastitis adversely affected the quality of pasteurized fluid milk. It is recommended that the fluid milk industry consider implementation of premium quality payment programs for low SCC milks.

The objective was to investigate the effect of different dry cow feeding strategies on the degree of ketonemia postpartum. Epidemiologic studies provide evidence of an association between elevated β-hydroxybutyrate (BHBA) concentrations in postpartum dairy cows and a decreased risk for reproductive success as well as increased risk for several diseases in early lactation, such as displacement of the abomasum and metritis. The plane of energy fed to cows in the prepartum period has been shown to influence ketogenesis and the degree of negative energy balance postpartum. Our hypothesis was that a high-fiber, controlled-energy diet (C) fed during the dry period would lead to a lower degree of hyperketonemia in the first weeks postpartum compared with either a high-energy diet (H), or a diet where an intermediate level of energy would only be fed in the close-up period (starting at 28d before expected parturition), following the same controlled-energy diet in the far-off period. Hyperketonemia in this study was defined as a blood BHBA concentration of ≥1.2mmol/L. Holstein cows (n=84) entering parity 2 or greater were enrolled using a randomized block design and housed in individual tiestalls. All treatment diets were fed for ad libitum intake and contained monensin. Cows received the same fresh cow ration after calving. Blood samples were obtained 3 times weekly before and after calving and analyzed for BHBA and nonesterified fatty acids (NEFA). Milk components, production, and dry matter intake were recorded and energy balance was calculated. Repeated measures ANOVA was conducted for the outcomes dry matter intake, energy balance, BHBA and NEFA concentrations, milk and energy-corrected milk yield, as well as milk composition. Predicted energy balance tended to be less negative postpartum in group C and cows in this group had fewer episodes of hyperketonemia compared with both the intermediate group and group H in the first 3 wk after calving. Postpartum BHBA and NEFA concentrations over time were highest in group H and lowest in group C, whereas milk production was not affected by prepartum plane of energy. Analysis of milk fatty acid composition showed a higher yield of preformed fatty acids in group H compared with group C, suggesting higher lipid mobilization for cows fed H. In this study, a 1-group, controlled-energy dry period approach decreased the degree of negative energy balance as well as the number of episodes and degree of hyperketonemia postpartum.

A viable and cost-effective approach to managing P on dairy farms is to minimize excess P in diets, which in turn leads to less excretion of P in manure without impairing animal performance. A questionnaire survey was conducted, coupled with on-site feed and fecal sample collection and analysis on dairy farms in New York, Pennsylvania, Delaware, Maryland, and Virginia. The purpose was to assess dietary P levels and to identify critical control points pertaining to P feeding management. Survey responses, 612 out of 2500 randomly selected farms, revealed a wide range of dietary P concentrations for lactating cows, from 3.6 to 7.0 g/kg of feed DM. The mean was 4.4 g/kg, which was 34% above the level recommended by the NRC for 27.9 kg milk/d, the mean milk yield in the survey. Higher P concentrations in diets were not associated with higher milk yields (n = 98, R2 = 0.057 for the survey farms; n = 92, R2 = 0.043 for farms selected for on-site sampling). However, higher dietary P led to higher P excretion in feces (n = 75, R2 = 0.429), with much of the increased fecal P being water soluble. Phosphorus concentrations in diet samples matched closely with P concentrations in formulated rations, with 67% of the feed samples deviating <10% from the formulations. On 84% of the survey farms, ration formulation was provided by professionals rather than producers themselves. Most producers were feeding more P than cows needed because it was recommended in the rations by these consultants. In conclusion, P fed to lactating cows averaged 34% above NRC recommendations; to reduce excess dietary P, ration formulation is the critical control point.

The objectives of this study were to determine the effect of decreasing dietary cation-anion difference [DCAD; (Na + K) - (Cl + S)] of the prepartum diet on aspects of mineral metabolism, energy metabolism, and performance of peripartum dairy cows. Multiparous Holstein cows (n = 89) were enrolled between 38 and 31 d before expected parturition and randomized to treatments in a completely randomized design (restricted to balance for previous 305-d mature equivalent milk production, parity, and body condition score) at 24 d before expected parturition. Treatments consisted of a low-K ration without anion supplementation [CON; n = 30, DCAD = +18.3 mEq/100 g of dry matter (DM)]; partial anion supplementation to a low-K ration (MED; n = 30, DCAD = +5.9 mEq/100 g of DM); and anion supplementation to a low-K ration to reach a targeted average urine pH between 5.5 and 6.0 (LOW; n = 29, DCAD = -7.4 mEq/100 g of DM). Cows were fed a common postpartum diet and data collected through 63 d in milk. Urine pH (CON = 8.22, MED = 7.89, and LOW = 5.96) was affected quadratically by decreasing prepartum DCAD. A linear relationship between urine pH and urine Ca:creatinine ratio was observed (r = -0.81). Plasma Ca concentrations in the postpartum period (d 0 to 14; CON = 2.16, MED = 2.19, and LOW = 2.27 mmol/L) were increased linearly with decreasing prepartum DCAD. A treatment by parity (second vs. third and greater) interaction for postpartum plasma Ca concentration suggested that older cows had the greatest response to the low DCAD diet and older cows fed LOW had decreased prevalence of hypocalcemia after calving. A quadratic effect of decreasing DCAD on prepartum DMI was observed (CON = 13.6, MED = 14.0, and LOW = 13.2 kg/d). Milk production in the first 3 wk postpartum was increased linearly with decreasing DCAD (CON = 40.8, MED = 42.4, and LOW = 43.9 kg/d) and DMI in this period also tended to linearly increase (CON = 20.2, MED = 20.9, and LOW = 21.3 kg/d). Overall, effects on intake and milk yield analyzed over wk 1 to 9 postpartum were not significant. This study demonstrates that feeding lower DCAD diets prepartum improves plasma Ca status in the immediate postpartum period and results in increased DMI and milk production in the 3 wk after parturition. Compared with no anion supplementation or lower levels of anion supplementation, greater improvements were observed with the lower DCAD feeding strategy, in which an average urine pH of 5.5 to 6.0 was targeted.

PurposeAngiosarcoma is a rare aggressive endothelial cell cancer with high mortality. Isolated reports suggest immune checkpoint inhibition efficacy in angiosarcoma, but no prospective studies have been published. We report results for angiosarcoma treated with ipilimumab and nivolumab as a cohort of an ongoing rare cancer study.MethodsThis is a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks) for metastatic or unresectable angiosarcoma. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free (PFS) and overall survival, and toxicity. A two-stage design was used.ResultsOverall, there were 16 evaluable patients. Median age was 68 years (range, 25–81); median number of prior lines of therapy, 2. Nine patients had cutaneous and seven non-cutaneous primary tumors. ORR was 25% (4/16). Sixty per cent of patients (3/5) with primary cutaneous scalp or face tumors attained a confirmed response. Six-month PFS was 38%. Altogether, 75% of patients experienced an adverse event (AE) (at least possibly related to drug) (25% grade 3–4 AE); 68.8%, an immune-related AE (irAE) (2 (12.5%), grade 3 or 4 irAEs (alanine aminotransferase/aspartate aminotransferase increase and diarrhea)). There were no grade 5 toxicities. One of seven patients in whom tumor mutation burden (TMB) was assessed showed a high TMB (24 mutations/mb); that patient achieved a partial response (PR). Two of three patients with PDL1 immunohistochemistry assessed had high PDL1 expression; one achieved a PR.ConclusionThe combination of ipilimumab and nivolumab demonstrated an ORR of 25% in angiosarcoma, with three of five patients with cutaneous tumors of the scalp or face responding. Ipilimumab and nivolumab warrant further investigation in angiosarcoma.Trial registration numberNCT02834013.

The objective of this study was to evaluate the effect of dietary starch content and monensin (MON) on metabolism of dairy cows during early lactation. Before parturition, primiparous (n=21) and multiparous (n=49) Holstein cows were fed a common controlled-energy close-up diet with a daily topdress of either 0 or 400mg/d monensin. From d 1 to 21 postpartum, cows were fed a high-starch (HS; 26.2% starch, 34.3% neutral detergent fiber, 22.7% acid detergent fiber, 15.5% crude protein) or low-starch (LS; 21.5% starch, 36.9% neutral detergent fiber, 25.2% acid detergent fiber, 15.4% crude protein) total mixed ration with a daily topdress of either 0mg/d monensin (CON) or 450mg/d monensin (MON), continuing with prepartum topdress assignment. From d 22 through 63 postpartum, all cows were fed HS and continued with the assigned topdress treatment until d 63. Cows fed HS had higher plasma glucose and insulin and lower nonesterified fatty acids (NEFA) than cows fed LS during d 1 to 21 postpartum. Cows fed LS had elevated early-lactation β-hydroxybutyrate (BHBA) compared with cows fed HS. Cows fed HS had greater insulin resistance and increased plasma haptoglobin in the early lactation period. There was no effect of MON on postpartum plasma NEFA. Cows fed MON had higher plasma glucose compared with CON cows, which was driven by a MON × parity interaction in which primiparous cows fed MON had greater plasma glucose concentrations than cows fed CON. Cows fed MON had lower plasma BHBA compared with CON, which was contributed to by a MON × parity interaction in which primiparous cows fed MON had lower BHBA concentrations than CON. Starch treatment had no effect on overall liver triglyceride content. Primiparous cows fed MON had increased liver triglyceride content compared with CON primiparous cows, and multiparous cows fed MON had decreased liver triglyceride content compared with CON cows. Multiparous cows fed LS with MON had higher liver glycogen content than multiparous cows fed the LS without MON, with no effect of MON treatment for multiparous cows fed HS. There was no effect of starch or MON treatment on liver capacity to oxidize propionate to CO2, and effects of starch on gluconeogenesis were not significant. Cows fed MON tended to have greater capacity to convert propionate to glucose than CON. Supplementation with MON increased the ratio of glucose to CO2, which indicated that cows fed MON had a greater propensity to convert propionate to glucose. Overall, cows fed more propiogenic diets in early lactation (high starch or monensin) exhibited improved energy metabolism during early lactation.

The objective of this study was to evaluate the effect of postpartum dietary starch content and monensin supplementation throughout the periparturient period and into early lactation on production performance of dairy cows during early lactation. Prior to parturition, primiparous (n=21) and multiparous (n=49) Holstein cows were fed a common controlled-energy close-up diet with a daily topdress of either 0 or 400mg/d monensin. From d 1 to 21 postpartum, cows were fed a high-starch (HS; 26.2% starch, 34.3% NDF, 22.7% ADF, 15.5% CP) or low-starch (LS; 21.5% starch, 36.9% NDF, 25.2% ADF, 15.4% CP) total mixed ration with a daily topdress of either 0mg/d of monensin or 450mg/d monensin (MON), continuing with prepartum topdress treatment assignment. From d 22 through 63 postpartum, cows were fed HS and continued with their assigned daily topdress. Interactions of starch content and MON supplementation were not significant for any of the variables measured. Cows fed HS from wk 1 to 3 postpartum had higher early-lactation milk yields (starch × week interaction) compared with LS cows, but HS cows also had lower percentages of milk fat, true protein, lactose, and total solids during the same period, resulting in similar yields of energy-corrected milk (ECM) between starch treatments. Cows fed HS had higher early-lactation dry matter intake (DMI; starch × week interaction) and lost less body condition score during wk 1 to 3, contributing to improved energy balance postpartum. No effect of starch treatment was observed on apparent total-tract dry matter or starch digestibilities assessed during d 18 to 19 (±2) postpartum, although cows fed the LS diet had greater apparent total-tract NDF digestibility compared with cows fed the HS diet. Cows fed MON had higher DMI and higher milk yields during the first 9 wk of lactation. However, all cows had similar yields of ECM because of trends for lower milk fat content during early lactation. In part because of similar yields of ECM between these treatments and higher DMI for cows fed MON, ECM per DMI during the first 9 wk of lactation was not affected by MON treatment. There was no effect of MON treatment on apparent total-tract dry matter, NDF, or starch digestibilities. Overall, cows fed more propiogenic diets in early lactation (HS or MON) had increased milk yield and DMI during the immediate postpartum period, indicating that diets with greater propiogenic capacity do not have detrimental effects on early-lactation DMI.

Multiparous Holstein cows (n = 337) on two commercial dairy farms were used to determine the effects of feeding a close-up diet for 21 (treatment S) or 60 d (treatment L). Milk yield was not affected by treatment; however, cows fed treatment S tended to have increased yields of fat, 3.5% fat-corrected milk, and protein during the first 5 mo of their subsequent lactation compared to treatment L. Cows fed treatment L gained more body condition score (BCS) during the dry period and had longer days to first service. As a secondary objective, relationships of BCS at dry off and subsequent performance were evaluated. Cows with initial BCS < or =3.0 (thinner) tended to produce more milk during early lactation than cows with initial BCS > or = 3.25 (fatter). A trend for an interaction of treatment and initial BCS existed for milk yield such that thinner cows fed treatment S produced the most milk and fatter cows fed treatment S produced the least amount of milk; cows fed treatment L regardless of BCS produced an intermediate amount of milk. Subsequent reproductive performance was similar among thinner and fatter cows. These data indicate that 2 group nutritional strategies for dry cows are preferred, and BCS at dry off should be considered when determining grouping and nutritional strategies for dry cows. Furthermore, moderately thin cows at dry off do not have impaired performance during their subsequent lactation compared to cows of greater BCS.