Hyperthermic chest wall re-irradiation in recurrent breast cancer: a prospective observational study.

PURPOSE: To prospectively investigate the role of re-irradiation (re-RT) combined with hyperthermia (HT) in a contemporary cohort of patients affected by recurrent breast cancer (RBC). METHODS: Within the prospective registry HT03, patients with resected RBC and previous irradiation were included. Re-RT was applied to the recurrence region with doses of 50-50.4 Gy, with a boost up to 60-60.4 Gy to the microscopically or macroscopically positive resection margins (R1/R2) region. Concurrent HT was performed at 40-42 ℃. Primary endpoint was LC. Acute and late toxicity, overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) were also evaluated. RESULTS: 20 patients and 21 RBC were analyzed. Median re-RT dose was 50.4 Gy and a median of 11 HT fractions were applied. Re-RT+HT was well tolerated, with three patients who experienced a grade (G) 3 acute skin toxicity and no cases of ≥G3 late toxicity. With a median follow up of 24.7 months, two local relapses occurred. Ten patients experienced regional and/or distant disease progression. Five patients died, four of them from breast cancer. PFS was favorable in patients treated with re-RT+HT for the first recurrence with doses of 60 Gy. A trend towards better CSS was found in patients with negative or close margins and after doses of 60 Gy. CONCLUSION: Full-dose re-RT+HT for RBC is well tolerated, provides good LC, and seems to be more effective when applied at the time of the first relapse and after doses of 60 Gy. The registry will be continued for validation in a larger cohort and with longer follow-up.

Responses to metabolic challenges in dairy cows with high or low milk yield during an extended lactation.

Responses of dairy cows with high or low milk yield (MY) beyond 450 d in milk (DIM) to 3 metabolic challenges were investigated. Twelve multiparous Holstein-Friesian cows that calved in late winter in a pasture-based system were managed for a 670-d lactation by delaying re-breeding. Cows were selected for either high MY (18.9 ± 1.69 L/cow per d; n = 6) or low MY (12.3 ± 3.85 L/cow per d; n = 6) at 450 DIM. Cows were housed indoors for 2 periods of 12 d at approximately 460 and 580 DIM. Each cow was fed freshly cut pasture (460 DIM) or pasture silage (580 DIM) plus 6.0 kg of DM barley grain daily (approximately 200 MJ of total metabolizable energy/cow per day). At all other times, cows were managed as a single herd and grazed pasture supplemented with cereal grain to an estimated intake of 180 MJ of metabolizable energy/cow per d. Cows were fitted with a jugular catheter during the final week of each experimental period. Over a period of 3 d, each cow underwent an intravenous glucose tolerance test (0.3 g/kg of body weight), an insulin tolerance test (0.12 IU of insulin/kg of body weight), and a 2-dose epinephrine challenge (0.1 and 1.6 µg/kg of body weight). Cows selected for high MY had greater milk and milk solids yields between 450 and 580 DIM than low MY cows (17.3 vs. 10.8 ± 1.49 kg of milk/d and 2.4 vs. 1.5 ± 0.23 kg of milk solids/d). The results indicated that whole body and peripheral tissue responsiveness to insulin may vary between cows of high and low MY. Following the glucose tolerance test, high MY cows had a lower plasma insulin response with a greater glucose area under the curve than low MY cows. Further, high MY cows had slower plasma glucose clearance compared with low MY cows during an insulin tolerance test. The plasma nonesterified fatty acid (NEFA) responses to the IVGTT and the ITT were similar between cows of high and low MY, but the clearance of NEFA from the plasma following both the IVGTT and ITT were slower at 580 compared with 460 DIM. The sensitivity to epinephrine was greater in high MY cows compared with low MY cows as the glucose and NEFA area under the curve and the percentage change in NEFA were greater in high MY after the low dose epinephrine challenge. However, the lipolytic but not the glucose appearance in response to epinephrine was greater in high MY cows than low MY cows. Following the high dose of epinephrine, the glucose response was lower, but the NEFA response was greater in high MY compared with low MY cows. Cows able to sustain greater MY to 580 DIM had a greater propensity for lipid mobilization, possibly enhancing nutrient partitioning to the mammary gland during the late stages of an extended lactation.

Plasma glucose and nonesterified fatty acids response to epinephrine challenges in dairy cows during a 670-d lactation.

This experiment investigated the metabolic response to a 2-dose epinephrine challenge of dairy cows undergoing an extended lactation. Twelve multiparous Holstein-Friesian cows that calved in late winter in a seasonally calving pasture-based dairying system were managed for a 670-d lactation by delaying rebreeding. In each of four 40-d experimental periods commencing at 73, 217, 422, and 520 (±9.1) d in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM), supplemented with 1 (CON; n = 6) or 6 kg of grain (GRN; n = 6) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with a jugular catheter during the final week of each experimental period. Two doses of epinephrine (0.1 and 1.6 µg/kg of body weight) were infused via the catheter 2 h apart to each cow at approximately 100, 250, 460, and 560 DIM. Blood plasma concentrations of glucose and nonesterified fatty acids (NEFA) were measured before and after infusions. Cows in the GRN treatment had greater milk yield, milk fat and protein yields, and body weight than cows in the CON treatment. The maximum plasma glucose concentration was observed at 100 DIM for both the low and high doses of epinephrine. Thus, sensitivity and responsiveness to exogenous epinephrine were greater during early lactation, coinciding with increased priority of milk synthesis. Both the sensitivity and responsiveness to epinephrine decreased with decreasing milk yield, as measured by the acute appearance of NEFA in the plasma. Increased plasma glucose and NEFA clearance rates before 300 DIM indicated greater uptake of these substrates by the mammary gland for milk synthesis in early and mid lactation. These results support previous findings that major changes occur in terms of adipose tissue metabolism during extended lactations. Overall, sensitivity to epinephrine was not affected by diet, but responsiveness was greater in cows fed the GRN diet. The endocrine regulation of nutrient partitioning throughout traditional and extended lactations is complex, with many interactions between stage of lactation, diet, and milk yield potential.

Increased feeding frequency increased milk fat yield and may reduce the severity of subacute ruminal acidosis in higher-risk cows.

The objectives of this study were to determine whether feeding behavior is different between cows at higher or lower risk for subacute ruminal acidosis (SARA) and whether increasing feeding frequency could be used to reduce the severity of SARA in higher-risk cows. In preliminary studies, 16 ruminally cannulated lactating cows were fed high-grain diets once per day to increase the risk of SARA. After a 17-d diet adaptation, ruminal pH was measured every 30 s over 24 h. Cows were classified as higher-risk (n = 7) or lower-risk (n = 9) for SARA based on an acidosis index (area of pH <5.8/dry matter intake). Feeding behavior was recorded every 5 min over the same 24 h. The 24-h observation period was analyzed in 3 periods of 8 h after feeding. Although there was no significant difference in overall dry matter intake, higher-risk cows spent more time eating in the first 8-h period after feeding than lower-risk cows (186 vs. 153 min) and less time eating in the third 8-h period (19 vs. 43 min). In the primary experiment, 8 ruminally cannulated lactating cows were fed a high-grain diet once per day (1×; 0800 h) or 3 times per day (3×; 0800, 1500, and 2000 h) in a crossover design with 21-d periods (16 d of treatment adaptation and 5 d of data collection). Rumen pH and feeding behavior were measured over 72 h. Behavior data were summarized separately for the 3 periods (0800 to 1500, 1500 to 2200, and 2200 to 0800 h). Four cows were categorized as higher-risk and 4 as lower-risk, based on their acidosis index. The 3× feeding reduced eating time between 0800 and 1500 h (99 vs. 145 min) and increased eating time between 2200 and 0800 h (76 vs. 43 min) for all cows, regardless of category, compared with 1× feeding. For higher-risk cows, 3× feeding reduced the area below pH 5.8 (51 vs. 98 pH × min/d), but it did not affect rumen pH for the lower-risk cows. Milk yield was not different between groups, but 3× feeding increased milk fat yield (1.22 vs. 1.08 kg/d) for all cows, regardless of category, compared to 1× feeding. Our results suggest that cows at higher risk for SARA eat less evenly throughout the day; increasing feeding frequency may reduce the severity of SARA in higher-risk cows and may also increase milk fat yield.

Short communication: Optimization of a timed artificial insemination program for reproductive management of heifers in Canadian dairy herds.

Pregnancy per AI (P/AI) following the use of 1 of 2 timed AI (TAI) protocols and 2 different intervals between TAI and resynchronization were compared in heifers that were inseminated with either conventional or sex-sorted semen. Holstein heifers (n = 317; 527 inseminations) were submitted to a 5-d Cosynch protocol with (+) or without (-) GnRH at the time of controlled internal drug release (CIDR) insertion on d 0, CIDR removal and a single PGF2α treatment on d 5, and TAI plus GnRH on d 8 (72 h later). Visual estrus detection (ED) was conducted on d 6 in the afternoon and d 7 in the morning and heifers observed in estrus were artificially inseminated on d 7 in the afternoon. Heifers were alternately assigned conventional or sex-sorted semen. Pregnancy was diagnosed by ultrasound 27 and 42 d after AI, and heifers diagnosed as nonpregnant were resynchronized, up to 3 times, starting on d 27 or 34 to provide an interbreeding interval of 35 or 42 d. Overall, TAI protocol had no effect on P/AI at 27 or 42 d after artificial insemination or on pregnancy loss, but P/AI following the first service tended to be higher in the -GnRH TAI group (66.3 vs. 56.8%). Pregnancy per AI at 27 d (61.9 vs. 55.5%) tended to differ between conventional and sex-sorted semen. Heifers artificially inseminated based on ED tended to have a greater P/AI (67.6 vs. 58.2%) and had decreased pregnancy loss (0.0 vs. 4.1%) than those submitted to TAI. A greater number of heifers in the -GnRH TAI protocol were artificially inseminated on ED than the +GnRH TAI protocol (21.5 vs. 13.7%). No difference in P/AI was observed between the 35- and 42-d interbreeding intervals; however, more heifers in the 42-d group were artificially inseminated based on ED than in the 35-d group (22.7 vs. 7.8%). A 5-d Cosynch+CIDR TAI protocol without the initial GnRH and with a single PGF2α at CIDR removal is an acceptable alternative to achieve high P/AI when either conventional or sex-sorted semen is used in Holstein heifers. Breeding heifers based on detected estrus increases labor, but has the potential to increase fertility.

Responses of plasma glucose and nonesterified fatty acids to intravenous insulin tolerance tests in dairy cows during a 670-day lactation.

The metabolic response of dairy cows undergoing an extended lactation to an insulin tolerance test (ITT) was investigated. Twelve multiparous Holstein-Friesian cows that calved in late winter in a pasture-based system were managed for a 670-d lactation by delaying rebreeding. Four 5-wk experimental periods commenced at approximately 73, 217, 422, and 520 d in milk (DIM). Cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1 kg dry matter (DM) of grain (control; CON) or 6 kg DM of grain (GRN). Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for CON and GRN, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated daily intake of 180 MJ of metabolizable energy/cow. Cows were fitted with a jugular catheter during the final week of each experimental period. An ITT using 0.12 IU of insulin/kg of body weight (BW) was conducted on each cow at approximately 100, 250, 460, and 560 DIM. Cows in the GRN treatment had greater milk yield, milk solids yield, and BW than cows in the CON treatment. Within treatment, individual cow responses to the ITT were highly variable. Plasma glucose and nonesterified fatty acid (NEFA) concentrations declined at all stages of lactation. The clearance rate of plasma glucose was slower before 300 DIM than after 300 DIM, which indicates greater inhibition of hepatic glucose synthesis and uptake of glucose by insulin-dependent tissues later in the lactation. The clearance rate, area under the curve, and recovery of plasma NEFA were greatest at 100 DIM, indicating greater responsiveness to the antilipolytic effect of insulin in early lactation, but also greater lipolytic responsiveness. The variation in response to the ITT was mostly a result of DIM rather than diet. However, the plasma NEFA response showed interactions between diet and DIM, indicating that energy intake may affect tissue responses to insulin. The responsiveness of peripheral tissues to insulin, primarily adipose tissue, changed throughout a 670-d lactation and contributed to a greater proportion of nutrients being partitioned to body reserves at the expense of milk yield as lactation progressed. Both stage of lactation and dietary intake have a role in the determination of whole-body and peripheral tissue responses to insulin; however, the exact mechanisms in control of this are unclear.

A 100-Year Review: A century of change in temperate grazing dairy systems.

From 1917 to 2017, dairy grazing systems have evolved from uncontrolled grazing of unimproved pastures by dual-purpose dairy-beef breeds to an intensive system with a high output per unit of land from a fit-for-purpose cow. The end of World War I signaled significant government investments in agricultural research institutes around the world, which coincided with technological breakthroughs in milk harvesting and a recognition that important traits in both plants and animals could be improved upon relatively rapidly through genetic selection. Uptake of milk recording and herd testing increased rapidly through the 1920s, as did the recognition that pastures that were rested in between grazing events yielded more in a year than those continuously grazed. This, and the invention and refinement of the electric fence, led to the development of "controlled" rotational grazing. This, in itself, facilitated greater stocking rates and a 5 to 10% increase in milk output per hectare but, perhaps more importantly, it allowed a more efficient use of nitrogen fertilizer, further increasing milk output/land area by 20%. Farmer inventions led to the development of the herringbone and rotary milking parlors, which, along with the "unshortable" electric fence and technological breakthroughs in sperm dilution rates, allowed further dairy farm expansion. Simple but effective technological breakthroughs in reproduction ensured that cows were identified in estrus early (a key factor in maintaining the seasonality of milk production) and enabled researchers to quantify the anestrus problem in grazing herds. Genetic improvement of pasture species has lagged its bovine counterpart, but recent developments in multi-trait indices as well as investment in genetic technologies should significantly increase potential milk production per hectare. Decades of research on the use of feeds other than pasture (i.e., supplementary feeds) have provided consistent milk production responses when the reduction in pasture intake associated with the provision of supplementary feed (i.e., substitution rate) is accounted for. A unique feature of grazing systems research over the last 70 yr has been the use of multi-year farm systems experimentation. These studies have allowed the evaluation of strategic changes to a component of the system on all the interacting features of the system. This technique has allowed excellent component research to be "systemized" and is an essential part of the development of the intensive grazing production system that exists today. Future challenges include the provision of skilled labor or specifically designed automation to optimize farm management and both environmental sustainability and animal welfare concerns, particularly relating to the concentration of nitrogen in each urine patch and the associated risk of nitrate leaching, as well as concerns regarding exposure of animals to harsh climatic conditions. These combined challenges could affect farmers' "social license" to farm in the future.

A survey of manufacturing and handling practices for monoclonal antibodies by pharmacy, nursing and medical personnel.

INTRODUCTION: There is a paucity of data available to assess the occupational health and safety risk associated with exposure to monoclonal antibodies. Industry standards and published guidelines are conflicting or outdated. Guidelines offer contrary recommendations based on an array of methodological approaches. This survey aimed to describe current practices, beliefs and attitudes relating to the handling of monoclonal antibodies by Australian medical, nursing and pharmacy clinicians. METHODS: An electronic survey was distributed between June and September 2013. Respondents were surveyed on three focus areas: institutional guideline availability and content, current practices and attitudes. Demographic data relating to respondent and primary place of practice were also collected. RESULTS: A total of 222 clinicians completed the survey, with representation from all targeted professional groups and from a variety of geographic locations. 92% of respondents reported that their institution prepared or administered monoclonal antibodies, with 87% specifically handling anti-cancer monoclonal antibodies. Monoclonal antibodies were mostly prepared onsite (84-90%) and mostly within pharmacy clean-rooms (75%) and using cytotoxic cabinets (61%). 43% of respondents reported access to institutional monoclonal antibody handling guidelines with risk reduction strategies including training and education (71%), spill and waste management (71%), procedures for transportation (57%) and restricted handling (50%). Nurses had a stronger preference towards pharmacy manufacturing than both doctors and pharmacists for a range of clinical scenarios. 95% of all respondents identified that professional or regulatory body guidelines are an important resource when considering handling practices. CONCLUSION: Monoclonal antibodies are most commonly handled according to cytotoxic drug standards and often in the absence of formal guidelines.

Associations between milk protein concentration at various stages of lactation and reproductive performance in dairy cows.

Milk protein concentration has been positively associated with a range of measures of reproductive performance in dairy cows. These beneficial associations are most likely due to factors affecting both milk protein concentration and reproductive performance possibly being mediated, in part, by energy balance during early lactation. However, it is likely that factors other than energy balance are also involved in these relationships. A retrospective single cohort study was conducted using subsets of data collected from 74 dairy herds with seasonal or split calving patterns. Associations between milk protein concentration at various stages of lactation and reproductive performance in Holstein dairy cows were assessed using random effects logistic regression and survival analysis with milk protein concentration during the cow's breeding period fitted as a time-varying covariate. The beneficial associations between milk protein concentration and each of the 4 selected indices for measuring reproductive performance were evident when milk protein concentration was derived for each 30-d period from calving up to 300d in milk. For the first 150d of lactation the adjusted odds ratios were highest from 31 to 60d and only slightly lower for all periods up to 150d of lactation. Estimated associations for 31 to 60d were stronger than for 0 to 30d. In addition, milk protein concentration during a cow's breeding period was positively associated with the subsequent daily hazard of conception, even after adjusting for milk protein concentration in the cow's first or second month of lactation. Milk protein concentrations from 0 to 30d of lactation were less closely correlated with concentrations measured at subsequent 30-d intervals; correlations were closer between other periods in lactation. These results indicate that the association between milk protein concentration and reproductive performance is partly due to factors other than the extent of negative energy balance in early lactation. However, it is possible that energy balance accounts for some of the relationship as the magnitude and direction of energy balance can vary within and between cows throughout lactation. Factors determining milk protein concentration during the first 30d of lactation are not identical to the causes of milk protein concentration later in lactation, and some of the latter causes of milk protein concentration may be more closely related to the underlying mechanisms contributing to the milk protein concentration-reproductive performance relationship. Milk protein concentrations from a single test day from any day of lactation predict subpopulations of cows with differing average reproductive performance; milk protein concentrations measured after 30d of lactation are more useful than concentrations measured in the first 30d for identifying these subpopulations. Further research is required to identify the causes of these associations.

Associations between milk protein concentration, milk yield, and reproductive performance in dairy cows.

Milk protein concentration in dairy cows has been positively associated with a range of measures of reproductive performance. It was possible that these associations were due to confounding by milk volume. A retrospective single cohort study was conducted using data collected from 74 dairy herds with seasonal or split calving patterns. Associations between milk protein concentration and reproductive performance in Holstein dairy cows were assessed using random effects logistic regression. The key finding from this study was that the associations between milk protein concentration in early lactation and reproductive performance were not due to confounding by milk yield. Associations between milk protein concentration and reproductive performance were weaker at higher early lactation milk yields, but positive associations were evident at all milk volumes assessed. The second major finding was that increases in milk yield were associated with improved proportions of cows pregnant by wk 6 and 21 at low to moderate milk protein concentrations but with decreases in these reproductive measures at high milk protein concentrations. Thus, no simple relationship is present between milk yield and reproductive performance; effects of milk yield depend on milk protein concentration. These results indicate that mechanisms causing the associations between milk protein concentration and reproductive performance may be linked to milk yield but these mechanisms operate over a wide range of milk yields (<2,000 to ≥5,000kg in the first 120d of lactation). Further research is required to identify the causes of these associations.

Associations of high and low milk protein concentrations with energy allocation, milk production, and concentrations of blood plasma metabolites and hormones in Holstein-Friesian cows.

A positive association between milk protein concentration (MPC) and reproductive performance in dairy cows has been shown in several studies globally. This association may positively influence farm productivity and profitability, particularly in seasonally calving, pasture-based herds. However, the differences in milk production and energy allocation, physical characteristics, and blood plasma nutrient status between cows with differing MPC have not been examined, and the underlying mechanisms responsible for the association remain undefined. The objective of this study was to examine associations between MPC and nutrient partitioning in primiparous Holstein-Friesian cows managed under pasture-based dairying conditions, and to identify differences that may indicate the underlying mechanisms. Data were collected from 85 cows at regular intervals during the early part of the 2013 to 2014 seasonal lactation, including daily milk yield, weekly milk composition, weekly body condition score measurements, as well as weekly blood plasma metabolite and hormone concentrations. Cows were retrospectively separated into quartiles based on their average MPC during the first 120d of lactation, and comparisons were made between cows within the highest (high; 3.22 to 3.40%) and the lowest (low; 2.87 to 3.00%) MPC quartiles. The high-MPC cows had lower daily milk yields, yet did not differ in the daily yields of milk solids (protein + fat) compared with the low-MPC cows. After parturition, the high-MPC cows had greater blood plasma concentrations of glucose, insulin, insulin-like growth factor-1 and leptin compared with the low-MPC cows and maintained their body condition score, despite no differences in these variables prepartum. These results indicate an increased partitioning of nutrients toward milk synthesis at the expense of body condition for cows in the low MPC quartile. However, average daily energy outputs in milk were similar in the high- and low-MPC cows. The high-MPC cows calved 12d earlier in the seasonal calving period, reflecting superior reproductive performance when cows in this quartile were 15mo of age. These results suggest that at least part, but not all, of the reported associations between MPC and dairy cow fertility are related to nutrient status during early lactation. Further research is required to understand and use the association.

Response of plasma glucose, insulin, and nonesterified fatty acids to intravenous glucose tolerance tests in dairy cows during a 670-day lactation.

This experiment investigated the metabolic response of dairy cows undergoing an extended lactation to a frequently sampled intravenous glucose tolerance test. The experiment used 12 multiparous Holstein cows that calved in late winter in a seasonally calving pasture-based system and were managed for a 670-d lactation by delaying rebreeding. In each of four 5-wk experimental periods commencing at approximately 73, 217, 422, and 520 (±9.1) days in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1kg of DM grain (control; CON) or 6kg of DM grain (GRN) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated minimum daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with an indwelling jugular catheter during the final week of each experimental period. The standard intravenous glucose tolerance test using 0.3g of glucose per kilogram of body weight was performed on each cow at approximately 100, 250, 460, and 560 DIM. Plasma concentrations of glucose, insulin, and nonesterified fatty acids (NEFA) responses were measured. Milk yield, milk solids yield, body weight, and basal plasma glucose were greater in the GRN compared with the CON treatment. The area under the plasma response curve relative to baseline (AUC) for glucose, insulin, and NEFA and their apparent fractional clearance rates indicated varied whole body responsiveness to insulin in terms of glucose metabolism throughout the 670-d lactation. The glucose AUC 0 to 20 min postinfusion was increased at 560 DIM, indicating reduced utilization of glucose by the mammary gland at this stage of lactation. The NEFA clearance rate, 6 to 30 min postinfusion, was greater at 460 and 560 DIM. These data indicated an increase in lipogenic activity or a decrease in lipolysis as lactation progressed, suggestive of an overall increase in responsiveness to insulin in terms of whole body lipid metabolism as lactation progressed. These observations are consistent with decreased priority of lactation beyond 300 DIM. Cows in the GRN treatment had decreased whole body responsiveness to hyperglycemia compared with CON cows in terms of glucose clearance and AUC for the glucose response. Variation in the response curves of plasma glucose, NEFA, and insulin was predominantly a result of stage of lactation and not diet. This may be due to changes in mammary gland uptake of glucose that is independent of insulin and the responsiveness of peripheral tissues to the actions of insulin at different stages of the lactation that are independent of diet.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.

Temporal changes in plasma concentrations of hormones and metabolites in pasture-fed dairy cows during extended lactation.

This experiment measured variations in plasma concentrations of metabolic hormones and metabolites in cows undergoing extended lactations of up to 670 d at 2 planes of nutrition. Thirty-seven Holstein-Friesian cows that calved in late winter were selected for varying milk yield and then managed for a lactation of 670 d by delaying breeding until approximately 450 d in milk (DIM). Cows grazed fresh pasture supplemented with pasture silage or hay and crushed wheat or triticale grain. Dietary intake was reduced by approximately 1.8 kg (dry matter) grain/cow per day for 19 of the cows from 300 DIM until the end of lactation to assess the effect of restricted energy intake on the persistency of milk production. Samples of blood were collected monthly from each cow to measure plasma concentrations of selected hormones and metabolites. Dietary restriction beyond 300 DIM reduced yields of milk, protein, and fat, but did not alter the proportion of cows reaching the 670-d lactation target. Dietary restriction had no effect on cow BW or plasma concentrations of any hormones or metabolites. Overall, blood plasma concentrations of insulin-like growth factor-I, leptin, and glucose were elevated from 301 to 600 DIM compared with 0 to 300 DIM, whereas concentrations of growth hormone and nonesterified fatty acids were lower after 300 DIM. Plasma concentrations of insulin and prolactin were unaffected by stage of lactation, but prolactin concentrations increased during summer. These changes were consistent with a decrease in milk yield and an increase in the partitioning of nutrients to body tissue gain, primarily adipose tissue, throughout the later stages of the extended lactation. Cows that continued milking beyond 600 DIM had increased plasma concentrations of growth hormone and decreased concentrations of glucose and leptin compared with cows that milked <600 DIM. These differences, coupled with reduced body weight gain, indicated an increased priority for nutrient partitioning to milk production at the expense of body tissue gain throughout the extended lactation period in cows with greater lactation persistency.

Economic comparison of an ear tag automated activity monitor for estrus detection with timed-AI in Holstein heifers.

The objective of this study was to compare the economic performance of an ear tag automated activity monitor system (AAM) versus a timed-AI (TAI) protocol in Holstein heifers. In total, 340 heifers were enrolled onto the study at 13.5 mo of age and randomly assigned to receive either an AAM (n = 170) or TAI (n = 170) protocol before breeding eligibility (D 0). Heifers in the AAM group were fitted with an ear tag AAM and bred based on high activity alert from the system. Heifers in the TAI group received a progesterone releasing intravaginal device on D -8, followed by device removal and prostaglandin on D -3 and gonadotropin-releasing hormone with TAI on D 0. In both treatments, the majority of heifers received sex-sorted semen for the first AI and conventional semen for subsequent AIs, with three opportunities to become pregnant. All heifers were diagnosed for pregnancy approximately 25 d post AI using transrectal ultrasonography, with confirmation at 30 and 45 d. Non-pregnant heifers in the TAI group, were resynchronized using the same TAI protocol. A partial budget was used to compare the costs and benefits of switching from a TAI to an AAM protocol in heifers, including protocol, labour, and rearing costs for each treatment, as well as estimated calf and milk value. Sensitivity analyses were also conducted to determine the effect of pregnancy per AI (P/AI), outsourcing AI, AAM tag cost and herd size on the net outcome. There was no difference in overall P/AI or days to pregnancy between treatments. However, number of AI was greater in the TAI than the AAM group. For the first AI, the P/AI was less in the TAI compared to the AAM group; however, the interval to first AI was less in TAI. There was minimal difference in performance for the second and third AI. There was a net gain of $11.97 per heifer when switching from a TAI to AAM protocol, due to the increased P/AI to the first AI and reduced cost of hormones. Several variables in the sensitivity analyses affected the net outcome. Considering only the first AI, switching to an AAM collar and a larger herd size all increased the net gain. Considering a greater P/AI to the first AI in the TAI group, outsourcing AI, using more AAM ear tags, and smaller herd sizes resulted in a net loss when switching from TAI to AAM. The AAM system resulted in exceptional P/AI and may be an economically viable alternative to improve heifer reproductive efficiency in herds with suboptimal P/AI to TAI.

The effect of altering the timing of GnRH administration and artificial insemination in a modified 5-d CO-Synch protocol using sex-sorted semen in dairy heifers.

The objective was to optimize fertility in a modified 5-d CO-Synch protocol by altering the timing of GnRH administration and AI. Holstein heifers (14-16 mo) received a controlled internal drug releasing device (CIDR) on d 0 and on d 5, CIDR were removed, prostaglandin F2α was administered and estrus detection patches were applied. Estrus was detected at 36, 48, 56 and 72 h after CIDR removal. In Experiment 1, control heifers (n = 195) received GnRH concurrent with timed-AI (TAI) 72 h after CIDR removal, regardless of expression of estrus. Treatment heifers expressing estrus at 36 or 48 h were AI at 56 h (n = 101) and the remaining heifers were randomly assigned to one of two groups: GnRH administration at 56 h and TAI at 72 h (GnRH56, n = 147) or GnRH administered concurrently with TAI at 72 h (GnRH72, n = 148). In Experiment 2, heifers expressing estrus at 36 or 48 h following CIDR removal were AI at 56 h (n = 118) and the remaining heifers were either TAI at 72 h (TAI72, n = 102) or 80 h (TAI80, n = 102), with only heifers not displaying estrus by TAI given GnRH concurrent with AI. All heifers were inseminated with sex-sorted semen and pregnancy diagnosis was performed at 28 d following TAI. In Experiment 1, estrus rate (P = 0.81) and pregnancy per AI (P/AI; P = 0.34) did not differ among control, GnRH56 and GnRH72 groups, so GnRH56 and GnRH72 groups were combined into one split-TAI (STAI) group. The P/AI was greater in heifers displaying estrus by 48 h compared to those not displaying estrus and receiving GnRH in both groups (69.5 vs. 31.3%; P < 0.01) and there was a tendency for P/AI to increase in STAI heifers displaying estrus compared to control heifers displaying estrus (73.3 vs. 62.1%; P = 0.10). In Experiment 2, the estrus rate was increased in TAI80 compared to TAI72 heifers (81.4 vs. 62.7%, P < 0.01); however, there was no difference in P/AI (P = 0.74). Heifers displaying estrus in the TAI72 group had a greater P/AI than heifers not displaying estrus in either group (P < 0.01) and tended to have a greater P/AI than heifers in estrus in the TAI80 group (87.5 vs. 69.9%, P = 0.07). Across both experiments, P/AI was increased in heifers that displayed estrus before AI compared with heifers that did not and performing a STAI tended to increase P/AI in heifers that displayed estrus before AI. Other attempts made to optimize P/AI in the modified 5-d CO-Synch protocol by altering the timing of GnRH administration and/or AI were unsuccessful.

Comparison of two intravaginal progesterone-releasing devices in shortened-timed artificial insemination protocols in beef cattle.

Commercially available intravaginal progesterone (P4) devices differ in shape, surface area and P4 load, which may affect the resulting pregnancy per AI (P/AI) following timed-AI (TAI). The objective of this study was to compare two intravaginal P4 devices on estrus rate, follicular dynamics and P/AI in beef cattle subjected to shortened-TAI protocols. In Expt. 1, nulliparous heifers were randomly assigned to a P4-releasing intravaginal device (PRID-Delta, 1.55 g P4) or a controlled internal drug release (CIDR, 1.38 g P4) at the initiation of a J-synch protocol. Heifers that displayed estrus 72 h following device removal were TAI, or if not in estrus given GnRH at 72 h and TAI at 90 h. In Expt. 2, nulliparous heifers and non-suckling cows were randomly assigned to either PRID or CIDR groups and either 1 or 2 mg of estradiol benzoate (EB) at initiation of a J-synch protocol. All cattle were TAI concurrent with GnRH 72 h after device removal. In Expt. 3, nulliparous heifers and suckling cows were randomly assigned to either PRID or CIDR groups and initiated a 5-d Cosynch protocol, with TAI concurrent with GnRH 72 h following device removal. In each experiment, cattle received estrus detection patches at device removal, which were then scored from 0 to 3 based on color change between initial application and TAI; 0 = unchanged, 1 = ≤50% change, 2 = >50% change, 3 = missing. Estrus was defined to have occurred when the patch was scored 2 or 3. Transrectal ultrasonography was used to determine cyclicity, diagnose pregnancy in all experiments, and the size of the ovulatory follicle in Expt. 3. In Expt. 1, the estrus rate was greater (72.0% vs. 61.0%; P = 0.04) in the PRID compared to the CIDR group. In Expt. 2, a parity by EB dose interaction (P = 0.02) was attributed to an increased estrus rate (52.8% vs. 41.4%; P = 0.05) in heifers given 1 vs. 2 mg EB. In Expt. 3, there was no difference in the ovulatory follicle diameter at device removal (P = 0.22) or TAI (P = 0.28) between P4 groups. Treatment with a PRID tended (P = 0.10) to increase the P/AI in cows compared to a CIDR (73.5% vs. 61.0%). In all experiments combined, the overall P/AI tended to increase (55.2% vs. 51.0%; P = 0.08) and P/AI in cattle exhibiting estrus increased (64.4% vs. 59.7%; P = 0.02) in cattle given a PRID compared to those given a CIDR, respectively. In summary, the type of intravaginal P4 device affected estrus response and P/AI following TAI in beef cows.

Blood plasma concentrations of metabolic hormones and glucose during extended lactation in grazing cows or cows fed a total mixed ration.

An experiment was conducted to measure the effect of diet on circulating concentrations of metabolic hormones and metabolites in cows undergoing extended lactations. Two groups of 6 Holstein-Friesian cows managed for lactations of 670 d were used in the experiment. One group was fully fed on a total mixed ration (TMR), whereas the other group grazed fresh pasture supplemented with grain (P+G). On 7 occasions between 332 and 612 d in milk, concentrations of metabolic hormones and glucose were measured in the blood plasma of each cow. Cows fed TMR gained more weight and body condition than P+G cows, but did not produce more milk during the study period. Only 3 of the TMR cows continued to lactate until 612 d in milk compared with all 6 of the P+G cows. Blood plasma from cows fed TMR had higher concentrations of glucose, insulin, glucagon, insulin-like growth factor 1, and leptin, but lower concentrations of growth hormone, than that from P+G cows. These changes were consistent with the preferential deposition of energy into adipose tissue at the expense of milk production and presumably were induced by a diet that provided precursors for gluconeogenesis that were in excess of the requirements for maintenance and prevailing milk production. The mechanism responsible for some TMR cows putting on excess weight and reducing or ceasing milk production is uncertain, but this observation has important implications for the nutritional management of cows in extended lactation programs.

Performance and optimization of an ear tag automated activity monitor for estrus prediction in dairy heifers.

The objectives of this study were to evaluate the performance of the SCR eSense ear tag automated activity monitor (AAM) to detect estrus behavior in Holstein heifers and to determine the optimal time from estrus alert to artificial insemination (AI) using sex-sorted or conventional semen. In total, 281 heifers were fitted with the AAM once eligible for breeding (>13.5 m of age). For the first AI, estrus was synchronized using 500 µg of cloprostenol (PGF), given 14 d apart, and heifers were given estrus detection patches (Estrotect™) after the second PGF. Heifers were inseminated at randomly attributed times after high activity alert from the AAM system or if the estrus patch had ≥ 50% colour change. Most heifers received sex-sorted semen for the first AI and conventional semen for subsequent inseminations. Pregnancy diagnosis was performed at 30 d post AI and heifers had four opportunities to become pregnant. In a subset of heifers (n = 149), ovaries were scanned every 12 h from the time of AI until ovulation (OV). The system recorded a heat index (measure of estrus strength), maximum activity change, maximum rumination change and duration of high activity. The sensitivity was 91.0%, with a false positive and false negative rate of 8.0%, and the positive predictive value to detect true estrus events was 83.5%. Pregnancy per AI to first AI was 67.6% and 97.9% of heifers become pregnant after four inseminations. Most false positive estrus events had a heat index < 45 and a rumination change < -20, while false negative events had a rumination change ≥ -20. Odds of pregnancy was not associated with any estrus characteristics measured by the system. However, pre-ovulatory follicle diameter had a weak correlation (r < 0.25) with all estrus characteristics. The average (range) interval of onset of high activity, peak activity and end of high activity to OV was 28 h (16-46 h), 22 h (10-40 h) and 16 h (0-36 h), respectively. For conventional semen, each hour increase in interval from activity onset or peak activity to AI reduced the predicted probability of pregnancy by 3.8 and 4.2%, respectively. For sex-sorted semen, the relationship between activity onset or peak activity to AI and predicted probability of pregnancy was quadratic, but not significant. Overall, the SCR eSense ear tag AAM performed well and strategies to identify false positive and false negative estrus events, along with optimization of timing of AI, should further improve performance in Holstein heifers.

The relationships among sire's predicted transmitting ability for daughter pregnancy rate and cow conception rate and daughter's reproductive performance in Canadian Holstein cows.

The objectives of this study were to (1) characterize the variability for sire's predicted transmitting ability (PTA) for daughter's pregnancy rate (DPR) and cow conception rate (CCR), (2) determine the relationships among sire's PTA for DPR, sire's PTA for CCR, daughter's parity, and daughter's 305-d mature-equivalent (ME) milk production, and (3) evaluate the associations among sire's PTA for DPR and CCR and daughter's reproductive performance [pregnancy to first artificial insemination (P/AI), pregnancy by 150 d in milk (PR150) and pregnancy loss (PL) after first AI] in Canadian Holstein cows. The data were obtained from 822 lactating Holstein cows from 10 commercial dairy herds located in Alberta. Overall mean (range) for sire's PTA for DPR and CCR was -0.09 (-9.6 to 8.2) and -0.05 (-9.9 to 7.4), respectively. Sire's PTA for DPR was strongly and positively associated with sire's PTA for CCR (r = 0.89; P < 0.01). Sire's PTA for DPR and CCR were weakly and negatively associated with parity (r = -0.15 and -0.17, respectively; P < 0.01); however, the amount of phenotypic variation in sire's PTA for DPR and CCR explainable by parity was small (coefficient of determination; R2 = 0.02). The daughter's 305-d ME milk production tended to be weakly but positively associated with sire's PTA for DPR (r = 0.06; P = 0.07) and CCR (r = 0.06; P = 0.10); however, the amount of phenotypic variation in daughter's 305-d ME milk production explainable by changes in sire's PTA for DPR or CCR was small (R2 = 0.004 and 0.003, respectively). Overall P/AI, PR150 and PL were 38, 65 and 12%, respectively. Sire's PTA for DPR tended to be associated with P/AI (P = 0.08) but was significantly associated with PR150 (P = 0.03). For every unit increase in sire's PTA for DPR, the estimated probabilities for P/AI and PR150 increased by 6.2 and 7.5%, respectively. Sire's PTA for CCR was not associated with P/AI or PR150. Neither sire's PTA for DPR nor CCR were associated with PL. In summary, sire's PTA for DPR and CCR were highly variable and positively correlated. Sire's PTA for DPR was associated with daughter's P/AI and PR150, but sire's PTA for CCR was not associated with any of the measured reproductive outcomes. Therefore, selecting sires with high PTA for DPR has the potential to improve the reproductive efficiency of Canadian dairy herds.