The objectives of this study were to 1) establish cow-level critical thresholds for serum concentrations of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA) to predict periparturient ...diseases displaced abomasa (DA), clinical ketosis (CK), metritis and retained placenta, or any of these three, and 2) investigate the magnitude of the metabolites’ association with these diseases within 30 d in milk. In a prospective cohort study of 100 freestall, total mixed ration-fed herds in the northeastern United States, blood samples were collected from approximately 15 prepartum and 15 different postpartum transition animals in each herd, for a total of 2,758 samples. Serum NEFA concentrations were measured in the prepartum group, and both NEFA and BHBA were measured in the postpartum group. The critical thresholds for NEFA or BHBA were evaluated with receiver operator characteristic analysis for all diseases in both cohorts. The risk ratios (RR) of a disease outcome given NEFA or BHBA concentrations and other covariates were modeled with multivariable regression techniques, accounting for clustering of cows within herds. The NEFA critical threshold that predicted any of the 3 diseases in the prepartum cohort was 0.29mEq/L and in the postpartum cohort was 0.57mEq/L. The critical threshold for serum BHBA in the postpartum cohort was 10mg/dL, which predicted any of the 3 diseases. All RR with NEFA as a predictor of disease were >1.8; however, RR were greatest in animals sampled postpartum (e.g., RR for DA=9.7; 95% CI=4.2 to 22.4. All RR with BHBA as the predictor of disease were >2.3 (e.g., RR for DA=6.9; 95% CI=3.7 to 12.9). Although prepartum NEFA and postpartum BHBA were both significantly associated with development of clinical disease, postpartum serum NEFA concentration was most associated with the risk of developing DA, CK, metritis, or retained placenta during the first 30 d in milk.
The objectives were to evaluate the effects of elevated pre- and postpartum nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA) concentrations during the transition period on reproductive ...performance and milk production in dairy cattle. In a prospective cohort study of 91 freestall, total mixed ration-fed herds in the northeastern United States, blood samples were collected from approximately 15 prepartum and 15 different postpartum transition animals in each herd. All samples were stratified based on pre- or postpartum status at the time of sample collection, and 2,259 and 2,290 animals were used to evaluate reproductive and milk production performance, respectively. Reproductive performance was assessed by time to conception within 70 d post-voluntary waiting period (VWP) and milk production was assessed using mature-equivalent 305-d (ME305) milk yield estimated at 120 d in milk. While controlling for body condition score (BCS), calving season, median ME305 milk production, and parity, NEFA and BHBA concentrations were evaluated with time to event analysis to investigate reproductive performance. These same predictor variables were used to determine the effects of elevated NEFA and BHBA concentrations on ME305 milk yield with herd as a random effect. Heifers and cows were grouped in the final analyses if the results between groups were similar. In all animals sampled prepartum, the risk of pregnancy within 70 d post-VWP was reduced by 19% when NEFA concentrations were ≥0.27mEq/L. In all animals sampled postpartum, those with NEFA concentrations ≥0.72mEq/L had a 16% decrease in risk of pregnancy and those with BHBA concentrations ≥10mg/dL had a 13% decrease in risk. In cows and heifers, ME305 milk yield was decreased by 683kg when prepartum NEFA concentrations were ≥0.33mEq/L. In heifers sampled postpartum, ME305 milk yield was increased by 488kg when NEFA concentrations were ≥0.57mEq/L and increased by 403kg when BHBA concentrations were ≥9mg/dL. In cows sampled postpartum, ME305 milk yield was decreased by 647kg when NEFA concentrations were ≥0.72mEq/L and decreased by 393kg when BHBA concentrations were ≥10mg/dL. With the exception of milk production in heifers, this study indicates that increased concentrations of serum NEFA and BHBA had a detrimental effect on reproductive performance and milk production.
It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although ...many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize male mice expressing green fluorescence protein under the serotonin transporter (SERT) promoter to map the topography of serotonergic fibers across the rostro‐caudal extent of each brain area. We demonstrate previously unreported regional density and fine‐grained anatomy of serotonergic fibers. Our findings include: (a) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, (b) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, (c) unique, filamentous type of straight terminal fibers within the nucleus accumbens, (d) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, (e) cortical labeling density gradually decreases rostro‐caudally, (f) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and (g) most of the highly labeled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse.
A comprehensive look at the whole brain serotonergic projection using the SERT‐EGFP transgenic mice. The area‐specific pattern and rostro‐caudal change from the raphe nuclei in brainstem were mapped.
Our aim in this Journal of Dairy Science centennial review is to describe the evolution of focus on metabolic indicators, from discovery and description to evaluation at the individual cow and ...subsequently herd levels, over the past 100 yr. Furthermore, we discuss current and future technologies that will be used in the dairy industry to utilize these indicators widely going forward. Knowledge of chemical changes in various fluids (e.g., blood, urine, and milk) accompanying numerous metabolic disease states in the dairy cow has existed since almost the beginning of the Journal of Dairy Science 100 yr ago. However, only during the last 25 yr have these metabolic indicators been developed into useful tools for cow- and herd-level monitoring for disease and management. From the 1920s through the 1940s, our understanding of the changes in blood chemistry accompanying milk fever and ketosis increased, as did our understanding of the underlying biology. In the 1950s and 1960s, workers studying ketosis and energy metabolism began to evaluate changes in lipid metabolism reflected by concentrations of circulating nonesterified fatty acids; furthermore, initial development occurred for on-farm tests of milk ketones. During the 1970s, blood metabolic profiling was applied to dairy farms but found to be of varied and limited usefulness. The turning point occurred when large epidemiologic studies of periparturient cow disease were pioneered in the United States, Canada, and Europe in the 1980s; these studies further solidified our understanding of risk factors and epidemiological interrelationships among disease, production, and reproduction. In the early 1990s, scientists first incorporated indicators of metabolic health into large observational studies and determined important epidemiological relationships between these indicators and outcomes of interest. This field of study blossomed during the 2000s as several research groups conducted multiple investigations into metabolic indicators related to energy metabolism and began to develop cow-level thresholds and herd-level alarms for use in monitoring and management. This work was accompanied by additional studies to validate point-of-care instruments that could be used to implement these strategies at the cow and herd levels. Work in the 2000s continued to identify and evaluate other physiological indicators of inflammation and oxidative stress; however, these have yet to be incorporated into large-scale cohort studies. Finally, use of technology (e.g., activity monitoring, cow-monitoring collars and tags, milk-based analysis using Fourier transform infrared spectroscopy) continues to receive significant attention going forward to eventually allow for real-time and automatic monitoring of metabolic indicators and improved health and herd management on dairy farms.
Trace minerals have critical roles in the key interrelated systems of immune function, oxidative metabolism, and energy metabolism in ruminants. To date, the primary trace elements of interest in ...diets for dairy cattle have included Zn, Cu, Mn, and Se although data also support potentially important roles of Cr, Co, and Fe in diets. Trace minerals such as Zn, Cu, Mn, and Se are essential with classically defined roles as components of key antioxidant enzymes and proteins. Available evidence indicates that these trace minerals can modulate aspects of oxidative metabolism and immune function in dairy cattle, particularly during the transition period and early lactation. Chromium has been shown to influence both immune function and energy metabolism of cattle; dairy cows fed Cr during the transition period and early lactation have evidence of improved immune function, increased milk production, and decreased cytological endometritis. Factors that complicate trace mineral nutrition at the farm level include the existence of a large number of antagonisms affecting bioavailability of individual trace minerals and uncertainty in terms of requirements under all physiological and management conditions; therefore, determining the optimum level and source of trace minerals under each specific situation continues to be a challenge. Typical factorial approaches to determine requirements for dairy cattle do not account for nuances in biological function observed with supplementation with various forms and amounts of trace minerals. Trace mineral nutrition modulates production, health, and reproduction in cattle although both formal meta-analysis and informal survey of the literature reveal substantial heterogeneity of response in these outcome variables. The industry has largely moved away from oxide-based programs toward sulfate-based programs; however, some evidence favors shifting supplementation strategies further toward more bioavailable forms of inorganic and organic trace minerals. Furthermore, opportunities for specific modulation of aspects of health, milk production, and reproduction through supplementation strategies for diets of transition dairy cows are attractive because of the known dynamics of energy metabolism, immune function, and oxidative metabolism during this timeframe.
In this study the herd alarm level was defined as the proportion of sampled transition cows per herd with increased prepartum nonesterified fatty acid (NEFA), postpartum β-hydroxybutyrate (BHBA), or ...NEFA concentrations that were associated with herd-level incidence of displaced abomasum (DA) or clinical ketosis (CK), pregnancy rate (PR), and milk production. The objectives were to 1) identify the herd alarm level for excessive negative energy balance and 2) describe the herd-level prevalence of this proportion. This was a prospective cohort study of 60 free-stall herds fed total mixed rations in the northeast United States. Two cohorts of approximately 15 animals were assessed for prepartum NEFA and postpartum BHBA and NEFA. The herd alarm level (i.e., the proportion of sampled animals above a certain metabolite threshold) was as follows: 15% had prepartum NEFA of 0.27 mEq/L; 15 and 20% had BHBA of 10 and 12 mg/dL, respectively; and 15% had postpartum NEFA of 0.60 and 0.70 mEq/L. The different herd alarm levels correspond to differences between the metabolites and respective herd-level effect. The herd-level effects for herds above the herd alarm level for prepartum NEFA were 3.6% increase in DA and CK incidence, 1.2% decrease in PR, and 282kg decrease in average mature equivalent 305-d (ME 305) milk. For BHBA, the herd-level effects were a 1.8% increase in DA and CK, 0.8% decrease in PR, and 534 and 358kg decrease in projected ME 305 milk yield for heifers and cows, respectively. For postpartum NEFA, the herd-level effects were 1.7% increase in DA and CK, 0.9% decrease in PR, and 288 and 593kg decrease in projected ME 305 milk yield for heifers and cows, respectively. The prevalence of herds in which more than 15% of animals sampled had prepartum NEFA concentration ≥0.30 mEq/L was 75%, BHBA ≥12 mg/dL was 40%, and postpartum NEFA ≥0.70 mEq/L was 65%. This study showed that there were detrimental herd-level effects if a large enough proportion of cows had increased metabolite concentrations, and further demonstrated that a high prevalence of herds have opportunity for improvement.
Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection.
We conducted a phase 3, randomized, open-label trial in which adults with ...HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm).
At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval CI, -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48.
Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).
The insular cortex (IC) participates in diverse complex brain functions, including social function, yet their cellular bases remain to be fully understood. Using microendoscopic calcium imaging of ...the agranular insular cortex (AI) in mice interacting with freely moving and restrained social targets, we identified 2 subsets of AI neurons—a larger fraction of “Social-ON” cells and a smaller fraction of “Social-OFF” cells—that change their activity in opposite directions during social exploration. Social-ON cells included those that represented social investigation independent of location and consisted of multiple subsets, each of which was preferentially active during exploration under a particular behavioral state or with a particular target of physical contact. These results uncover a previously unknown function of AI neurons that may act to monitor the ongoing status of social exploration while an animal interacts with unfamiliar conspecifics.
New laboratory and animal sampling methods and data have been generated over the last 10 yr that had the potential to improve the predictions for energy, protein, and AA supply and requirements in ...the Cornell Net Carbohydrate and Protein System (CNCPS). The objectives of this study were to describe updates to the CNCPS and evaluate model performance against both literature and on-farm data. The changes to the feed library were significant and are reported in a separate manuscript. Degradation rates of protein and carbohydrate fractions were adjusted according to new fractionation schemes, and corresponding changes to equations used to calculate rumen outflows and postrumen digestion were presented. In response to the feed-library changes and an increased supply of essential AA because of updated contents of AA, a combined efficiency of use was adopted in place of separate calculations for maintenance and lactation to better represent the biology of the cow. Four different data sets were developed to evaluate Lys and Met requirements, rumen N balance, and milk yield predictions. In total 99 peer-reviewed studies with 389 treatments and 15 regional farms with 50 different diets were included. The broken-line model with plateau was used to identify the concentration of Lys and Met that maximizes milk protein yield and content. Results suggested concentrations of 7.00 and 2.60% of metabolizable protein (MP) for Lys and Met, respectively, for maximal protein yield and 6.77 and 2.85% of MP for Lys and Met, respectively, for maximal protein content. Updated AA concentrations were numerically higher for Lys and 11 to 18% higher for Met compared with CNCPS v6.0, and this is attributed to the increased content of Met and Lys in feeds that were previously incorrectly analyzed and described. The prediction of postruminal flows of N and milk yield were evaluated using the correlation coefficient from the BLUP (R2BLUP) procedure or model predictions (R2MDP) and the concordance correlation coefficient. The accuracy and precision of rumen-degradable N and undegradable N and bacterial N flows were improved with reduced bias. The CNCPS v6.5 predicted accurate and precise milk yield according to the first-limiting nutrient (MP or metabolizable energy) with a R2BLUP=0.97, R2MDP=0.78, and concordance correlation coefficient=0.83. Furthermore, MP-allowable milk was predicted with greater precision than metabolizable energy–allowable milk (R2MDP=0.82 and 0.76, respectively, for MP and metabolizable energy). Results suggest a significant improvement of the model, especially under conditions of MP limitation.
Colostrum yield and quality are influenced by prepartum nutrition and the metabolic status of the cow; however, data considering these associations on multiple dairy farms are limited. Our objective ...was to identify cow-level prepartum metabolic indicators, as well as farm-level nutritional strategies associated with colostrum yield and the indicator of colostrum quality, Brix %. A convenience sample of 19 New York Holstein dairies (median: 1,325 cows; range: 620 to 4,600 cows) were enrolled in this observational study. Records for individual colostrum yield and Brix % were collected by farm personnel between October 2019 and February 2021. Farms were visited 4 times, approximately 3 mo apart, to obtain feed samples of the prepartum diets, collect blood samples from 24 pre- and postpartum cows, respectively, and determine prepartum body condition score. Feed samples were submitted for analysis of chemical composition, and particle size was determined on-farm using a particle separator. Prepartum serum samples (n = 762) were analyzed for glucose and nonesterified fatty acid concentrations. Whole blood from postpartum cows was analyzed for herd prevalence of hyperketonemia (proportion of samples with β-hydroxybutyrate ≥1.2 mmol/L). A cohort of primiparous (PP; n = 1,337) and multiparous (MPS; n = 3,059) cows calving ± 14 d of each farm visit were included in the statistical analysis. Animals calving in this period were assigned results for the close-up diet composition and herd prevalence of hyperketonemia collected from the respective farm visit. Greatest colostrum yield from PP and MPS cows was associated with moderate starch 18.6–22.5% of dry matter (DM) and a moderate herd prevalence of hyperketonemia (10.1–15.0%). Greatest colostrum yield from MPS cows was associated with moderate crude protein (13.6–15.5% of DM) and a less severe negative dietary cation-anion difference (DCAD; >−8 mEq/100 g), whereas greatest colostrum yield from PP cows was associated with low crude protein (≤13.5% of DM). In addition, a moderate proportion of the diet with particle length ≥19 mm (15.3–19.1%) was associated with lowest colostrum yield from PP and MPS cows. Highest colostrum Brix % was associated with prepartum dietary factors of low neutral detergent fiber (≤39.0% of DM) and high proportion of the diet with particle length ≥19 mm (>19.1%). In addition, low starch (≤18.5% of DM) and low and moderate DCAD level (≥−15.9 mEq/100 g) were associated with greatest Brix % from PP cows, whereas moderate DCAD (−15.9 to −8.0 mEq/100 g) was associated with greatest Brix % from MPS cows. Prepartum serum nonesterified fatty acid concentration ≥290 µEq/L was associated with increased colostrum yield, but prepartum serum glucose concentration and body condition score were not associated with colostrum yield or Brix %. These data provide nutritional and metabolic variables to consider when troubleshooting colostrum production on farms.
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