Exploring the impact of sleep on emotional and physical well-being in professional cricketers: a cohort study over an in-season training period.

Background: Professional athletes navigate a multitude of unique challenges associated to sport-specific factors (e.g., training, travel and competition) and non-sport factors (e.g., performance pressure, stress and anxiety) that can interfere with healthy sleep behaviors. Sleep plays a key role in proper biopsychosocial development as well as short- and long-term biological, physical, psychological, and cognitive health. As poor sleep quality is known to impair proper brain function, this study aimed to investigate the effect of sleep quality on a professional athlete's ability to train, recover, and perform, as well as their overall emotional and physical well-being. Methods: A cohort study was performed in 40 professional male cricket athletes from the Dutch national cricket team (mean age 26.5 ± 5.1 years). The athletes were monitored across a 22 weeks in-season training period. Sleep quality and overall emotional and physical well-being were assessed using daily sleep diaries and questionnaires which scored the readiness to train, stress levels, fatigue, muscle soreness and flu symptoms respectively. Quality of sleep and subsequent association with the consecutive elements of the well-being questionnaire were assessed through statistical using the student t-test and clinical differences with the methodology of Osoba and colleagues: <5% "no change", 5%-10% "little change"; 10%-20% "moderate change"; and >20% "very much change". Results: The results demonstrated that the professional athletes assessed their sleep quality as average with a mean score of 3.4 out of 5. Lower perceived quality of sleep (<75th percentile) was correlated with a decreased readiness to train (mean score 3.2 [IQR: 3.0-4.0] vs. 3.5 [IQR: 3.0-5.0]; P < 0.001) and increased extent of muscle soreness (2.7 [IQR: 2.0-3.0] vs. 2.3 [IQR: 2-3]; P < 0.001), stress level (mean score 2.3 [IQR: 2.0-3.0] vs. 1.9 [IQR: 1.0-2.0]; P < 0.001) and perceived fatigue (mean score 2.9 [IQR: 2.0-3.0] vs. 2.3 [IQR: 2.0-3.0]; P < 0.001). Likewise, in patients with lower perceived quality of sleep, the proportion of players presenting with flu symptoms increased over 4-fold (4.1% vs. 17%; P < 0.001). Conclusions: This study highlights that good sleep quality positively influences the overall emotional and physical well-being of professional athletes. Our results emphasize the importance of targeted sleep interventions to improve sleep quality and subsequently optimize psychological and physiological wellness.

Reducing perceived barriers to scaling up overdose education and naloxone distribution and medications for opioid use disorder in the United States in the HEALing (helping end addiction long-term®) communities study.

BACKGROUND: Scaling up overdose education and naloxone distribution (OEND) and medications for opioid use disorder (MOUD) is needed to reduce opioid overdose deaths, but barriers are pervasive. This study examines whether the Communities That HEAL (CTH) intervention reduced perceived barriers to expanding OEND and MOUD in healthcare/behavioral health, criminal-legal, and other/non-traditional venues. METHODS: The HEALing (Helping End Addiction Long-Term®) Communities Study is a parallel, wait-list, cluster randomized trial testing the CTH intervention in 67 communities in the United States. Surveys administered to coalition members and key stakeholders measured the magnitude of perceived barriers to scaling up OEND and MOUD in November 2019-January 2020, May-June 2021, and May-June 2022. Multilevel linear mixed models compared Wave 1 (intervention) and Wave 2 (wait-list control) respondents. Interactions by rural/urban status and research site were tested. RESULTS: Wave 1 respondents reported significantly greater reductions in mean scores for three outcomes: perceived barriers to scaling up OEND in Healthcare/Behavioral Health Venues (-0.26, 95% confidence interval, CI: -0.48, -0.05, p = 0.015), OEND in Other/Non-traditional Venues (-0.53, 95% CI: - 0.84, -0.22, p = 0.001) and MOUD in Other/Non-traditional Venues (-0.34, 95% CI: -0.62, -0.05, p = 0.020). There were significant interactions by research site for perceived barriers to scaling up OEND and MOUD in Criminal-Legal Venues. There were no significant interactions by rural/urban status. DISCUSSION: The CTH Intervention reduced perceived barriers to scaling up OEND and MOUD in certain venues, with no difference in effectiveness between rural and urban communities. More research is needed to understand facilitators and barriers in different venues.

Combining short-term breath measurements to develop methane prediction equations from cow milk mid-infrared spectra.

Predicting methane (CH4) emission from milk mid-infrared (MIR) spectra provides large amounts of data which is necessary for genomic selection. Recent prediction equations were developed using the GreenFeed system, which required averaging multiple CH4 measurements to obtain an accurate estimate, resulting in large data loss when animals unfrequently visit the GreenFeed. This study aimed to determine if calibrating equations on CH4 emissions corrected for diurnal variations or modeled throughout lactation would improve the accuracy of the predictions by reducing data loss compared with standard averaging methods used with GreenFeed data. The calibration dataset included 1 822 spectra from 235 cows (Holstein, Montbéliarde, and Abondance), and the validation dataset included 104 spectra from 46 (Holstein and Montbéliarde). The predictive ability of the equations calibrated on MIR spectra only was low to moderate (R2v = 0.22-0.36, RMSE = 57-70 g/d). Equations using CH4 averages that had been pre-corrected for diurnal variations tended to perform better, especially with respect to the error of prediction. Furthermore, pre-correcting CH4 values allowed to use all the data available without requiring a minimum number of spot measures at the GreenFeed device for calculating averages. This study provides advice for developing new prediction equations, in addition to a new set of equations based on a large and diverse population.

Short communication: Correlation of methane production, intensity, and yield with residual feed intake throughout lactation in Holstein cows.

The environmental impact of dairy production can be reduced in several ways, including increasing feed efficiency and reducing methane (CH4) emissions. There is no consensus on their relationship. This study aimed at estimating the correlations between residual feed intake (RFI) and CH4 emissions expressed in g/d methane production (MeP), g/kg of fat- and protein-corrected milk methane intensity (MeI), or g/kg of DM intake methane yield (MeY) throughout lactation. We collected CH4 data using GreenFeed devices from 107 Holstein cows, as well as production and intake phenotypes. RFI was predicted from DM intake, fat- and protein-corrected milk, BW, and body condition score. Five-trait random regression models were used to estimate the individual variance components of the CH4 and production traits, which were used to calculate the correlations between RFI and CH4 traits throughout lactation. We found positive correlations of RFI with MeP and MeI ranging from 0.05 to 0.47 throughout the lactation. Correlations between RFI and MeY are low and vary from positive to negative, ranging from -0.18 to 0.17. Both MeP and MeI are favorably correlated with RFI, as is MeY during the first half of lactation. These correlations are mostly favorable for genetic selection, but the confirmation of these results is needed with genetic correlations over a larger dataset.

Effects of the Communities that Heal (CTH) intervention on perceived opioid-related community stigma in the HEALing Communities Study: results of a multi-site, community-level, cluster-randomized trial.

Background: Community stigma against people with opioid use disorder (OUD) and intervention stigma (e.g., toward naloxone) exacerbate the opioid overdose crisis. We examined the effects of the Communities that HEAL (CTH) intervention on perceived opioid-related community stigma by stakeholders in the HEALing Communities Study (HCS). Methods: We collected three surveys from community coalition members in 66 communities across four states participating in HCS. Communities were randomized into Intervention (Wave 1) or Wait-list Control (Wave 2) arms. We conducted multilevel linear mixed models to compare changes in primary outcomes of community stigma toward people treated for OUD, naloxone, and medication for opioid use disorder (MOUD) by arm from time 1 (before the start of the intervention) to time 3 (end of the intervention period in the Intervention arm). Findings: Intervention stakeholders reported a larger decrease in perceived community stigma toward people treated for OUD (adjusted mean change (AMC) -3.20 [95% C.I. -4.43, -1.98]) and toward MOUD (AMC -0.33 [95% C.I. -0.56, -0.09]) than stakeholders in Wait-list Control communities (AMC -0.18 [95% C.I. -1.38, 1.02], p = 0.0007 and AMC 0.11 [95% C.I. -0.09, 0.31], p = 0.0066). The relationship between intervention status and change in stigma toward MOUD was moderated by rural-urban status (urban AMC -0.59 [95% CI, -0.87, -0.32], rural AMC not sig.) and state. The difference in stigma toward naloxone between Intervention and Wait-list Control stakeholders was not statistically significant (p = 0.18). Interpretation: The CTH intervention decreased stakeholder perceptions of community stigma toward people treated for OUD and stigma toward MOUD. Implementing the CTH intervention in other communities could decrease OUD stigma across diverse settings nationally. Funding: US National Institute on Drug Abuse.

Differences in perceptions of community stigma towards opioid use disorder between community substance use coalition members and the general public.

INTRODUCTION: To examine differences in perceptions about community stigma towards individuals with opioid use disorder (OUD) between community members involved in the opioid response (i.e., coalition members) and the general public, and how community geography may moderate this relationship. METHODS: This study administered identical cross-sectional surveys about perceived community opioid-related stigma to two distinct populations in 66 communities participating in the HEALing Communities Study prior to the intervention period (i.e., coalition members, November 2019-January 2020; residents, March-April 2020). Linear-mixed models compared survey responses of populations, including the moderating effect of community rural/urban location. RESULTS: A total of 826 coalition members and 1131 residents completed the surveys. The study found no differences between the coalition members and residents for general perceived community opioid-related stigma. In both urban and rural communities, coalition members reported greater perceived community stigma than residents reported towards medication for opioid use disorder (MOUD), naloxone, and drug treatment as an alternative to incarceration. CONCLUSION: Our findings suggest similar perceived community opioid-related stigma between coalition members and residents, yet differences emerge related to evidence-based practices (i.e., MOUD, naloxone, and drug treatment as an alternative to incarceration) to reduce opioid overdose deaths. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04111939.

Comparison of methane production, intensity, and yield throughout lactation in Holstein cows.

Genetic selection to reduce methane (CH4) emissions from dairy cows is an attractive means of reducing the impact of agricultural production on climate change. In this study, we investigated the feasibility of such an approach by characterizing the interactions between CH4 and several traits of interest in dairy cows. We measured CH4, dry matter intake (DMI), fat- and protein-corrected milk (FPCM), body weight (BW), and body condition score (BCS) from 107 first- and second-parity Holstein cows from December 2019 to November 2021. Methane emissions were measured using a GreenFeed device and expressed in terms of production (MeP, in g/d), yield (MeY, in g/kg DMI), and intensity (MeI, in g/kg FPCM). Because of the limited number of cows, only animal parameters were estimated. Both MeP and MeI were moderately repeatable (>0.45), whereas MeY presented low repeatability, especially in early lactation. Mid lactation was the most stable and representative period of CH4 emissions throughout lactation, with animal correlations above 0.9. The average animal correlations of MeP with DMI, FPCM, and BW were 0.62, 0.48, and 0.36, respectively. The MeI was negatively correlated with FCPM (<-0.5) and DMI (>-0.25), and positively correlated with BW and BCS. The MeY presented stable and weakly positive correlations with the 4 other traits throughout lactation, with the exception of slightly negative animal correlations with FPCM and DMI after the 35th week. The MeP, MeI, and MeY were positively correlated at all lactation stages and, assuming animal and genetic correlations do not strongly differ, selection on one trait should lead to improvements in all. Overall, selection for MeI is probably not optimal as its change would result more from CH4 dilution in increased milk yield than from real decrease in methane emission. Instead, MeY is related to rumen function and is only weakly associated with DMI, FPCM, BW, and BCS; it thus appears to be the most promising CH4 trait for selection, provided that this would not deteriorate feed efficiency and that a system of large-scale phenotyping is developed. The MeP is easier to measure and thus may represent an acceptable alternative, although care would need to be taken to avoid undesirable changes in FPCM and BW.

Association between body condition genomic values and feed intake, milk production, and body weight in French Holstein cows.

Body condition score (BCS) offers a good estimate of the amount of stored fat on the body, and its variations can be used as a proxy for energy balance. Many countries have implemented a genomic evaluation of BCS, including France, where estimated breeding values are based on an individual BCS determination during the first lactation. In this article, we investigate the degree to which this genomic estimated breeding value based on a single phenotype record per cow might reflect different profiles of body reserves throughout lactation and be used to predict, and perhaps limit, their mobilization during early lactation. We also investigate whether selection on BCS affects other traits. A data set including 686 lactations of 435 Holstein cows from 3 experimental farms not used in the reference population for genomic evaluation was used to estimate the effects of the BCS direct genomic value (iBCS) on BCS, body weight, feed intake, milk production, and fat and protein contents throughout the lactation period. For each trait, the model included different iBCS regressions and an effect of the direct genomic value of the trait itself when available. It thus appeared that cows with a positive iBCS always had a higher BCS than negative iBCS cows, whatever the lactation stage, and that this difference increased during the first 6 mo to reach a difference of 0.8 point. A similar effect was seen regarding body weight, but it was the opposite for milk production, with negative iBCS cows producing slightly more milk (difference of about 3% over lactation). Feed intake increased slightly faster at the beginning of lactation for cows with positive iBCS. Therefore, iBCS is a promising tool that could help to limit intense mobilization during early lactation. Should feed efficiency be included in the breeding goal, greater attention should be paid to BCS to avoid further body mobilization in early lactation.

Understanding US Physician and Pharmacist Attitudes Toward Biosimilar Products: A Qualitative Study.

BACKGROUND: Biosimilars account for 30-40% of biologic medications dispensed in the United States (US), yet healthcare providers in relevant medical specialties have limited awareness of biosimilars and their characteristics. Likewise, many providers perceive biosimilars as less safe and effective than original biologics and are more comfortable prescribing original biologics to patients. METHODS: We conducted in-person focus groups at three clinical sites in California and Texas (n = 49) to explore the reasons behind US healthcare providers' limited understanding of, cautious attitudes toward, and reluctance to prescribe biosimilars. We conducted thematic analysis by having three researchers independently analyze verbatim transcripts and identify patterns in provider responses. RESULTS: Providers' limited knowledge of and cautious attitudes toward biosimilars are driven by uncertainty about how biosimilarity is defined and operationalized as well as negative past experiences with generic drugs that did not perform as well as branded counterparts. Additionally, healthcare providers are unfamiliar with the Food and Drug Administration's (FDA's) approval pathway for biosimilars and are skeptical that an abbreviated approval process is rigorous enough to ensure biosimilars deliver the same efficacy and have the same side effect profiles as original biologics. Physicians also expressed concerns about pharmacy substitution of biosimilars and interchangeables, explaining they would be unaware of which medication was ultimately given to their patients. CONCLUSIONS: Educating physicians and pharmacists about biosimilars-including how biosimilarity is defined and operationalized, the structure of the biosimilar approval process, and how analytical data can ensure biosimilar safety and efficacy-will be important for reducing healthcare providers' concerns and increasing biosimilar adoption in the US.

Opioid-Related Public Health Communication Campaigns: An Environmental Scan.

The opioid overdose epidemic continues to devastate lives across the United States and has worsened during the COVID-19 pandemic. In this paper, we review 166 online-accessible opioid-related campaigns to understand the current state of the science and practice of campaigns to address the opioid crisis. The findings suggest that health promotion practitioners can have a greater impact on reducing overdose deaths if they move beyond awareness-raising messaging about opioid misuse and place a greater emphasis on driving demand for evidence-based treatments such as medications for opioid use disorder and on reducing stigma related to treatment and recovery.

Incidence, clinical patterns, and risk factors of postpartum uterine diseases in dairy cows from high-altitude tropical herds.

The cow's uterus sustains bacterial contamination and active inflammation after calving as part of the normal physiological process of uterine involution. Although the definition, incidence, and risk factors for postpartum uterine diseases (PUD) have been documented in annual calving systems with high-producing cows on total mixed ration, the literature contains little information for other production systems. The objective of this study was to quantify the incidence risk and factors associated with metritis, clinical endometritis, and cytological endometritis in high-altitude tropical dairy herds in a pasture-based system. A total of 248 cows from 5 commercial dairy herds in northern Antioquia, Colombia, were enrolled in this prospective observational longitudinal cohort study. Data collection and PUD diagnosis were performed at d 0, 3, 10, 17, 24, 31, 38, 45, and 52 (±1) after parturition. Between 60 and 70 d, cows were systematically enrolled in a synchronization protocol, and herds were visited monthly for pregnancy diagnosis until 180 ±15 d. The multivariable logistic regression model of variables associated with PUD occurrence included (a) parity, season of calving, transition diet, and body condition score at calving; (b) blood calcium, phosphorus, and magnesium concentrations, and milk urea nitrogen, ß-hydroxybutyrate and fat-to-protein ratio; and (c) dystocia, retained placenta, and delayed uterine involution. The incidences of puerperal metritis, clinical metritis (MET), clinical endometritis (CE), and cytological endometritis (CYTO) were 2.8, 25, 29, and 26%, respectively. Retained placenta and dystocia were associated with MET, and MET was associated with CE. Low blood calcium concentration at calving was associated with CYTO. Overall, 51.2% of the cows suffered at least 1 category of PUD during the first 60 d postpartum (DPP). However, cows also suffered from different consecutive clinical events of PUD (MET, CE, and CYTO) during the follow-up period (0 to 180 ±15 DPP). These events could be grouped into 4 types (which were referred to as "clinical patterns") based on interactions between MET, CE, and CYTO.

Genome-wide association study for age at puberty and resumption of cyclicity in a crossbred dairy cattle population.

Fertility is of primary economic importance in dairy cattle and the most common reason for involuntary culling. However, standard fertility traits have very low heritability that renders genetic selection slow and difficult. In this study, we explored fertility from an endocrine standpoint. A total of 1,163 crossbred Holstein-Normande females in a 3-generation familial design were studied for progesterone level measured every 10 d to determine age at puberty (PUB) and commencement of postpartum luteal activity (CPLA). Genetic parameters were estimated using REML with WOMBAT software. The heritability estimates were 0.38 ± 0.10 and 0.16 ± 0.07 for PUB and CPLA, respectively. Moreover, the 2 traits were genetically correlated (0.45 ± 0.23), suggesting a partially common determinism. Because of the family structure, a linkage disequilibrium and linkage analysis approach was preferred over standard genome-wide association study to map genomic regions associated with these traits. Ten quantitative trait loci (QTL) were detected for PUB on chromosomes 1, 3, 11, 13, 14, 21, and 29, whereas 3 QTL were associated with CPLA on chromosomes 21 and 26. Only the QTL on chromosome 21 was common to both traits. Four functional candidate genes (NCOA2, GAS2, OVOL1, and FOSL1) were identified in the detected regions. These findings will contribute to a clearer understanding of fertility determinism and enhance the value of introducing endocrinological data in fertility studies.

Health communication campaigns to drive demand for evidence-based practices and reduce stigma in the HEALing communities study.

BACKGROUND: The HEALing Communities Study (HCS) is testing whether the Communities that Heal (CTH) intervention can decrease opioid overdose deaths through the implementation of evidence-based practices (EBPs) in highly impacted communities. One of the CTH intervention components is a series of communications campaigns to promote the implementation of EBPs, increase demand for naloxone and medications for opioid use disorder (MOUD), and decrease stigma toward people with opioid use disorder and the use of EBPs, especially MOUD. This paper describes the approach to developing and executing these campaigns. METHODS: The HCS communication campaigns are developed and implemented through a collaboration between communication experts, research site staff, and community coalitions using a three-stage process. The Prepare phase identifies priority groups to receive campaign messages, develops content for those messages, and identifies a "call to action" that asks people to engage in a specific behavior. In the Plan phase, campaign resources are produced, and community coalitions develop plans to distribute campaign materials. During the Implement stage, these distribution plans guide delivery of content to priority groups. Fidelity measures assess how community coalitions follow their distribution plan as well as barriers and facilitators to implementation. An evaluation of the communication campaigns is planned. CONCLUSIONS: If successful, the Prepare-Plan-Implement process, and the campaign materials, could be adapted and used by other communities to address the opioid crisis. The campaign evaluation will extend the evidence base for how communication campaigns can be developed and implemented through a community-engaged process to effectively address public health crises.

A missense mutation (p.Tyr452Cys) in the CAD gene compromises reproductive success in French Normande cattle.

We scanned the genome of 77,815 Normande cattle with different Illumina SNP chips (Illumina Inc., San Diego, CA) to map recessive embryonic lethal mutations using homozygous haplotype deficiency. We detected 2 novel haplotypes on chromosomes 11 and 24 but did not confirm 6 previously reported haplotypes. The one on chromosome 11 showed a marked reduction in conception rates and moderate decrease in nonreturn rate in at-risk versus control mating, supporting late embryonic mortality. After fine mapping and analyzing whole-genome sequences, we prioritized a missense mutation in CAD (g.72399397T>C; p.Tyr452Cys)-a gene encoding a protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) essential for de novo pyrimidine biosynthesis-as a candidate causal variant. This transition mutation replaces a tyrosine residue, which is perfectly conserved among living organisms, with a cysteine residue in the carbamoyl-phosphate synthetase 2 domain of the protein. A single animal was confirmed to be homozygous for the mutation based on Sanger sequencing. However, large-scale genotyping of the candidate variant with the Illumina EuroG10k BeadChip revealed an absence of live homozygotes in a panel of 33,323 Normande animals and an absence of carriers in 348,593 animals from 19 other cattle breeds. These results support recessive embryonic lethality with nearly complete penetrance, as was previously reported in CAD mutants in several eukaryote species. The only homozygous cow had extremely poor udder conformation, suggesting a potential role of CAD in udder development, but no effect was detected when comparing daughter yield deviations of 250 heterozygous bulls with that of 2,912 homozygotes for the ancestral allele. Together, our results showed the importance of large-scale screening for homozygous haplotype deficiency with hundreds of thousands of animals, validating results with an independent data set, and considering unexpected live homozygotes, to avoid both false-positive and false-negative discoveries. These discoveries will be used primarily in mating decisions to avoid at-risk mating. In addition, we recommend including CAD in the breeding objectives of Normande cattle.

Characterization of Holstein and Normande whole milk miRNomes highlights breed specificities.

The concept of milk as a healthy food has opened the way for studies on milk components, from nutrients to microRNAs, molecules with broad regulatory properties present in large quantities in milk. Characterization of these components has been performed in several species, such as humans and bovine, depending on the stages of lactation. Here, we have studied the variation in milk microRNA composition according to genetic background. Using high throughput sequencing, we have characterized and compared the milk miRNomes of Holstein and Normande cattle, dairy breeds with distinct milk production features, in order to highlight microRNAs that are essential for regulation of the lactation process. In Holstein and Normande milk, 2,038 and 2,030 microRNAs were identified, respectively, with 1,771 common microRNAs, of which 1,049 were annotated and 722 were predicted. The comparison of the milk miRNomes of two breeds allowed to highlight 182 microRNAs displaying significant differences in the abundance. They are involved in the regulation of lipid metabolism and mammary morphogenesis and development, which affects lactation. Our results provide new insights into the regulation of molecular mechanisms involved in milk production.

Genetic parameters of milk production traits in response to a short once-daily milking period in crossbred Holstein × Normande dairy cows.

Despite its potential utility for predicting cows' milk yield responses to once-daily milking (ODM), the genetic basis of cow milk trait responses to ODM has been scarcely if ever described in the literature, especially for short ODM periods. This study set out to (1) estimate the genetic determinism of milk yield and composition during a 3-wk ODM period, (2) estimate the genetic determinism of milk yield responses (i.e., milk yield loss upon switching cows to ODM and milk yield recovery upon switching them back to twice-daily milking; TDM), and (3) seek predictors of milk yield responses to ODM, in particular using the first day of ODM. Our trial used 430 crossbred Holstein × Normande cows and comprised 3 successive periods: 1 wk of TDM (control), 3 wk of ODM, and 2 wk of TDM. Implementing ODM for 3 wk reduced milk yield by 27.5% on average, and after resuming TDM cows recovered on average 57% of the milk lost. Heritability estimates in the TDM control period and 3-wk ODM period were, respectively, 0.41 and 0.35 for milk yield, 0.66 and 0.61 for milk fat content, 0.60 and 0.80 for milk protein content, 0.66 and 0.36 for milk lactose content, and 0.20 and 0.15 for milk somatic cell score content. Milk yield and composition during 3-wk ODM and TDM periods were genetically close (within-trait genetic correlations between experimental periods all exceeding 0.80) but were genetically closer within the same milking frequency. Heritabilities of milk yield loss observed upon switching cows to ODM (0.39 and 0.34 for milk yield loss in kg/d and %, respectively) were moderate and similar to milk yield heritabilities. Milk yield recovery (kg/d) upon resuming TDM was a trait of high heritability (0.63). Because they are easy to measure, TDM milk yield and composition and milk yield responses on the first day of ODM were investigated as predictors of milk yield responses to a 3-wk ODM to easily detect animals that are well adapted to ODM. Twice-daily milking milk yield and composition were found to be partly genetically correlated with milk yield responses but not closely enough for practical application. With genetic correlations of 0.98 and 0.96 with 3-wk ODM milk yield losses (in kg/d and %, respectively), milk yield losses on the first day of ODM proved to be more accurate in predicting milk yield responses on longer term ODM than TDM milk yield.

Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle.

BACKGROUND: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. METHODS: Circular smooth muscle strips were prepared from human large intestine; after incubation with [³H]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied. KEY RESULTS: The non-selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX. CONCLUSIONS & INFERENCES: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.

5-HT4 receptors facilitate cholinergic neurotransmission throughout the murine gastrointestinal tract.

BACKGROUND: In the gastrointestinal tract of several species, facilitating 5-HT4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5-HT4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract. METHODS: In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L-NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride. KEY RESULTS: Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 µmol/L onwards. The facilitation in the different series with 0.03 µmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 µmol/L prucalopride was concentration-dependently inhibited by GR 113808. CONCLUSIONS & INFERENCES: In the murine gastrointestinal tract, activation of 5-HT4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species.

Effectiveness of intrauterine treatment with cephapirin in dairy cows with purulent vaginal discharge.

The objective of this study was to assess the efficacy of cephapirin intrauterine treatment preceding a timed artificial insemination protocol in lactating dairy cows with purulent vaginal discharges (PVDs). Holstein dairy cows (n = 1247) from 18 herds were enrolled in a controlled randomized clinical trial. At 34 days in milk (DIM; ±7 days), cows had a genital examination (transrectal palpation, vaginoscopy, and uterine bacteriology). They were randomly assigned to either the control group (CONT, no treatment) or the treatment group (CEPH) consisting of 1 intrauterine infusion of 500-mg cephapirin benzathine (RCL) (Metricure, Merck Animal Health, Montreal, Canada) regardless of the uterine health status. All cows were systematically enrolled in a presynch-ovsynch protocol for the first insemination. A second genital examination was made 2 weeks later. Cows that received any systemic or local antibiotics 10 days prior sampling to the end of the synchronization protocol were excluded from the study. Reproductive data of cows were collected for at least 300 DIM, entered in a databank, and validated (health record management software, DSAHR). Pregnancy diagnosis was done by transrectal palpation at the routinely scheduled veterinarian visits. On the basis of the highest sum of sensibility and specificity for pregnancy status at 120 DIM, the optimal cutoff for vaginal discharge score was determined as the presence of cloudy discharge with or without purulent material (PVD+, score 2). With a prevalence of 21.6% at 34 DIM, PVD+ was detrimental to the first-service conception rate (FSCR; PVD+: 26 ± 5%; PVD-: 40 ± 3%; P = 0.02). The negative effect of PVD+ was indicated by a hazard ratio of 0.72 (chi-square = 8.58; P < 0.01; 95% confidence interval = 0.56-0.91). Treatment with cephapirin was associated with a significant improvement of the FSCR in PVD+ cows (PVD+ CEPH: 36 ± 5%, PVD+ CONT: 23 ± 5%; P < 0.05), although it did not produce a considerable clinical cure based on the second examination. Thus, a longer period of time following treatment may be needed to properly assess the efficacy of intrauterine treatment in PVD+ cows. In conclusion, cephapirin intrauterine treatment in PVD+ cows at 34 DIM considerably improves reproductive performance compared with untreated PVD+ cows.