The effect of abrupt weaning of suckler calves on the plasma concentrations of cortisol, catecholamines, leukocyte, acute-phase proteins and in vitro interferon-gamma production

End of project reportThe objective of this study was to examine the effect of abrupt weaning (inclusive of social group disruption and maternal separation) on the physiological mediators of stress and measures of immune function. Thirty-eight male and 38 female continental calves were habituated to handling for two weeks prior to bleeding. Calves were blocked on sex, weight and breed of dam and randomly assigned, within block, to either a control (cows remain with calves) or abruptly weaned group (calves removed from cows). Animals were separated into the respective treatment groups at weaning (0 h). Calves were bled at – 168 h, 6 h (males only), 24 h, 48 h and 168 h post weaning. At each sampling time an observer scored the behavioural reaction of calves to sampling. Blood samples were analysed for cortisol, catecholamine concentrations (not sampled at –168 h) and in vitro interferon-gamma production, neutrophil :lymphocyte ratio and acute phase protein concentrations. All continuous data were analysed using a split-plot ANOVA, except that collected at 6 h, which was analysed using a single factor ANOVA model. The effects of weaning, calf sex and time and respective interactions were described. Disruption of the established social groups at 0 h, increased (p<0.001) the plasma cortisol concentration and neutrophil: lymphocyte ratio and reduced the leukocyte concentration (p<0.001) and the in vitro interferon-gamma response to the mitogen concanavalin-A (p<0.001) and keyhole limpet haemocyanin (p<0.001) for weaned and control animals, when compared with –168h. Plasma adrenaline and noradrenaline concentrations were not affected by group disruption. There was no effect of weaning or sex on calf behavioural reaction to handling during blood sampling. Plasma cortisol and adrenaline concentrations were not affected by weaning or sex. Plasma noradrenaline concentration was influenced by weaning x sex (p<0.05) and time x sex (p<0.05). The response increased for male calves with weaning and increased with each sampling time post weaning. For heifers the response was not affected by weaning and plasma concentrations decreased at 168 h post weaning. There was no effect of weaning or sex on leukocyte concentration. The neutrophils : lymphocyte ration increased post weaning (p<0.01) and was affected by sex (p<0.05). Weaning decreased (p<0.05) the in vitro interferon-gamma response to the antigen KLH. There was a time x weaning x sex (p<0.05) interaction for fibrinogen concentration but no effect of treatment on haptoglobin concentration. Abrupt weaning increased plasma cortisol and nor-adrenaline concentrations, which was accompanied by attenuation of in vitro interferon gamma production to novel mitogen and antigen complexes up to 7 days post weaning.European Union Structural Funds (EAGGF

The use of in vitro techniques to examine the effect of ensiling on the ruminal digestion of perennial ryegrass

The objective of this study was to examine the effect of ensiling and maturity on the in vitro digestion kinetics of the perennial ryegrass cell wall fraction. Preliminary methodological studies concluded that (i) in vitro cell wall digestion profiles were optimised when fermentation tubes were horizontally incubated, (ii) perennial ryegrass cell wall isolation by neutral detergent extraction but not by aqueous extraction (70 °C) adversely affected in vitro digestion kinetics (iii) method of inoculum preservation (untreated and frozen at - 20 °C, with or without cryoprotectant, with or without pre-incubation) did not affect the rate but all imposed a lag (p<0.05) and altered the extent of dry matter (DM) digestion, when compared with fresh inoculum. Pre-incubation was beneficial in the absence of a cryoprotectant only (p<0.05) and the digestion kinetics of the frozen un-treated inoculum were similar to preservation with a cryoprotectant. A dual flow semicontinuous culture was established. In vitro protozoal numbers were less than in vivo (p<0.001) and in vivo ruminal diurnal trends for volatile fatty acid (VFA), ammonia and lactate were qualitatively simulated. When the fresh forage was incubated in vitro, ensiling reduced (p<0.001) the apparent extent of digestion (AED) of a late season perennial ryegrass cell wall fraction. Ensiling had no effect on the AED of the fractionated cell wall fraction, removed from the whole forage by aqueous extraction. There was a maturity x forage interaction for the cell wall digestion of fresh (p<0.01) and fractionated (p<0.05) perennial ryegrass ensiled at different maturities. Maturity (p<0.001) but not ensiling adversely affected the digestion of the isolated cell wall fraction. Ensiling per se decreased the microbial protein production (p<0.001) from the watersoluble fraction but did not affect VFA production. The AED of the isolated cell wall fraction from an extensively preserved perennial ryegrass forage was increased when supplemented with the water-soluble component of the fresh herbage (WG) (p<0.05) or with WG and nitrogen (p<0.05). The AED of the isolated cell wall fraction from the restrictively preserved forage was not influenced by supplementation. The biochemical alterations in the Wg fraction due to ensiling did not influence cell wall digestion of the fresh or extensively preserved forage nor did it influence protozoal numbers, microbial protein or VFA production in the rumen semi-continuous culture

Optimisation of Nutrient Supply for Beef Cattle Fed Grass or Silage.

End of Project ReportSince forage forms a large part of growing ruminant rations in Ireland, the trust of this project was to examine the effect of ensilage on ruminal digestion of grass and to examine ruminal microbial protein and intestinally absorbable protein supplied by grass and/or clover. A range of in vitro and in vivo techniques were employed and strategies used by commercial beef producers to optimise cattle growth (and nutrient supply) were also documented. To accomplish the aims of this project, a range of methodology developments/ modifications in vitro and in vivo was carried out. From in vitro methodology development it was concluded that : (i) Compared with fresh silage, drying per se may give artifically higher rates of dry matter (DM) digestion. (ii) Greater experimental precision can be obtained by ensuring a greater substrate surface area to reaction volume ratio in each reaction vessel. (iii) For studies where the rate of digestion is of greatest importance, pre-incubation of frozen inoculum in a nutrient medium best simulated the cellulolytic activity of unfrozen inoculum. In studies that require large volumes of inoculum for extended work, freezing directly is justified. (iv) Neutral detergent extraction altered in vitro digestion characteristics of silage. The residue after washing with water at 70°C has a high residual fibre concentration and is more representative of the structural components of silage ingested by ruminants. (v) A semi-continuous culture system developed at Grange Research Centre can successfully model in vitro ruminal digestion of fibre and starch-based diets in a controlled environment. From in vivo methodology development it was concluded that : (i) Oven drying at 60°C and correction for loss of volatiles gives a good estimation of DM concentration of ruminal particulate digesta. This procedure has the added advantage that drying at 60°C allows the residual materials to be analysed for fibre fractions without concern for heat damage which can occur at a higher drying temperature. (ii) A naso-ruminal sampling device can be used to measure the relative patterns of fermentation of contrasting diet types when in situ for up to 7 days. (ii) Application of a vacuum to withdraw samples had no negative effect on ruminal fluid variables. From in vitro studies on grass digestion, it was concluded that : (i) Ensiling of grass decreased the apparent extent of digestion of cell walls when in the presence of the whole plant and that this largely reflected an increase in the lag time before digestion commenced. (ii) Ensiling of grass did not negatively affect the digestion of isolated cell walls. (iii) There is a negative impact of ensiling on microbial protein production from the water soluble carbohydrate fraction of grass. (iv) Supplementation with the water soluble fraction of grass significantly improved the apparent extent of digestion for ensiled forages when compared with the supplementation of the post-ensiling fraction in a batch culture system. (v) There is a negative impact of maturity on the pattern of cell wall fermentation and that this impact can be decreased by ensiling method. From studies on herbage digestion in vivo it was concluded that : (i) Grass silage type had a greater effect than the rate of concentrate fermentation on ruminal microbal protein synthesis. (ii) Harvesting time had a bigger impact on nutrient supply from herbage than sward type (grass or grass/clover). (iii) Increasing clover content in the herbage decreased the biological value (g nitrogen retained/kg absorbed) of dietary protein. Diverse stratgies were used on commercial beef farms to optimise nutrient supply and animal growth. Average animal performance on individual farms was not better than would be typically recorded in a research environment. There was scope on many of the farms to improve technical performance and to decrease the costs of production.European Union Structural Funds (EAGGF

Evaluation of Parasite Control Programmes in Beef Cattle

End of Project ReportThe objective of this project was to examine the effect of methods of animal management in a dairy calf to beef (Study 1) and a suckler beef (Study 2) production system on parasitic burdens of calves and accompanying animals. Parasitic burdens were defined by quantifying faecal egg counts and plasma pepsinogen levels (concentrations greater than 1U/l are an indicator of a possible heavy parasitic burden). In the first study three different grazing systems for dairy calves and steers, were investigated. The leader follower system (L-F1) was described by calves grazing ahead of steers; the separate (S) system was described by calves and steers grazing separate areas and thirdly the combined (T) system where both calves and steers grazed together. In the second study, two different grazing systems for suckler cows and calves, and yearling animals were examined. The leader follower (L-F2) system was described by yearlings grazing ahead of suckler cows with calves at foot or a conventional (C) system where the cows and calves grazed areas separate to the yearlings

A protocol to evaluate the impact of embedding Public and Patient Involvement in a structured PhD program for stroke care

BackgroundEmbedding Public and Patient Involvement (PPI) in postgraduate research has been recognized as an important component of post-graduate training, providing research scholars with an awareness and a skillset in an area which prepares them for future roles as healthcare researchers. Improving Pathways for Acute STroke And Rehabilitation (iPASTAR) is a structured PhD training program [Collaborative Doctoral Award (CDA)] which aims to design a person-centered stroke pathway throughout the trajectory of stroke care, to optimize post-stroke health and wellbeing. PPI is embedded at all stages.PurposeThe iPASTAR research programme was strongly informed by a round-table PPI consultation process with individuals who experienced stroke and who provided broad representation across ages, gender, geographical locations (urban and rural) and the PhD themed areas of acute care, early supported discharge and lifestyle-based interventions after stroke. Four PhD scholars taking part in the CDA-iPASTAR now work collaboratively with four stroke champions, supported by a wider PPI advisory panel.MethodsThis study will evaluate the process and impact of embedding PPI during a PhD program. We will conduct a longitudinal mixed-methods evaluation, conducting focus groups at 24, 36, and 48 months to explore the experiences of the key stakeholders involved. The participants will include PhD scholars, PPI partners (PPI Advisory Group and PPI Champions), PhD supervisors and a PPI manager. An independent researcher will conduct the evaluation. We will include focus groups, individual interviews and participant reflections. Qualitative data will be analyzed using thematic and content analysis, quantitative data will be analyzed using descriptive statistics.DiscussionPPI and patient voice initiatives bring together researchers, family, and people with health care issues into meaningful dialogue and allow the development of a patient-voice learning network. Embedding PPI training within a PhD program can build meaningful capacity in PPI partnerships in stroke research

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial

Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The effect of housing on the diurnal behavioural profile of beef heifers

The objectives were to determine 1. the behaviour of heifers at pasture or housed on slats, and 2. the effect of housing on behavioural adaptation when moved to pasture. Forty-five continental crossbred heifers were assigned to either housing on slats at 3 m2 head-1for 5 months (H), grazing for 5 months (G) or housing for 4 months, prior to grazing (HG). Lying and eating behaviour was recorded periodically for H, G and for HG post-turnout. Per day, G animals spent longer (p&lt;0.01) eating and had a greater (p&lt;0.001) number of daily lying bouts than H animals. While there were minor differences between G and HG animals in the 24 h period after turnout, there was no difference between G and HG animals in time spent eating, lying or in the number of lying bouts on day 1, 2, 3 or 10 post turnout. While abnormal lying behaviour was observed in 3 animals before turnout, there was no abnormal lying behaviour in HG animals by 48 h post turnout. The alteration in behaviour due to housing was not permanent