The number of offspring weaned from ewe lambs is affected differently by liveweight and age at breeding

In this paper, we tested the hypothesis that ewe lambs that are heavier and older at breeding will wean more offspring, due to increased reproductive rate and offspring survival and lower maternal mortality. To test this hypothesis, we analyzed data from more than 11,500 maternal composite ewe lambs collected over eight years. The ewe lambs had full pedigree records including birth type, age and liveweight at breeding plus records of the birthweight and survival of their offspring and the dam. The average liveweight and age at breeding was 40.2 kg and 228 days. The reproductive rate and weaning rate responses to liveweight at breeding were curvilinear (p < 0.001), and if ewe lambs achieved 45 kg by the start of breeding, their reproductive rate and weaning rate were within 5% of their maximum. By contrast, the effects of age at breeding on weaning rate was linear and increased by 0.4% per day, despite a quadratic (p < 0.01) effect of age at breeding on reproductive rate which increased only marginally when ewe lambs were older than 8 months at breeding. Increasing liveweight (p < 0.05) or age (p < 0.001) at breeding increased survival of their offspring, however an extra 10 kg of liveweight or 30 days of age at breeding increased offspring survival by less than 5%. Both liveweight (p < 0.001) and age (p < 0.01) at breeding also influenced survival of the ewe lamb dam but survival rates exceeded 95% across the range in liveweights from 30 to 55 kg and ages from 6 to 9 months. This understanding of the trade-off between age and liveweight at breeding will assist farmers to optimize the management of their ewe lambs, given the earlier they can be bred successfully the easier they can be integrated with the breeding of the adult ewe flock the following year

Do exercise-associated genes explain phenotypic variance in the three components of fitness? a systematic review & meta-analysis

The aim of this systematic review and meta-analysis was to identify a list of common, candidate genes associated with the three components of fitness, specifically cardiovascular fitness, muscular strength, and anaerobic power, and how these genes are associated with exercise response phenotype variability, in previously untrained participants. A total of 3,969 potentially relevant papers were identified and processed for inclusion. After eligibility and study selection assessment, 24 studies were selected for meta-analysis, comprising a total of 3,012 participants (male n = 1,512; females n = 1,239; not stated n = 261; age 28 ± 9 years). Meta-Essentials spreadsheet 1.4 (Microsoft Excel) was used in creating the forest plots and meta-analysis. IBM SPSS statistics V24 was implemented for the statistical analyses and the alpha was set at p ≤ 0.05. 13 candidate genes and their associated alleles were identified, which were associated with the phenotypes of interest. Analysis of training group data showed significant differential phenotypic responses. Subgroup analysis showed; 44%, 72% and 10% of the response variance in aerobic, strength and power phenotypes, respectively, were explained by genetic influences. This analysis established that genetic variability explained a significant proportion of the adaptation differences across the three components of fitness in the participants post-training. The results also showed the importance of analysing and reporting specific gene alleles. Information obtained from these findings has the potential to inform and influence future exercise-related genes and training studies

‘The Rest is Silence’:Psychogeography, Soundscape and Nostalgia in Pat Collins’ Silence

Guy Debord defines the term psychogeography as 'the study of the precise laws and specific effects of the geographical environment, consciously organised or not, on the emotions and behaviour of individuals' (Debord 1955: 23). Similar to the belief of psychogeographers that the geography of an environment has a psychological effect on the human mind, proponents of acoustic ecology such as R. Murray Schafer hold that humans are affected by the sound of the environment in which they find themselves. Further to this, they examine the extent to which soundscapes can be shaped by human behaviour. Recently a body of Irish films has emerged that directly engages with the Irish soundscape and landscape on a psychogeographical level. Rather than using landscape as a physical space for the locus of action, these representations of the Irish landscape allow for an engagement with the aesthetic effects of the geographical landscape as a reflection of the psychological states of the protagonists. Bearing this in mind, this article examines how Silence (Collins 2012) arguably demonstrates the most overt and conscious incursion into this area to date. It specifically interrogates how the filmic representation of the psychogeography and soundscape of the Irish rural landscape can serve to express emotion, alienation and nostalgia, thus confronting both the Irish landscape and the weight of its associated history

Nonlocal electrostatics in heterogeneous suspensions using a point-dipole model

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Responsiveness to endurance training can be partly explained by the number of favorable single nucleotide polymorphisms an individual possesses

Cardiorespiratory fitness is a key component of health-related fitness. It is a necessary focus of improvement, especially for those that have poor fitness and are classed as untrained. However, much research has shown individuals respond differentially to identical training programs, suggesting the involvement of a genetic component in individual exercise responses. Previous research has focused predominantly on a relatively low number of candidate genes and their overall influence on exercise responsiveness. However, examination of gene-specific alleles may provide a greater level of understanding. Accordingly, this study aimed to investigate the associations between cardiorespiratory fitness and an individual’s genotype following a field-based endurance program within a previously untrained population. Participants (age: 29 ± 7 years, height: 175 ± 9 cm, mass: 79 ± 21 kg, body mass index: 26 ± 7 kg/m2) were randomly assigned to either a training (n = 21) or control group (n = 24). The training group completed a periodized running program for 8-weeks (duration: 20-30-minutes per session, intensity: 6–7 Borg Category-Ratio-10 scale rating, frequency: 3 sessions per week). Both groups completed a Cooper 12-minute run test to estimate cardiorespiratory fitness at baseline, mid-study, and post-study. One thousand single nucleotide polymorphisms (SNPs) were assessed via saliva sample collections. Cooper run distance showed a significant improvement (0.23 ± 0.17 km [11.51 ± 9.09%], p &lt; 0.001, ES = 0.48 [95%CI: 0.16–0.32]), following the 8-week program, whilst controls displayed no significant changes (0.03 ± 0.15 km [1.55 ± 6.98%], p = 0.346, ES = 0.08, [95%CI: -0.35–0.95]). A significant portion of the inter-individual variation in Cooper scores could be explained by the number of positive alleles a participant possessed (r = 0.92, R2 = 0.85, p &lt; 0.001). These findings demonstrate the relative influence of key allele variants on an individual’s responsiveness to endurance training

Intensive community care services for children and young people in psychiatric crisis: an expert opinion.

BACKGROUND: Children and young people's (CYP) mental health is worsening, and an increasing number are seeking psychiatric and mental health care. Whilst many CYPs with low-to-medium levels of psychiatric distress can be treated in outpatient services, CYPs in crisis often require inpatient hospital treatment. Although necessary in many cases, inpatient care can be distressing for CYPs and their families. Amongst other things, inpatient stays often isolate CYPs from their support networks and disrupt their education. In response to such limitations, and in order to effectively support CYPs with complex mental health needs, intensive community-based treatment models, which are known in this paper as intensive community care services (ICCS), have been developed. Although ICCS have been developed in a number of settings, there is, at present, little to no consensus of what ICCS entails. METHODS: A group of child and adolescent mental health clinicians, researchers and academics convened in London in January 2023. They met to discuss and agree upon the minimum requirements of ICCS. The discussion was semi-structured and used the Dartmouth Assertive Community Treatment Fidelity Scale as a framework. Following the meeting, the agreed features of ICCS, as described in this paper, were written up. RESULTS: ICCS was defined as a service which provides treatment primarily outside of hospital in community settings such as the school or home. Alongside this, ICCS should provide at least some out-of-hours support, and a minimum of 90% of CYPs should be supported at least twice per week. The maximum caseload should be approximately 5 clients per full time equivalent (FTE), and the minimum number of staff for an ICCS team should be 4 FTE. The group also confirmed the importance of supporting CYPs engagement with their communities and the need to remain flexible in treatment provision. Finally, the importance of robust evaluation utilising tools including the Children's Global Assessment Scale were agreed. CONCLUSIONS: This paper presents the agreed minimum requirements of intensive community-based psychiatric care. Using the parameters laid out herein, clinicians, academics, and related colleagues working in ICCS should seek to further develop the evidence base for this treatment model

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial

Background: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. Methods: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (&lt;6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. Findings: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029–2052) and median on-treatment follow-up was 1324 days (IQR 870–1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70–1·03], p&lt;0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. Funding: Menarini, Ipsen, and Teijin Pharma Ltd

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. Funding Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19