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Data sharing: The PHOSP-COVID study protocol, consent form, definition, and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online. UK Biobank information can be released once necessary approvals have been obtained. Other data (eg, the R code and protocol) will be made available on reasonable request to the corresponding author. Copyright © 2023 The Author(s). Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council. UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.

Data sharing statement: PHOSP-COVID: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, requests for data access and other relevant study materials are available online at https://www.phosp.org. COVIDENCE UK: De-identified participant data will be made available upon reasonable request to the corresponding author. Supplementary data is available online at: https://www.sciencedirect.com/science/article/pii/S2666776223000546?via%3Dihub#appsec1 . Copyright © 2023 The Author(s). Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders. PHOSP-COVID: This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma + Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. COVIDENCE UK: We thank all participants of COVIDENCE UK, and the following organisations who supported study recruitment: Asthma UK/British Lung Foundation, the British Heart Foundation, the British Obesity Society, Cancer Research UK, Diabetes UK, Future Publishing, Kidney Care UK, Kidney Wales, Mumsnet, the National Kidney Federation, the National Rheumatoid Arthritis Society, the North West London Health Research Register (DISCOVER), Primary Immunodeficiency UK, the Race Equality Foundation, SWM Health, the Terence Higgins Trust, and Vasculitis UK.

Four nationally representative studies ( N = 1,986; three preregistered) find evidence for a bias in how people perceive opposing viewpoints expressed through online discourse. These studies elucidate a political bot bias, where political partisans (vs. their out-party) are more likely to view counter-ideological (vs. ideologically consistent) tweets to be social media bots (vs. humans). Study 1 demonstrates that American Democrats and Republicans are more likely to attribute tweets to bots when those tweets express counter-ideological views. Study 2 demonstrated this bias with actual bot tweets generated by the Russian government and comparable human tweets. Study 3 demonstrated this bias manifests in the context of real recent elections and is associated with markers of political animosity. Study 4 experimentally demonstrates the consequences of bot attribution for perceptions of online political discourse. Our findings document a consistent bias that has implications for political discussion online and political polarization more broadly.

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research.

Background Acute appendicitis is a common general surgical condition where diagnosis is predominantly clinical, with the aid of adjunct investigations. This study reviews the relationship between normal and elevated biochemical inflammatory markers, duration of symptoms and proven appendicitis. Methods A multicentre prospective observational study was performed across 27 centres and included a total of 949 patients with clinical suspicion of appendicitis, who had both white cell count (WCC) and C-reactive protein (CRP) recorded and underwent appendicectomy. Results A total of 90.4% of patients with raised WCC and CRP had appendicitis with a positive predictive value (PPV) of 0.9 and negative predictive value (NPV) of 0.4. Sensitivity and specificity of elevated WCC (sensitivity 66.5%, specificity 66.0%) and elevated CRP (sensitivity 77.3%, specificity 52.0%) lie within ranges identified by previous studies. A total of 39.8% of patients with normal CRP and WCC had appendicitis. Sensitivity and PPV for patients with elevated inflammatory markers were high until 48 h of symptoms (sensitivity 94%, PPV 0.87). NPV was elevated after 24 h (NPV 0.65 in patients with 24-48 h of symptoms, and 0.61 after 48 h), whilst those with symptoms less than 24 h had a lower NPV of 0.52. Conclusion Whilst elevated inflammatory markers are a helpful aid in the diagnosis of appendicitis, they should not be relied on by themselves. Nor can normal inflammatory markers be used to exclude appendicitis, even in those with prolonged duration of symptoms. The diagnosis of appendicitis should be guided by a combination of clinical judgement with the assistance of inflammatory markers.

Stress influences the activity of the reproductive system at several sites. One of the most significant effects is at level of the GnRH secretory system to reduce GnRH pulsatility and thus LH pulsatility. This in turn reduces the oestradiol signal that stimulates the GnRH-LH surge in the follicular phase. Three sequential phases have been identified in the induction of the GnRH-LH surge by oestradiol: (i) activation, (ii) transmission and (iii) surge secretion. There is evidence that administration of endotoxin prevents activation but not transmission, hypoglycaemia blocks both activation and transmission, whereas truck transport is effective during the late, but not early, transmission phase. Opioids mediate the suppressive effects of hypoglycaemia on both LH pulsatility and the delayed onset of the LH surge in ewes. The exact neurocircuitry used in sheep is yet to be identified but many of the connections that are proposed as important in rats are present in sheep. Corticotrophin-releasing hormone (CRH) neurones in the paraventricular nucleus that project axons to the median eminence probably do not directly inhibit GnRH, but either afferent or parallel central pathways are involved. New members of the CRH peptide and receptor families have been identified, but roles in the control of reproduction have yet to be determined.

Transport of post-partum cows or sheep before an oestradiol-induced LH surge delayed gonadotrophin secretion possibly by affecting hypothalamic activity but not via an opioid mediated mechanism as the effect could not be reversed by naloxone. In addition, reduced LH responses to GnRH were observed in cattle during transport. In sheep, adrenocorticotrophic hormone (ACTH) also diminished the LH response to GnRH, but only when GnRH was administered 3 h after ACTH, not after 0.5 h. This finding suggests that very early suppression of LH secretion by stressors is not mediated by ACTH action at the pituitary but that immediate activation of the sympathetic nervous system may be involved. In ewes during the breeding season, repeated exposure to GnRH at intervals of 2 h during transport resulted in lower LH responses to the second and third injections. When anoestrous ewes were treated with oestradiol and GnRH while being restrained and isolated, the onset of the LH surge was delayed. The effects of hypothalamus-pituitary-adrenal hyperactivity on LH release may involve suppression of GnRH receptor activity, a reduction in releasable LH, or both factors. Studies in vitro with perifused ovine pituitaries showed that ACTH or corticotrophin releasing hormone markedly suppressed LH secretion in response to the second of two exposures to GnRH. This occurred with pituitaries obtained from anoestrous ewes irrespective of prior treatment with oestradiol, suggesting that compounds from the hypothalamus-pituitary-adrenal do not exert effects on the oestradiol-sensitizing mechanisms on the pituitary. In conclusion, stressors affect reproductive function via actions at the hypothalamus as well as impairing pituitary LH release induced by GnRH.

Summary Distal phalanx fractures are well documented in adult horses, but our knowledge of such fractures in foals is limited. Recent studies showed a high incidence of distal phalanx palmar process (PP) fractures in foals, the aetiology is not yet known. Several hypotheses have been suggested as possible causes, including uneven compressive forces, unequal forces from the deep digital flexor tendon, composition and shape of the PP, and conformation. A better understanding of the aetiology and predisposing factors requires further research. Radiography is the commonly used imaging modality for diagnosis of such fractures; however, those fractures might be missed on routine radiographic projections. In order to have a high probability of identifying fractures, a series of 5 radiographs including the oblique views is required. This article reviews the incidence of distal phalanx PP fractures and discusses the diagnosis of such fractures.

In the ewe, steroid hormones act on the hypothalamic arcuate nucleus (ARC) to initiate the GnRH/LH surge. Within the ARC, steroid signal transduction may be mediated by estrogen receptive dopamine-, β-endorphin- or neuropeptide Y (NPY)-expressing cells, as well as those co-localising kisspeptin, neurokinin B (NKB) and dynorphin (termed KNDy). We investigated the time during the follicular phase when these cells become activated (i.e., co-localise c-Fos) relative to the timing of the LH surge onset and may therefore be involved in the surge generating mechanism. Furthermore, we aimed to elucidate whether these activation patterns are altered after lipopolysaccharide (LPS) administration, which is known to inhibit the LH surge. Follicular phases of ewes were synchronised by progesterone withdrawal and blood samples were collected every 2 h. Hypothalamic tissue was retrieved at various times during the follicular phase with or without the administration of LPS (100 ng/kg). The percentage of activated dopamine cells decreased before the onset of sexual behaviour, whereas activation of β-endorphin decreased and NPY activation tended to increase during the LH surge. These patterns were not disturbed by LPS administration. Maximal co-expression of c-Fos in dynorphin immunoreactive neurons was observed earlier during the follicular phase, compared to kisspeptin and NKB, which were maximally activated during the surge. This indicates a distinct role for ARC dynorphin in the LH surge generation mechanism. Acute LPS decreased the percentage of activated dynorphin and kisspeptin immunoreactive cells. Thus, in the ovary-intact ewe, KNDy neurones are activated prior to the LH surge onset and this pattern is inhibited by the administration of LPS.

Summary Reasons for performing study Recent studies indicate a high prevalence of fractures of the palmar processes (PP) of the distal phalanx in foals. However, information on the prevalence of such fractures in different breeds and the effect of predisposing factors, such as hoof conformation, is limited. Objectives To examine the prevalence of distal phalanx PP fractures in foals and report the relationship of distal limb and hoof conformation with the prevalence of fracture. Study design Longitudinal study. Methods Front hooves of 19 Thoroughbred, Quarter Horse and Arabian foals were examined. Digital radiographic and photographic images of the distal aspect of the forelimbs were taken at ∼2.5 month intervals. Five radiographic projections of each limb were as follows: lateromedial; horizontal beam dorsopalmar; dorso60°proximal-palmarodistal oblique; dorso60°proximo45°lateral-palmarodistomedial oblique; and dorso60°proximo45°medial-palmarodistolateral oblique. The relationship between measurements and the prevalence of fractures was assessed by 3-way ANOVA. Results Fractures were found in 74% (n = 14) of the foals during the study period. The prevalences of lateral PP and medial PP fractures were not significantly different. Several hoof measurements were associated with PP fractures. Longer dorsal length of the distal phalanx was associated with medial PP fractures, while smaller lateral angle and shorter lateral palmar length were associated with a higher prevalence of lateral PP fractures. Conclusions This study revealed a high prevalence of PP fractures in young foals, particularly in Thoroughbred foals. The hoof conformation may be one of the contributory factors to PP fractures in foals.

Background The advent of high-throughput next-generation sequencing (NGS) technologies has resulted in a deluge of data for a wide variety of clinical uses, with millions of samples sequenced to date. Data generated at an "-omics" level (genomics, transcriptomics, epigenomics, proteomics, etc) in cancer research and for clinical decision making is ushering in a new era of personalized cancer care. However this requires fast, accurate, and easily automatable bioinformatics pipelines capable of large scale analytics on big datasets without sacrificing accuracy. Here we present OncOS, a cloud-based auto-scaling architecture capable of performing highly accurate molecular profiling for personalized clinical insights. Methods A flexible cloud architecture implements bioinformatics pipelines dynamically depending on the input data, including a range of possible sample types (FFPE, fresh frozen, plasma/cfDNA), and clinical insights (clinical trial matching, drug matching, and genomic insights such as mutation calls, copy number variant calls, and MSI/TMB). This is powered by a pipeline scheduler and an elastic container service cluster that is capable of initializing a large number of elastic compute cloud instances for scalable and parallelized processing. Data is stored on HIPAA compliant and securely encrypted databases and simple storage services, with key information relayed to a web app for use in a clinical setting. Results OncOS has also been optimized for Positive Predictive Value (PPV), with testing on samples from the Multi-Center Mutation Calling in Multiple Cancers (MC3) project, a collaborative effort to provide a high confidence set of variants for patients in The Cancer Genome Atlas (TCGA). Benchmarking shows OncOS performs with a PPV of 87.4%, outperforming similar variant calling pipelines (BROAD institute 75.4%; MD Anderson 80.1%). Conclusions OncOS is a precision oncology platform with a cloud architecture capable of processing a variety of sample types at scale, optimized for variant calling PPV and drawing of key clinical insights. Legal entity responsible for the study The authors. Funding Cambridge Cancer Genomics. Disclosure J.S. Thompson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. J.H.R. Farmery: Shareholder / Stockholder / Stock options: Cambridge Cancer Genomics. H. Dobson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. S. Frost: Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. J.W. Cassidy: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Cambridge Cancer Genomics. N. Patel: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H. Thompson: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics. H.W. Clifford: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Cambridge Cancer Genomics.

The objective of this study was to examine the effect of a chronic stressor, lameness, on reproductive parameters. Seventy cows 30–80 days post-partum were scored for lameness and follicular phases synchronized with GnRH followed seven days later by prostaglandin (PG). Fifteen Lame animals did not respond to GnRH ovarian stimulation. Milk progesterone for 5 days prior to PG was lower in the remaining Lame cows than Healthy herdmates. Fewer Lame cows ovulated (26/37 versus 17/18; P = 0.04) and the interval from PG to ovulation was shorter in Lame cows. In Subset 1 (20 animals), the LH pulse frequency was similar in ovulating animals (Lame and Healthy) but lower in Lame non-ovulators. An LH surge always preceded ovulation but lameness did not affect the interval from PG to LH surge onset or LH surge concentrations. Before the LH surge, estradiol was lower in non-ovulating cows compared to those that ovulated and estradiol concentrations were positively correlated with LH pulse frequency. In Subset 2 (45 cows), Lame ovulating cows had a less intense estrus than Healthy cows, although Lame cows began estrus and stood-to-be-mounted earlier than Healthy cows. In conclusion, we have identified several parameters to explain poor fertility in some chronically stressed animals. From 30 to 80 days post-partum, there was a graded effect that ranged from 29% Lame cows with absence of ovarian activity, whereas another 21% Lame cows failed to express estrus or ovulate a low estrogenic follicle; in 50% cows, many reproductive parameters were unaffected by lameness.

Summary A blind randomised study using two groups of age- and sex-matched Quarter Horse foals was conducted by feeding a low copper diet containing 8 ppm of copper (Cu) and a control diet containing 25 ppm. Foals in the low-Cu group had declining liver Cu values and developed osteochondritis (OCD), epiphysitis and limb deformities over a 6-month period. Erosion and separation of cartilage from the subchondral bone in the dorsal facets of the cervical spine were the most consistent post-mortem lesions. Foals fed the high-Cu diet had no significant musculoskeletal lesions. Scoring of standing lateral cervical radiographs was a moderately sensitive (0.68) and specific (0.70) test and had moderate agreement with post-mortem findings (κ = 0.35). Technetium scintigraphy of the limbs and cervical spine failed to detect occult or known lesions in the limbs and cervical spine. Microscopic examination of growth plates and metaphyseal bone from affected foals showed that fractures disrupted or displaced the normal growth plate architecture and interfered with orderly bone growth, similar to Cu deficiency in cattle. Bone morphometry indicated there was less subchondral bone volume in the distal cannon bone (P

The objectives of the present study were to quantify the effects of a biological chronic stressor (lameness) on the duration and frequency of different oestrous behaviours in parallel with milk hormone profiles. Dairy cows 51.8 +/- 1.4 days postpartum (n = 59), including 18 non-lame control cows, were scored for lameness and closely observed for signs of oestrus having had their follicular phases synchronized by administration of gonadotrophin-releasing-hormone (GnRH) followed by prostaglandin F(2alpha) (PG) 7 days later. Lameness shortened the period when herd-mates attempted to mount the lame cows (1.83 +/- 0.69 h vs 5.20 +/- 1.53 h; p = 0.042) but did not affect the overall duration of total behaviours (lame 12.3 +/- 1.3 h vs non-lame 15.2 +/- 1.3 h). Lameness also lowered the intensity of oestrus [1417 +/- 206 points (n = 18) vs 2260 +/- 307 points (n = 15); p = 0.029]. Throughout the synchronized oestrous period, lame cows mounted the rear of herd-mates less frequently (p = 0.020) and tended to chin rest less (p = 0.075). Around the period of maximum oestrous intensity, lameness also diminished the proportion of cows mounting the rear of another cow and chin resting (p = 0.048, p = 0.037, respectively). Furthermore, lame cows had lower progesterone values during the 6 days before oestrous (p < or = 0.05). Fewer lame cows were observed in oestrus following PG (non-lame 83%, lame 53%; p = 0.030); however, if prior progesterone concentrations were elevated, lame cows were just as likely to be observed in oestrus. In conclusion, following endogenous progesterone exposure, lameness shortens the period when herd-mates attempt to mount lame cows but does not affect the incidence of oestrous. However, lame cows are mounted less frequently and express oestrus of lower intensity. This is associated with lower progesterone prior to oestrus but not with abnormal oestradiol or cortisol profiles in daily milk samples.

The objective of this study was to investigate the effect of somatic cell count (SCC), body condition score (BCS) or lameness score on ovarian follicular growth and ovulation in dairy cows. Seventy four animals 30–80 days post-partum were monitored for all three conditions before synchronization of ovarian follicular phases by administration of gonadotrophin releasing hormone (GnRH) followed seven days later with prostaglandin F2alpha (PG). Ultrasonography of both ovaries twice daily throughout the follicular phase revealed that fewer animals with combined high SCC and lameness (4/9) ovulated compared to healthy animals (19/21; P = 0.006) or animals with only high SCC (11/11; P = 0.004) or only lameness (21/27; P = 0.06). Overall, regardless of the presence of other concurrent conditions, fewer lame cows ovulated than Non Lame animals (30/42 and 30/32; P = 0.015). Mean follicular growth and maximum follicular diameter were unaffected by any of the three conditions. However, dominant follicle growth and maximum diameter were greater in the 60 animals that ovulated compared to the 14 that did not; 1.83 ± 0.16 versus 0.96 ± 0.26 mm/day (P = 0.014) and 19.4 ± 0.4 versus 16.4 ± 1.2 mm (P = 0.003), respectively. In conclusion, lameness reduced the proportion of cows that ovulated and the synergistic effect of high SCC and lameness reduced that proportion further. However, follicular growth and maximum follicular diameter were unaffected by high SCC, low BCS or lameness.

The aims of this study were to determine whether the equine distal phalanx changes in shape in response to exercise and to relate any osseous changes to those in the hoof capsule. Eighteen mature Standardbred horses were randomly divided into exercise and control groups. Exercised horses were jogged on a straight track at individual mean speeds between 4 and 8 m s− 1for 10–45 min, 4 days per week for 16 weeks. Both groups were similarly shod and pastured on the same field. Before and after the training period, each horse had digital photographs and magnetic resonance images (MRI) made of the right forehoof. Five linear measurements of the distal phalanx were recorded from the MRI and 24 measurements of the hoof capsule were made on the digital photographs. Small but significant changes in bone width (P = 0.039) were found in the controls and in two sagittal measurements of bone length (P = 0.039, 0.001, respectively) for the exercise group. These changes were slight and did not correlate with changes in shape of the hoof capsule, suggesting that the bone acts as a stable platform for supporting the capsule and withstanding loads.

Cyclooxygenase-2 and prostaglandin E2 (PGE2) levels are increased in colorectal cancers and a subset of adenomas. PGE2 signaling through the EP4 receptor has previously been associated with colorectal tumorigenesis. However, changes in EP4 expression during adenoma to carcinoma progression have not been investigated, neither has whether levels of EP4 influence important markers of malignant potential, such as anchorage-independent growth or the tumors growth response to PGE2. We report using immunohistochemistry that in vivo EP4 receptor protein expression was increased in colorectal cancers (100%) as well as adenomas (36%) when compared with normal colonic epithelium. EP4 expression was also higher in colorectal carcinoma compared with adenoma cell lines and increased with in vitro models of tumor progression. Adenoma (PC/AA/C1 and RG/C2) and carcinoma cell lines (HT29) were growth stimulated by PGE2 up to 0.5 μmol/L. However, although carcinoma and transformed adenoma (PC/AA/C1SB10C, a transformed derivative of PC/AA/C1) cells remain stimulated by higher doses of PGE2 (10 μmol/L), the adenoma cell lines were inhibited. Interestingly, enforced expression of EP4 in the adenoma cell line, RG/C2, resulted in stimulation of growth by 10 μmol/L PGE2 and promoted anchorage-independent growth. Both in vivo and in vitro data from this study suggest that increased EP4 receptor expression is important during colorectal carcinogenesis. We propose that high levels of PGE2 in a tumor microenvironment would select for cells with increased EP4 expression, and that the EP4 receptor may therefore represent an important target for colorectal cancer prevention and treatment. (Cancer Res 2006; 66(6): 3106-13)

Glucose transport across the chondrocyte membrane is essential for chondrogenesis and the development of the skeletal system. We have previously used RT-PCR to show that fully developed human articular chondrocytes express transcripts for the GLUT1 and GLUT9 glucose transporters. In this study we report on the expression and immunohistochemical localization of the GLUT1 and GLUT9 proteins in embryonic and mature ovine cartilage. We also provide Western blot evidence for GLUT1 and GLUT9 expression in mature ovine chondrocytes. Ovine embryos (developmental stages E32 to E36 and E42 to E45) were obtained from pregnant ewes humanely killed by injection with sodium pentobarbitone. Embryos were fixed and processed for immunohistochemistry. Polyclonal antibodies to GLUT1 and GLUT9 revealed that both transporters are expressed in developing chondrocytes in ovine embryos and in the superficial, middle and deep layers of ovine cartilage from mature animals. GLUT1 expression was observed in erythrocytes and organs including heart, liver, and kidney. GLUT9 was also found in heart, kidney and liver. Western blotting confirmed the presence of the GLUT1 protein which migrated between the 50 and 64 kDa markers and two specific GLUT9 bands migrating under the 50 and 60 kDa markers, respectively. The presence of GLUT1 and GLUT9 in developing joints of ovine embryos suggests that these proteins may be important in glucose delivery to developing chondroblasts. Expression of these GLUT isoforms may be an important bioenergetic adaptation for chondrocytes in the extracellular matrix of developing cartilage.

Cells in the medial preoptic area (mPOA), arcuate nucleus (ARC), and ventromedial nucleus (VMN) that possess estrogen receptor alpha (ER alpha) mediate estradiol feedback to regulate endocrine and behavioral events during the estrous cycle. A percentage of ER alpha cells located in the ARC and VMN express somatostatin (SST) and are activated in response to estradiol. The aims of the present study were to investigate the location of c-Fos, a marker for activation, in cells containing ER alpha or SST at various times during the follicular phase and to determine whether lipopolysaccharide (LPS) administration, which leads to disruption of the luteinizing hormone (LH) surge, is accompanied by altered ER alpha and/or SST activation patterns. Follicular phases were synchronized with progesterone vaginal pessaries, and control animals were killed at 0, 16, 31, and 40 h (n = 4–6/group) after progesterone withdrawal (PW [time 0]). At 28 h, other animals received LPS (100 ng/kg) and were subsequently killed at 31 h or 40 h (n = 5/group). Hypothalamic sections were immunostained for c-Fos and ER alpha or SST. LH surges occurred only in control ewes with onset at 36.7 ± 1.3 h after PW; these animals had a marked increase in the percentage of ER alpha cells that colocalized c-Fos (%ER alpha/c-Fos) in the ARC and mPOA from 31 h after PW and throughout the LH surge. In the VMN, %ER alpha/c-Fos was higher in animals that expressed sexual behavior than in those that did not. SST cell activation in the ARC and VMN was greater during the LH surge than in other stages in the follicular phase. At 31 or 40 h after PW (i.e., 3 or 12 h after treatment, respectively), LPS decreased %ER alpha/c-Fos in the ARC and the mPOA, but there was no change in the VMN compared to that in controls. The %SST/c-Fos increased in the VMN at 31 h after PW (i.e., 3 h after LPS) with no change in the ARC compared to controls. These results indicate that there is a distinct temporal pattern of ER alpha cell activation in the hypothalamus during the follicular phase, which begins in the ARC and mPOA at least 6–7 h before the LH surge onset and extends to the VMN after the onset of sexual behavior and LH surge. Furthermore, during the surge, some of these ER alpha-activated cells may be SST-secreting cells. This pattern is markedly altered by LPS administered during the late follicular phase, indicating that the disruptive effects of this stressor are mediated by suppressing ER alpha cell activation at the level of the mPOA and ARC and enhancing SST cell activation in the VMN, leading to the attenuation of the LH surge.

Recent studies indicate a high prevalence of fractures of the palmar processes (PP) of the distal phalanx in foals. However, information on the prevalence of such fractures in different breeds and the effect of predisposing factors, such as hoof conformation, is limited.To examine the prevalence of distal phalanx PP fractures in foals and report the relationship of distal limb and hoof conformation with the prevalence of fracture.Longitudinal study.Front hooves of 19 Thoroughbred, Quarter Horse and Arabian foals were examined. Digital radiographic and photographic images of the distal aspect of the forelimbs were taken at ∼2.5 month intervals. Five radiographic projections of each limb were as follows: lateromedial; horizontal beam dorsopalmar; dorso60°proximal-palmarodistal oblique; dorso60°proximo45°lateral-palmarodistomedial oblique; and dorso60°proximo45°medial-palmarodistolateral oblique. The relationship between measurements and the prevalence of fractures was assessed by 3-way ANOVA.Fractures were found in 74% (n = 14) of the foals during the study period. The prevalences of lateral PP and medial PP fractures were not significantly different. Several hoof measurements were associated with PP fractures. Longer dorsal length of the distal phalanx was associated with medial PP fractures, while smaller lateral angle and shorter lateral palmar length were associated with a higher prevalence of lateral PP fractures.This study revealed a high prevalence of PP fractures in young foals, particularly in Thoroughbred foals. The hoof conformation may be one of the contributory factors to PP fractures in foals.

Aims To assess local and systemic recurrence rates and factors predicting for recurrence in patients treated for ductal carcinoma of the breast (DCIS). Methods Patients with DCIS treated between January 1986 and January 1997 were identified. All pathology specimens were reviewed. DCIS type, lesion size, nuclear grade and margin clearance were assessed. Mammograms were reviewed and mammographic patterns, size, type of lesion and distance from the nipple were measured. Treatments and subsequent outcomes were established by case note review. Factors predicting for recurrence were analysed by both univariant and multivariant analysis. Results Of the 220 patients, 153 (70%) had breast-conserving surgery. Sixty-seven (30%) had a mastectomy. Ninety-seven patients had adjuvant therapy of which 22 had radiotherapy alone, 54 had tamoxifen alone and 21 had radiotherapy and tamoxifen. Following mastectomy, two patients developed axillary recurrences. Following breast-conserving surgery 20 (13%) patients developed local recurrences, of which one developed systemic disease and died from breast cancer. Conclusions Mammographic nipple to lesion distance of

To mimic the abnormal patterns of follicular growth in the early post-partum period, heifers were injected with 15 mg oestradiol and 37•5 mg progesterone every 12 h for 7 days starting on day 15 of the oestrous cycle. Control and treated animals (no. = 8 per group) were monitored by daily ultrasonography and plasma hormone measurements. Five treated animals had quiescent ovaries for 11 days during which period oestradiol concentrations exceeded 30 pg/ml. After this, the first post-treatment follicular wave produced a normal ovulatory follicle. The other three heifers had quiescent ovaries for 17 days during exposure to high oestradiol values but this was followed by the formation of persistent follicles. The prolonged exposure to oestradiol probably disrupted normal LH surges in the latter animals. Growth rates and internal diameters for normal, ovulatory and prolonged persistent follicles were similar for the first 6 days after emergence, but the persistent follicles grew larger (P < 0·05) than normal follicles over the next 20 days. Luteinization of a subsequent persistent follicle was observed in one heifer. For 2 to 3 days prior to follicular growth, FSH concentrations were similar in controls, and heifers with ovulatory or persistent follicles (P > 0·05). When follicles first emerged and for the next 4 days, oestradiol concentrations were greater in follicles which later persisted (P < 0·05). For the second half of the life-span of persistent follicles, oestradiol concentrations were basal, thus the structure remained for many days after endocrine function had declined. These observations allow new interpretation of previously confusing findings in subfertile cattle presented to veterinarians.

Stress is revealed by the inability of an animal to cope with its environment, a phenomenon that is often reflected in a failure to achieve genetic potential. Field data from dairy cows show that stressors such as milk fever or lameness increase the calving to conception interval by 13–14 days, and an extra 0.5 inseminations are required per conception. We suggest that a variety of endocrine regulatory points exist whereby stress limits the efficiency of reproduction. Transport produces an immediate constant increase in arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) secretion in ewes, but adrenocorticotrophic hormone (ACTH) reaches a maximum in the first hour while cortisol is highest during the second hour. In contrast, after an insulin injection, the hypothalamo–pituitary–adrenal (HPA) response is delayed occurring only after glucose decreases below a threshold. Changes in AVP, CRH and ACTH each follow a similar time course, but eventually the secretion of AVP and CRH decreases while glucose is still at a nadir. Negative feedback effects appear to operate mainly at the pituitary level during transport but at the hypothalamus during hypoglycaemia. We also have endocrine evidence to show that stressors interfere with precise timings of reproductive hormone release within the follicular phase. Transport, or insulin, reduce the frequency and amplitude of gonadotrophin-releasing hormone and LH pulses, suggesting that these stressors exert effects at the hypothalamus or higher centres in the brain. Both stressors also delay the onset of the luteinising hormone (LH) surge. Preliminary results suggest that opioids mediate these effects but progesterone/glucocorticoid receptors are not involved because the antagonist, RU486, is unable to reverse insulin-induced delays in the LH surge. There is also evidence to support effects at pituitary level because exogenous ACTH, or transport, reduce the amount of LH released by challenges with GnRH. The reduction in endogenous GnRH/LH secretion ultimately deprives the ovarian follicle of adequate gonadotrophin support leading to reduced oestradiol production by slower growing follicles. Thus, there is a level of interference by stressors at the ovary. Reproduction is such an important physiological system that animals have to ensure that they can respond to their surroundings; thus, it is advantageous to have several protein mechanisms, i.e. at higher brain, hypothalamus, pituitary and target gland levels. However, when pushed too far, subfertility occurs.

This study tested the hypothesis that increased oestradiol secretion by large follicles in the ovary ipsilateral to the previously gravid uterine horn has a local effect to increase the rate of uterine involution. Cows were administered an i.m. water placebo (n = 19), 250 iu equine chorionic gonadotrophin (eCG) (n = 18) or 750 iu eCG (n = 20) 14 days post partum (day 0). Transrectal ultrasonography at the time of treatment and 2, 4 and 6 days later monitored uterine horn diameter and ovarian structures. Blood samples collected contemporaneously were assayed for 15-keto-13, 14-dihydro-prostaglandin F(2alpha) and oestradiol concentration. For control cows, accumulated diameter of the largest follicle in the ovary ipsilateral to the previously gravid uterine horn, compared with the contralateral ovary, was smaller on day 0 (P < 0.05) and days 2, 4 and 6 (P < 0.001). There were no significant differences in the eCG-treated animals. There were 12, 8 and 11 cows with a plasma oestradiol concentration < 1 pg ml(-1) on day 0 in the control, 250 and 750 iu eCG treatment groups, respectively. For control cows, the peripheral oestradiol concentrations were higher on day 6 compared with days 0, 2 and 4 (P < 0.05); for cows treated with 250 iu eCG, concentrations were higher on days 4 and 6 compared with day 0 (P < 0.05); and for cows treated with 750 iu eCG, concentrations were higher on days 2 and 4 compared with day 0 (P < 0.01). Treatment with eCG, or the presence of a follicle > 8 mm in diameter in the ovary ipsilateral to the previously gravid uterine horn, did not affect the rate of uterine involution or plasma 15-keto-13,14-dihydro-prostaglandin F(2alpha) concentration. In conclusion, administration of eCG to increase follicular growth and oestradiol production overcame the inhibition of follicular growth in the ovary ipsilateral to the previously gravid uterine horn, but did not affect uterine involution.

Information on the losses associated with lower milk production and reproductive performance, as well as information from a survey of uk dairy herds using beef semen was used to estimate the economic importance of calving difficulties in uk dairy herds. The survey covered information on cow and calf mortality, cow culling and the need for veterinary assistance, the incidences of which were related to the degree of calving difficulty experienced. The total cost of a slightly difficult calving was estimated to be approximately 110 pounds, and of a seriously difficult calving between 350 pounds and 400 pounds, depending on assumptions of the veterinary costs. However, the major costs were associated with the labour required at the delivery, the increase in the number of days open, and the costs associated with the deaths of cows and calves, and cow culling.

SummaryA retrospective case series study was done to determine the long-term outcome of operations upon dogs treated for canine hip dysplasia by means of a triple pelvic osteotomy (TPO). Twentyfour dogs with bilateral hip dysplasia, that received a unilateral TPO between January 1988 and June 1995, were re-examined at the Ontario Veterinary College. The assessment included physical, orthopedic and lameness examinations, standard blood work, pelvic radiographs and force plate gait analysis. They were compared to bilaterally dysplastic dogs that had not been treated, and also to normal dogs. Force plate data analysis demonstrated a significant increase in peak vertical force (PVF) and mean vertical force over stance (MVF) in the limb that underwent surgical correction by means of a TPO, when compared to the unoperated hip. It was determined that performing a unilateral TPO on a young dysplastic dog resulted in greater forces and weight bearing being projected through the TPO corrected limb when compared to the unoperated limb.Dogs with bilateral hip dysplasia treated with a unilateral triple pelvic osteotomy (TPO) were assessed by force plate gait analysis, radiographs and orthopedic examination. There was a significant increase in hip Norberg angles over time, although degenerative changes did progress. Limbs that had been operated upon had significantly greater peak and mean ground reaction forces than limbs that had not received an operation.

Experiments are reported on pool fires of transformer oil (flash point 157°C) burning over a rock bed in a 1.2 m diameter pan, with and without drainage from the bottom of the pan. Levels in the pool are referenced to the mean rock surface level (MRSL), defined as the horizontal plane (level of oil) where 50% of the area of the plane is broken by the surface rocks of the rock bed. Without drainage, using a rock type having a mass median diameter of 23 mm and with an initial oil level 51 mm above the MRSL, there was little change in heat release rate until the oil level regressed 25 mm below the MRSL; subsequently, the heat release rate fell sharply and continued at a low rate for >3 h, when the flames were extinguished manually. With drainage at regression rates of 16–26 mm/min, used in most of the experiments, there was no appreciable decrease in heat release rate until the oil regressed below the MRSL in this case, and the fires self-extinguished when the oil level dropped 23–29 mm below the MRSL, depending on rock type (two types investigated). Heat release rates during active combustion (∼ 570 kW/m2 convective) were little affected by oil drainage, the initial oil level, the preburn interval or the rock type in the ranges investigated.

Contents Normal reproductive function is dependent upon availability of glucose and insulin-induced hypoglycaemia is a metabolic stressor known to disrupt the ovine oestrous cycle. We have recently shown that IIH has the ability to delay the LH surge of intact ewes. In the present study, we examined brain tissue to determine: (i) which hypothalamic regions are activated with respect to IIH and (ii) the effect of IIH on kisspeptin cell activation and CRFR type 2 immunoreactivity, all of which may be involved in disruptive mechanisms. Follicular phases were synchronized with progesterone vaginal pessaries and at 28 h after progesterone withdrawal (PW), animals received saline (n = 6) or insulin (4 IU/kg; n = 5) and were subsequently killed at 31 h after PW (i.e., 3 h after insulin administration). Peripheral hormone concentrations were evaluated, and hypothalamic sections were immunostained for either kisspeptin and c-Fos (a marker of neuronal activation) or CRFR type 2. Within 3 h of treatment, cortisol concentrations had increased whereas plasma oestradiol concentrations decreased in peripheral plasma (p

SummaryThe purpose of this study was to evaluate the use of three dimensional imaging techniques in veterinary orthopaedic surgery to measure hip congruity and predict changes in congruity resulting from triple pelvic osteotomies of canine hips. Preoperative, postoperative, and post-simulation measurements of congruity were obtained from eight canine hips by determination of Norberg angles from ventrodorsal pelvic radiographs (1), and lateral centre-edge (CE) angles from three dimensional (3 D) reconstructions of computed tomography (CT) scan data (2). Half of the hips were treated with a triple pelvic osteotomy with 30 degrees of axial rotation, and the other half served as approached but unoperated controls. Each measurement was performed three times by a single evaluator blinded to the identity of each hip. Lateral centre-edge angle measurements were more precise than Norberg angle measurements as determined by the calculated measurement of reliability (R = 0.78 and 0.68 respectively). Triple pelvic osteotomy resulted in an increase in congruity (as measured by lateral CE angles) of 52.2 ± 4.6 degrees compared to -3.0 ± 6.3 degrees in the control hips. The medical imaging programme used to perform the 3D reconstructions from CT scan data also allowed manipulation of the resulting preoperative 3D images to simulate on the computer screen the triple pelvic osteotomies performed on the gross specimens. Surgical procedure simulation predicted the change in congruity (as measured by lateral CE angles) of operated hips to be 43.5 ± 8.8 degrees. The images obtained by 3D reconstruction were very sensitive indicators of gross hip morphology. Visualization of structures, superimposed or surrounded by bone, was easily performed on the computer by interactive manipulation of the three dimensional CT scan reconstructions. In addition to its unique imaging capabilities, this technique appears to be a useful method for non-invasive measurement and prediction of the effects of triple pelvic osteotomy on hip congruity in dogs.Three dimensional (3D) computer aided image reconstructions were performed on tomographic scan data collected from dysplastic canine pelves before and after triple pelvic osteotomy (TPO). Descriptions of imaging capabilities and the application of lateral centre-edge angles for the determination of hip congruity are reported. Simulations performed on the computer accurately predicted the changes in congruity achieved by surgery.

Relationships among spatial abilities, as assessed by a battery of psychometric tests and experimental tasks, and environmental learning, as assessed by a series of macrospatial tasks, were examined in two studies using confirmatory factor analysis with directional paths. The initial study indicated the utility of a five-factor model, one (general spatial ability) derived from psychometric tests, two (spatial-sequential memory and spatial perspective-taking latency) from experimental tasks, and two (topological knowledge and Euclidean direction knowledge) from measures of environmental learning. The best fitting path model further indicated that the spatial-sequential memory factor mediated the relationship between general spatial ability and topological knowledge, and that perspective-taking latency mediated the relationship between general spatial ability and Euclidean direction knowledge. The second study confirmed the five-factor path model using a different participant sample and environmental setting. The only failure to replicate involved the path between perspective-taking latency in the lab and Euclidean direction knowledge in the environment. Results indicate that the relationship between basic spatial abilities and environmental learning is significantly mediated by cognitive processes that can be assessed using laboratory tasks.

The present investigation aims to establish the reason(s) why dairy cows with high somatic cell counts (SCCs; >100,000 cells/ml) are less fertile than cows with low SCCs alone. The objective of Study One was to determine whether differences in steroid hormone profiles could explain the low incidence of ovulation in cows with combined High SCC and lameness. Between 30 and 80 days post-partum, animals were scored for SCC and lameness and three groups were formed: Healthy (n=22), High SCC alone (n=12) or High SCC + Lame (n=9). The ovarian follicular phases of all cows were synchronised by administering gonadotrophin releasing hormone (GnRH) followed seven days later by prostaglandin F2alpha (PG). Milk samples were collected daily throughout the entire study period; twice daily during the follicular phase, blood samples were taken and the ovaries were monitored using ultrasonography. Progesterone concentrations were similar in all three groups during each of five specific time periods, i.e. throughout the five days before PG injection, the peri-ovulatory period, on Day 5 and on Day 7, and during the mid luteal phase 12-17 days after ovulation (P>0.13). Mean plasma oestradiol concentrations monitored every 12h during the 36h period before ovulation were similar in all groups (Healthy, 2.80±0.30pg/ml; High SCC alone, 3.82±0.48pg/ml; High SCC+Lame 2.94±0.51pg/ml; P=0.175). The objective of Study Two was to establish whether cows with High SCC (scored and synchronised as above) display different behaviours, especially the intensity and timing of oestrus. Intervals from PG to the onset of oestrus or to the first stand-to-be-mounted (STBM) were longer for the High SCC cows than the Low SCC animals (n=8 and 20; P=0.011 and 0.002, respectively). Also, cows with High SCC tended to have a less intense oestrus and a lower maximum oestrus score per 30-min period than Low SCC cows (P=0.063 and 0.066, respectively). In conclusion, High SCC±lameness did not affect progesterone or twice daily oestradiol profiles but the onset of oestrus was delayed and oestrus tended to be less intense in cows with High SCC. These factors could explain low fertility associated with High SCC.

The pre-operative mammograms for 231 patients undergoing conservation surgery for breast cancer between March 1988 and September 1992 were analysed for features that may predict the presence of pathological risk factors of local recurrence (residual microscopic disease, extensive intraduct carcinoma (EIC) and lymphatic/vascular invasion). Residual microscopic disease was detected in 40% of patients and was associated with a DY mammographic pattern (p = 0.03), casting calcification (p = 0.0002) and absence of mammographic nidus (p = 0.0006). Residual microscopic disease was found in 75-88.9% of patients when two of these preoperative mammographic features were present in combination. The mean lumpectomy diameter was significantly smaller for patients with DY compared to N1 mammographic pattern on Wolfe grade (p = 0.039). Both residual disease and Wolfe grade were related to age (p = 0.0032 and p0.0001). EIC was found in 22% of patients and was associated with casting (p0.0001) and non-casting (p = 0.04) calcification, absence of mammographic nidus (p0.0001) and stellate mammographic nidus (p = 0.02). No significant association was found between mammographic features and lymphatic/vascular invasion. Pre-operative mammographic features can predict patients likely to have residual microscopic disease or EIC following conservation surgery for breast cancer. These patients should be selected for wider primary excision.

This survey analysed the history of cows which were pregnant when they were slaughtered at an abattoir in south west England by sending a questionnaire to their farm of origin to determine the reason(s) for culling them and their recent reproductive history. Of the slaughtered cows, 23.5 per cent were pregnant and 26.9 per cent of these were in the third trimester. The three main reasons for culling were infertility (28.2 per cent), mastitis (21.8 per cent) and old age (15.8 per cent). In 50.9 per cent of cases the farmer thought that the cow was not pregnant. In 66 per cent of the returns the cow had run with a bull. The average age of the slaughtered cows was 7.9 years. The records were categorised as 'OK' when they were consistent with the stage of pregnancy found post mortem, as 'error' when there were slight inconsistencies and 'gross error' when there were more serious discrepancies. Thirty-six per cent of the returns were classed as 'OK', 56.6 per cent as 'error' and 27.2 per cent as 'gross error'. It is estimated that these errors represent an annual loss of 30.78 million pounds to the cattle industry of the United Kingdom.

The aim of this study was to test the feasibility of intravaginal culture for in vitro fertilisation and production of bovine embryos. Oocytes were collected from five cows, superovulated with ovine follicle stimulatory hormone (oFSH), by using a 7.5 MHz rectal linear array ultrasound transducer. From 124 follicles punctured, the oocyte recovery rate was 48 per cent. Fifty-one oocytes were placed in capsules either in the vagina or in an incubator, and cocultured with sperm for 24 hours followed by coculture with oviductal cells for 48 hours. There was no significant difference between the fertilisation rates or the cleavage rates achieved by the two systems and the mean fertilisation rate was 44 per cent. However, the fertilised oocytes did not develop beyond the eight-cell stage.