Multiple model triangulation to identify factors associated with lameness in British sheep flocks.

Identification of factors associated with an outcome can be challenging when the number of explanatory variables is large in relation to the number of observations. Multiple model triangulation, where results from several model types are combined, improves the likelihood of identifying true predictor variables. The aim of this study was to use triangulation to identify covariates likely to be truly associated with the prevalence of lameness in sheep flocks in Great Britain. Data were collected using a questionnaire sent to 3200 sheep farmers in Great Britain in 2018. The useable response rate was 14.1 %. The geometric mean prevalence of lameness was 1.4 % (95 % CI 1.2-1.7) for ewes, and 0.6 % (95 % CI 0.5-0.9) for lambs, however, approximately 60 % flocks had >2% prevalence of lameness in ewes. Four model types were investigated, two generalised linear models (negative binomial and quasi-Poisson) built using stepwise selection, and two elastic net models (Poisson and Gaussian distributions) refined with selection stability estimation. Triangulated covariates were those selected in three or all four models - 10 for ewes and 12 for lambs. Higher prevalence of lameness in ewes was associated with 5-100% feet bleeding during routine foot trimming compared with not foot trimming, footbathing the flock to treat severe footrot (SFR) and always using formalin in footbaths, both compared with not footbathing, using FootVax™ for <1 year compared with not using FootVax™, and never quarantining new or returning sheep to the farm for >3 weeks compared with always. Lower prevalence of lameness in ewes was associated with vaccinating with FootVax™ for >5 years compared with not vaccinating, peat soil compared with no peat soil, and having no lame ewes to treat. Higher prevalence of lameness in lambs was associated with 5-100% feet bleeding during routine foot trimming, always foot trimming ewes with SFR, not knowingly selecting replacement ewes from ewes that were never lame compared with always, replacement sheep purchased and homebred compared with only homebred, treating lambs >3 days after recognition of lameness compared with 0-3 days and footbathing the flock to treat interdigital dermatitis compared with not footbathing at all. Lower prevalence of lameness in lambs was associated with peat soil, flocks in Scotland versus England, an altitude of >230-500 m compared with ≤230 m, never using antibiotic injection to treat lambs with SFR compared with always, and having no lame lambs to treat. We conclude triangulation identified reliable management practices for farmers to implement to minimise lameness in sheep.

Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody.

BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.

Detection of Lewis antigen structural change by FTIR spectroscopy.

Mucins are a family of extensively glycosylated, high molecular weight glycoproteins. Secretion of mucins with altered terminal carbohydrate moieties alters the rheological and viscoelastic properties of mucus and observed glycosylation changes in respiratory diseases may vary with disease status. Structural modifications to the Lewis x antigen with sialic acid (sialyl-Lewis x) and sulphate (sulfo-Lewis x) in particular are associated with respiratory diseases and deemed potential biomarkers for disease diagnosis, severity and progression. The major aim of this study was to evaluate the ability of Fourier transform infrared spectroscopy (FTIR) to detect, via infrared (IR) spectra, the structural changes between the Lewis x antigen and sialylated and sulphated derivatives. Although FTIR only provides information on vibrations of chemical groups, we show that by comparing mono- and oligosaccharide specific IR spectra it is possible to determine the contribution of key sugar moieties to the altered Lewis x spectral pattern.

Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding.

BACKGROUND: Obesity surgery is associated with improvement in type 2 diabetes mellitus. Our aim was to examine the effects of biliopancreatic diversion (BPD) and laparoscopic adjustable gastric banding (LAGB) on the body mass index, fasting insulin level, glucose level, and insulin resistance in morbidly obese subjects with type 2 diabetes mellitus. The setting was the Department of Surgery, Morriston Hospital (Swansea, Wales, United Kingdom). METHODS: A total of 13 morbidly obese patients (7 BPD, 6 LAGB) underwent serial measurements of fasting glucose and insulin at baseline, immediately after surgery (days 1-7), and 1, 6, and 12 months postoperatively. The homeostasis model of assessment-insulin resistance was calculated. RESULTS: In the BPD group, the glucose levels had normalized by day 3 (5.6 ± 1 mmol/L) and the difference was statistically significant at 6 and 12 months postoperatively (5 ± .7 and 4.4 ± .5 mmol/L, respectively). The insulin levels had improved from day 1, and the difference was statistically significant at days 2, 5, 6, and 7 (19 ± 9, 14.2 ± 7, 15.2 ± 8, and 17.4 ± 8 mU/L, respectively). All diabetes medications were stopped on the fourth postoperative day. In the LAGB group, no statistically significant changes were seen in the glucose levels. Statistically significant changes in insulin were seen on days 1 and 2 (19 ± 13 and 13 ± 6.5 mU/L, respectively). The homeostatic model of assessment-insulin resistance had improved in both groups (BPD, 1.6 ± 1.2, P < .01; and LAGB, 4.3 ± 1.4, P < .05). CONCLUSION: BPD causes immediate remission of type 2 diabetes mellitus. Leptin might play an important role in the early improvement of insulin resistance in fasting states after BPD. In the LAGB group, glucose homeostasis improved, but the patients still required diabetes medications, although the dosages were reduced.

Smoking habits and attitudes toward tobacco bans among United Kingdom hospital staff and students.

SETTING: A group of United Kingdom (UK) hospitals. OBJECTIVE: To estimate the current smoking habits of health care professionals (HCPs) in a country with active tobacco control measures, and to record their attitudes to national and hospital tobacco bans. DESIGN: A cross-sectional survey of 500 HCPs. RESULTS: HCPs reported a lower rate of current smoking (7%) than the general population (24%). Doctors (2.6%) and medical students (3.8%) were less likely to be current smokers than both nurses (8.7%) and allied health professionals (10.9%, P < 0.001). The vast majority felt national legislation had been effective (88%) and well complied with (82%). Around a third of respondents believed the ban had led to a reduction in admissions for acute coronary syndrome. Almost all respondents were in favour of restrictions on smoking in health care premises. A higher proportion of UK doctors (69%) than nurses (52%) favoured a complete ban (odds ratio 2.01, 95% confidence interval 1.14-3.56). CONCLUSION: Self-reported smoking patterns in UK health professionals are lower than previously and compared to other industrialised and developing countries. Support for bans is very high, but differences remain in behaviour and especially attitudes to local bans according to professional status, although this gap is also narrowing.

Influence of long-term oxygen therapy on cardiac acceleration and deceleration capacity in hypoxic patients with chronic obstructive pulmonary disease.

BACKGROUND: There is increasing interest in cardiovascular co-morbidities of chronic obstructive pulmonary disease (COPD). Heart rate turbulence (HRT) and phase-rectified signal averaging (PRSA) techniques quantify the heart's acceleration/deceleration capacities. We postulated that these methods can help assess the integrity of cardiac control in hypoxic COPD. METHODS: Eight hypoxic stable COPD patients, nine healthy age-matched older adults and eight healthy young adults underwent ECG monitoring for 24 h. Patients with COPD were also monitored following 4 weeks of standardized oxygen therapy. HRT measures [turbulence onset (TO), turbulence slope (TS)] and PRSA-derived acceleration/deceleration (AC, DC) indices were quantified within 6-h blocks to assess circadian variation. RESULTS: There were between-group differences for variables TS, DC and AC (P<0·0005, η(2) = 0·54-0·65), attributable solely to differences between healthy young and COPD subjects. Only HR (P<0·0005) and DC index (P = 0·008) showed circadian variation. A significant interaction 'trend' effect for HR (F(9,87) = 2·52, P = 0·015, η(2) = 0·21) reflected the strong influence of COPD on HR circadian variation (afternoon and night values being different to those in healthy subjects). CONCLUSIONS: As expected, heart rate dynamics were substantially diminished in older (healthy and COPD) groups compared with healthy young controls. Patients with COPD showed similar heart rate dynamics compared with age-matched controls, both before and after hypoxia correction. However, there was a suggestion of diminished DC in COPD compared with age-matched controls (P = 0·059) that was absent following oxygen therapy. TS, DC and AC indices were altered by similar degrees in older subjects, apparently indicating equivalent tonic dysfunction of sympathetic/parasympathetic systems with ageing.

Influence of smoking abstinence and nicotine replacement therapy on heart rate and QT time-series.

SUMMARY: Many smokers attempt to quit without using nicotine replacement therapy (NRT) or pharmacotherapy, i.e. 'cold-turkey'. The cardiac implications of this are important but are incompletely understood. Previous studies have associated smoking cessation with improvements in heart rate (HR) and its variability, but its influence on QT time-series is unclear. Furthermore, the relative influence on these parameters of acute nicotine withdrawal and of NRT has not been adequately compared. Additional insight might come from analysing the dynamic (e.g. fractal) properties of electrocardiographic data during different levels of nicotine exposure. We examined the influence of smoking cessation, during cold-turkey and subsequent NRT, on HR and QT time-series during 30 days of smoking abstinence. Seven smokers and sixteen healthy non-smokers received ECG monitoring at baseline (Day 0). Smokers subsequently refrained from smoking without using NRT for 24 h, and then received NRT for 29 days. ECG monitoring was repeated at Days 1, 7, 30. Following smoking cessation we observed that: HR and rate-corrected QT were both reduced, heart rate variability (HRV) increased (improved), and QT variability index (QTVI) showed signs of improvement (trend only). Improvements in HR and QT were maintained throughout NRT use, whilst improvements in HRV and QTVI were sustained for at least the early stages of NRT. The dynamic (multifractal) properties of HR and QT were similar for smokers and non-smokers, and were unchanged by smoking abstinence or NRT. Our results provide tentative evidence that electrocardiographic improvements during a cold-turkey smoking quit attempt (acute nicotine withdrawal) are maintained during NRT pharmacotherapy.

Influence of bariatric surgery on indices of cardiac autonomic control.

BACKGROUND: Obesity is associated with reduced heart rate variability (HRV), reflecting detrimental changes in cardiac regulation by the autonomic nervous system (ANS). Weight loss reverses this change and ANS dysfunction is thought to have a role in obesity-related cardiac pathology. Few studies have examined the influence of weight-reduction (bariatric) surgery on cardiac autonomic control. This study therefore sought to assess longitudinal changes in indices of cardiac autonomic control following two types of bariatric procedure, laparascopic gastric banding (LGB) and biliopancreatic diversion (BPD). METHODS: Eleven morbidly obese subjects aged 47.8 +/- 7.9 years (mean+/-SD) with BMI 48.2 +/- 6.9 kg x m(-2) underwent weight-reduction surgery: five received BPD and six received LGB. Holter ECG was recorded and HRV was quantified together with a QT variability index (QTVI), a complexity index (SampEn), and a fractal (scaling) index (DFAalpha). Repeated measures ANOVA compared the indices for the two groups as a function of time (1, 6 and 12 months follow-up). RESULTS: BMI was reduced by up to 24% (p=0.008) post-surgery despite patients remaining obese at one-year follow-up. Several indices showed prompt and persistent improvement with progressive weight loss, QTVI being the most sensitive discriminator of recovery time (F(3,216)=16.86; p<0.0005; eta(2)=0.190). Autonomic responsiveness was functionally normal throughout. The bariatric procedures induced similar changes in cardiac autonomic control, despite their differing mechanisms of action. CONCLUSIONS: This pilot study suggests that the mechanism responsible for improving cardiac regulation following bariatric surgery might be the weight loss itself. Furthermore, post-surgery improvement in QTVI implies that weight loss reduces the risk of ventricular arrhythmic events.

A review of novel biological tools used in screening for the early detection of lung cancer.

Lung cancer is the most common cancer worldwide and causes more deaths per year than any other cancer. It has a very poor 5-year survival rate of 8-16%, partly because of comorbidity preventing curative treatments but mainly because of the disease presenting with symptoms only when it is at an advanced and incurable stage. When lung cancer is detected earlier and is amenable to radical treatments such as potentially curative surgery and radical radiotherapy, 5-year survival rates are much higher (up to 67%). Therefore reliable detection of lung cancer at this earlier (usually asymptomatic) stage of disease should be an important way to improve outcomes. This review discusses the principles of screening with respect to lung cancer, concentrating mainly on the biological modalities used to detect it. The lack of impact achieved by early studies using sputum cytology (in conjunction with chest radiographs) is described, and then newer technology used to measure other biomarkers in sputum, serum, exhaled breath and bronchial mucosa to diagnose (early) lung cancer is detailed. Many techniques show promise, but debate continues about which population to screen and what is the most (cost) effective modality to use. Moreover, no single biomarker or combination of biomarkers in screening has yet been shown to reduce lung cancer mortality in large prospective randomised studies.

Sleep-disordered breathing and cardiovascular disease.

Sleep-disordered breathing (SDB) describes a group of disorders characterised by abnormalities in the frequency and/or depth of breathing while asleep. The most common type is the obstructive sleep apnoea/hypopnoea syndrome (OSAHS); it affects 2-4% of the adult population and is an independent risk factor for hypertension. Another type is central sleep apnoea (CSA), which includes Cheyne-Stokes respiration; it is most commonly seen in patients with congestive heart failure and other critical illnesses including cerebrovascular accidents. There is accumulating evidence that both these types of SDB are associated with cardiac failure, arrhythmias and coronary artery disease. Treatment of OSAHS with continuous positive airway pressure (CPAP) has lowered blood pressure, reduced the frequency and severity of some arrhythmias, and improved markers of endovascular inflammation. CPAP has had a mild positive effect on left ventricular function in chronic heart failure by treating co-existent SDB, but it has not improved mortality, possibly because it does not fully treat associated CSA. Clinicians need to be aware of the increasing associations of SDB, especially OSAHS, with cardiovascular dysfunction, as treatment of co-existent SDB will not only improve sleepiness, quality of life, and driving risk, but there is growing evidence that it may also improve cardiovascular risk itself, even in non-sleepy subjects.

Transtracheal lignocaine: effective treatment for postextubation stridor.

Three cases of post-extubation stridor due to suspected laryngospasm are described in which a small dose of lignocaine injected intra-tracheally, through the cricothyroid membrane, produced rapid and effective relief of stridor with no early recurrence or side-effects. The procedure was performed safely and quickly and was well tolerated by patients. Trans-tracheal injection of local anaesthetic should be considered for treatment of post-extubation stridor in adults, so long as there is no risk of pulmonary aspiration, and pathological causes of laryngospasm have been excluded.

Autonomic nervous system control of the cardiovascular and respiratory systems in asthma.

Patients with asthma have exaggerated bronchoconstriction of their airways in response to certain indirect (e.g. cold air, allergens, dust, exercise) or direct (e.g. inhaled methacholine) stimuli. This 'hyper-reactivity' usually co-exists with airway inflammation, although the pathophysiological mechanisms underlying these changes are not fully understood. It is likely that this hyper-reactivity is associated with abnormal autonomic nervous system (ANS) control. In particular, the parasympathetic (vagal) component of the ANS appears to be implicated in the pathogenesis of asthma. In addition, several studies have suggested the existence of differential alteration in ANS function following exercise in asthmatics compared with non-asthmatic individuals. Several early studies suggested that the altered autonomic control of airway calibre in asthma might be reflected by a parallel change in heart rate. Cardiac vagal reactivity does indeed appear to be increased in asthma, as demonstrated by the cardiac response to various autonomic functions tests. However, other studies have reported a lack of association between bronchial and cardiac vagal tone, and this is in accord with the concept of system-independent ANS control. This review provides a discussion of cardiovascular-autonomic changes associated with either the pathophysiology of asthma per se or with asthma pharmacotherapy treatment. Previous investigations are summarised suggesting an apparent association between altered autonomic-cardiovascular control and bronchial asthma. The full extent of autonomic dysfunction, and its clinical implications, has yet to be fully determined and should be the subject of future investigation.

Delay in starting treatment for tuberculosis in east London.

In the United Kingdom there is little information about the delay between the onset of symptoms in patients with tuberculosis and the time it takes for them to be correctly diagnosed and treatment started. We have examined the duration and possible causes of such delay in our own district. The records of 93 patients were examined. Total delay in starting treatment was estimated as the time from the start of symptoms to commencement of chemotherapy. Patient delays were estimated from the time between the start of symptoms to the time taken to first attend their general practitioner (GP) with symptoms. Healthcare system delays were estimated from the interval between first being assessed by their GP and starting anti-tuberculosis treatment. Median total delay was 18 weeks (0-219). The time when patients first presented to their GP was determined for 64 patients: median patient delay was then estimated as nine weeks (range 0-104 weeks), and median healthcare delay five weeks, with a very wide range (0.5-210). Prolonged delay was seen in three patients with cervical lymph node disease. Patient delay was significantly longer than healthcare system delay (p = 0.019). Pulmonary disease was associated with shorter total delay in starting treatment compared with extra-pulmonary disease (p = 0.035). In patients with tuberculosis there were considerable delays in first presentation to medical services, in diagnosis and in starting treatment. Patient delays were longer than healthcare system delays. There is a need to improve awareness of the symptoms of tuberculosis both on the part of the general population and of health professionals, especially in areas of high incidence.

Urogenital infection by Mycobacterium bovis relapsing after 50 years.

A 64-year-old man was referred to chest clinic after presenting initially with painless haematuria. Bladder biopsies showed granulomatous inflammation and subsequent urine cultures grew Mycobacterium bovis. He had been treated empirically for genito-urinary tuberculosis twice previously and on both occasions his haematuria ceased. Although the early hospital notes have been destroyed we believe this represents a very late and recurrent relapse of cystitis due to M. bovis.

Multi-system Infection with Nocardia farcinica-therapy with linezolid and minocycline.

We describe a case of disseminated infection with a multiple-resistant strain of Nocardia farcinica, probably resulting from direct inoculation during a road traffic accident. Initial presentation was with pulmonary symptoms, with subsequent development of cutaneous, renal, soft tissue and cerebral involvement. Precise microbiological diagnosis was delayed. Once sensitivity test results were available, the patient was stabilised on linezolid and minocycline. Premature withdrawal of therapy at one month resulted in recrudescence of infection, requiring re-institution of treatment. Linezolid was discontinued after a total of 4 months, because of evidence of myelosuppression and visual impairment, which subsequently improved. Monotherapy with minocycline was continued for a total of 12 months. The patient now remains well.

Sleep deprivation and junior doctors' performance and confidence.

PURPOSE OF STUDY: To determine whether sleep deprivation affects not only junior doctors' performance in answering medical questions but whether their ability to judge their own performance is also affected by lack of sleep. METHODS: A questionnaire based follow up study in two district general hospitals of the Carmarthenshire NHS Trust. Eleven house officers and 15 senior house officers (SHOs) within the medical directorate participating in the on-call rota were recruited between July 1999 and May 2000. RESULTS: SHOs answered significantly more questions correctly (p=0.04) and were more confident than house officers when they were either correct or incorrect (p<0.001). Length of unbroken or continuous sleep is associated with more correct answers (p=0.03) and higher energy (p=0.09) and confidence (p=0.07) scores self rated by the profile of mood states. Length of continuous sleep was not related to the appropriateness of confidence, as measured by the "within-subject confidence-accuracy correlation" (p=0.919). CONCLUSIONS: SHOs performed better than house officers even allowing for sleep loss. Sleep deprivation had adverse effects on mood and performance but junior doctors can still monitor their performance and retain insight into their own ability when sleep deprived.

Recurrence of Wegener's granulomatosis 13 years after renal transplantation.

Wegener's granulomatosis (WG) can cause renal failure, requiring long-term renal replacement therapy. Renal transplantation in patients with WG is successful, but the risk for recurrence of the disease necessitates continued vigilance. We report a patient that originally presented with acute renal failure secondary to a pauci-immune focal necrotizing crescentic glomerulonephritis. Subsequent nasal involvement and serologic tests for antineutrophil cytoplasmic antibodies suggested a diagnosis of WG.

Hedgehog signaling is required for primary motoneuron induction in zebrafish.

Sonic hedgehog (Shh) is crucial for motoneuron development in chick and mouse. However, zebrafish embryos homozygous for a deletion of the shh locus have normal numbers of motoneurons, raising the possibility that zebrafish motoneurons may be specified differently. Unlike other vertebrates, zebrafish express three hh genes in the embryonic midline: shh, echidna hedgehog (ehh) and tiggywinkle hedgehog (twhh). Therefore, it is possible that Twhh and Ehh are sufficient for motoneuron formation in the absence of Shh. To test this hypothesis we have eliminated, or severely reduced, all three Hh signals using mutations that directly or indirectly reduce Hh signaling and antisense morpholinos. Our analysis shows that Hh signals are required for zebrafish motoneuron induction. However, each of the three zebrafish Hhs is individually dispensable for motoneuron development because the other two can compensate for its loss. Our results also suggest that Twhh and Shh are more important for motoneuron development than Ehh.

Zebrafish smoothened functions in ventral neural tube specification and axon tract formation.

Sonic hedgehog (Shh) signaling patterns many vertebrate tissues. shh mutations dramatically affect mouse ventral forebrain and floor plate but produce minor defects in zebrafish. Zebrafish have two mammalian Shh orthologs, sonic hedgehog and tiggy-winkle hedgehog, and another gene, echidna hedgehog, that could have overlapping functions. To examine the role of Hedgehog signaling in zebrafish, we have characterized slow muscle omitted (smu) mutants. We show that smu encodes a zebrafish ortholog of Smoothened that transduces Hedgehog signals. Zebrafish smoothened is expressed maternally and zygotically and supports specification of motoneurons, pituitary cells and ventral forebrain. We propose that smoothened is required for induction of lateral floor plate and a subpopulation of hypothalamic cells and for maintenance of medial floor plate and hypothalamic cells.