The effect of fertilizer nitrogen input to grass-clover swards and calving date on the productivity of pasture-based dairy production.

The objective of this systems-scale study was to investigate grazing season timeframes on pasture and milk production and on milk processability of dairy systems with compact spring-calving dairy cows grazing white clover (Trifolium repens L.) based grassland. Fifty-four primiparous and multiparous Holstein-Friesian dairy cows were used in a one-factor study with 3 systems (n = 18) and repeated over 2 yr (2008/09 and 2009/10). The 3 systems were: early spring calving with annual fertilizer N input of 100 kg·ha-1 applied in spring (ES100N; 2.1 cows·ha-1; grazing February to November), early spring calving without fertilizer N (ES0N; 1.6 cows·ha-1; grazing February to November) and late spring calving without fertilizer N (LS0N; 1.53 cows·ha-1; grazing April to January). Annual pasture production was affected by an interaction between grazing system and year: Mean annual pasture yields for 2008 and 2009 were ES100N; 10.35 and 9.88, ES0N; 8.88 and 8.63, LS0N; 9.18 and 10.31 t of dry matter (DM)·ha-1 (SEM 0.39). LS0N had higher pasture DM yield in 2009 due to higher clover DM production and biological N fixation compared with the other systems. Clover stolon and root mass in the following February was correlated with stolon and root mass in the previous November with 64% of stolon mass present on LS0N in February (R2 = 0.84). There were no detectable differences in per-lactation milk yield (6,335 kg·cow-1), fat, protein and lactose yields (271, 226, 297 kg·cow-1, respectively), cow liveweight (585 kg) or body condition score (3.02). Although winter grazing favored subsequent clover DM production, biological N fixation and pasture DM production, delaying calving date in spring and extending lactation into the following winter led to inefficient use of this pasture by the grazing herd and lowered the quality of late-lactation milk for processing purposes. Hence, a mean calving date in mid- to late-February is recommended for zero-fertilizer N input clover-based grassland.

Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer.

Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

Managing preconceived expectations: mental health service users experiences of going home from hospital: a grounded theory study.

ACCESSIBLE SUMMARY: What is known on the subject? The time of discharge from a mental health hospital can be challenging for mental health service users, with high rates of readmission in the immediate months following discharge. Although some research exists that explores service users' perspectives of being discharged, little evidence exists that explores the processes influencing or used by service users' to adapt to the transition from in-patient acute mental health service. What this papers adds to existing knowledge? The findings of this grounded theory study demonstrates the strategies service users used to managed their own, as well as their social audiences, preconceived expectations arising from their new identity as 'psychiatric patients' following their discharge from hospital. While there is a move to develop recovery-orientated mental health services, key indicators of recovery-oriented practices were often absent from service users' experiences of service provision. What are the implications for practice? Nurses and other mental health professionals need to recognize their contribution to the architecture of stigma that transcends the physical structures of hospital or ward and are entrenched within attitudes, interactions and practices. The findings of this study can provide guidance to those working with service users and help them to understand the complexities of their experiences when using mental health services, which go far beyond the management of their symptoms. INTRODUCTION: Following a period of hospitalization, the transition to home can result in increased vulnerability and a source of stress for mental health service users. Readmission rates have been suggested as one indicator of the success of the transition from hospital to community care. Despite knowledge of some of the factors that impact on service users following discharge, no coherent model or theoretical framework could be located in the literature, which explains or aides an in-depth understanding of the transition from hospital to community for service users. AIM: The aim of this study was to develop a grounded theory that explored service users' experiences of going home from hospital. METHOD: This qualitative study used grounded theory, and a total of 35 interviews were conducted with 31 service users. RESULTS: The core category was 'Managing Preconceived Expectations', which had seven subcategories, describes how the participants were negatively perceived by themselves and others following their admission and discharge from hospital. IMPLICATIONS FOR PRACTICE: This theory presents the strategies that the participants used to manage this new identity. This theory demonstrates that although there has been a move to adopt recovery-orientated services, key indicators of recovery were often absent for service users being admitted and subsequently discharged.

'We have got the tools': Qualitative evaluation of a mental health Wellness Recovery Action Planning (WRAP) education programme in Ireland.

In recent years, there has been a consistent drive to incorporate Recovery principles into the Irish mental health services. A group of Irish mental health service providers came together and delivered a 5-day Wellness Recovery Action Planning (WRAP) facilitator's programme. The programme was developed and delivered by key stakeholders including people with self-experience of mental health problem. This paper presents the qualitative findings from an evaluation of these facilitator's programmes. Three focus groups were held with 22 people, the majority of who described themselves as mental health professionals and/or people with self-experience of mental health problems. Data were analysed using a thematic approach and yielded four themes. Although the participants were positive about the programme and felt that their knowledge of Recovery and WRAP had improved, they felt that they still lacked confidence in terms of the presentation skills required for facilitating Recovery and WRAP programmes. The findings suggest that mental health service providers who wish to develop service users and clinicians as WRAP facilitators need to put more emphasis on the provision of facilitation and presentation skills in the programmes they develop.

Randomized, double-blind, placebo-controlled, dose-escalating phase I, healthy subjects study of intravenous OPN-305, a humanized anti-TLR2 antibody.

Upregulation of Toll-like receptor 2 (TLR2) plays a critical role in inflammation associated with ischemia/reperfusion-induced tissue damage. OPN-305 is the first humanized IgG4 monoclonal antibody against TLR2 in development and is intended for the prevention of reperfusion injury following renal transplantation and other indications. A phase I, single-center, prospective randomized, double-blind, placebo-controlled study was performed to evaluate single ascending doses of OPN-305 in 41 healthy male subjects (age range: 19-58 years) randomized to OPN-305 or placebo across six cohorts. OPN-305 was well tolerated across all doses, with no elevations in endogenous cytokines. A dose-proportional increase in maximum serum concentration (Cmax) was observed, with area under the curve increasing in a greater-than-dose-proportional manner with increasing elimination half-life. OPN-305 produced full TLR2 receptor blockade on CD14(+)CD45(+) cells (monocytes), from 14 (0.5 mg/kg) to >90 (10 mg/kg) days, with a linear effect on the duration of inhibition of interleukin-6 release after TLR2 stimulation.

Weekend hospitalization and additional risk of death: an analysis of inpatient data.

OBJECTIVE: To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk. DESIGN: Retrospective observational survivorship study. We analysed all admissions to the English National Health Service (NHS) during the financial year 2009/10, following up all patients for 30 days after admission and accounting for risk of death associated with diagnosis, co-morbidities, admission history, age, sex, ethnicity, deprivation, seasonality, day of admission and hospital trust, including day of death as a time dependent covariate. The principal analysis was based on time to in-hospital death. PARTICIPANTS: National Health Service Hospitals in England. MAIN OUTCOME MEASURES: 30 day mortality (in or out of hospital). RESULTS: There were 14,217,640 admissions included in the principal analysis, with 187,337 in-hospital deaths reported within 30 days of admission. Admission on weekend days was associated with a considerable increase in risk of subsequent death compared with admission on weekdays, hazard ratio for Sunday versus Wednesday 1.16 (95% CI 1.14 to 1.18; P < .0001), and for Saturday versus Wednesday 1.11 (95% CI 1.09 to 1.13; P < .0001). Hospital stays on weekend days were associated with a lower risk of death than midweek days, hazard ratio for being in hospital on Sunday versus Wednesday 0.92 (95% CI 0.91 to 0.94; P < .0001), and for Saturday versus Wednesday 0.95 (95% CI 0.93 to 0.96; P < .0001). Similar findings were observed on a smaller US data set. CONCLUSIONS: Admission at the weekend is associated with increased risk of subsequent death within 30 days of admission. The likelihood of death actually occurring is less on a weekend day than on a mid-week day.

TLR2 and TLR4 in ischemia reperfusion injury.

Ischemia reperfusion (I/R) injury refers to the tissue damage which occurs when blood supply returns to tissue after a period of ischemia and is associated with trauma, stroke, myocardial infarction, and solid organ transplantation. Although the cause of this injury is multifactorial, increasing experimental evidence suggests an important role for the innate immune system in initiating the inflammatory cascade leading to detrimental/deleterious changes. The Toll-like Receptors (TLRs) play a central role in innate immunity recognising both pathogen- and damage-associated molecular patterns and have been implicated in a range of inflammatory and autoimmune diseases. In this paper, we summarise the current state of knowledge linking TLR2 and TLR4 to I/R injury, including recent studies which demonstrate that therapeutic inhibition of TLR2 has beneficial effects on I/R injury in a murine model of myocardial infarction.

Survival of Cryptosporidium parvum oocysts in the presence of hydrated lime.

To investigate the effects of hydrated lime on the survival of Cryptosporidium oocysts, the percentage viability of oocysts was assessed using fluorescent in situ hybridisation. In the absence of lime and with lime at a concentration of 1 per cent, there was a gradual decline in oocyst viability during the 10-day trial. Although the addition of 5 or 10 per cent lime caused the total number of oocysts to decrease, there appeared to be an increase in the proportion of potentially viable oocysts.

The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.

OBJECTIVE: To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG). DATA SOURCES: MEDLINE and EMBASE were searched from 1966 until 30 November 2008. REVIEW METHODS: We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model. RESULTS: We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario). CONCLUSIONS: Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.

Social deprivation and prognostic benefits of cardiac surgery: observational study of 44 902 patients from five hospitals over 10 years.

OBJECTIVE: To assess the effects of social deprivation on survival after cardiac surgery and to examine the influence of potentially modifiable risk factors. DESIGN: Analysis of prospectively collected data. Prognostic models used to examine the additional effect of social deprivation on the end points. SETTING: Birmingham and north west England. PARTICIPANTS: 44 902 adults undergoing cardiac surgery, 1997-2007. MAIN OUTCOME MEASURES: Social deprivation with census based 2001 Carstairs scores. All cause mortality in hospital and at mid-term follow-up. RESULTS: In hospital mortality for all cardiac procedures was 3.25% and mid-term follow-up (median 1887 days; range 1180-2725 days) mortality was 12.4%. Multivariable analysis identified social deprivation as an independent predictor of mid-term mortality (hazard ratio 1.024, 95% confidence interval 1.015 to 1.033; P<0.001). Smoking (P<0.001), body mass index (BMI, P<0.001), and diabetes (P<0.001) were associated with social deprivation. Smoking at time of surgery (1.294, 1.191 to 1.407, P<0.001) and diabetes (1.305, 1.217 to 1.399, P<0.001) were independent predictors of mid-term mortality. The relation between BMI and mid-term mortality was non-linear and risks were higher in the extremes of BMI (P<0.001). Adjustment for smoking, BMI, and diabetes reduced but did not eliminate the effects of social deprivation on mid-term mortality (1.017, 1.007 to 1.026, P<0.001). CONCLUSIONS: Smoking, extremes of BMI, and diabetes, which are potentially modifiable risk factors associated with social deprivation, are responsible for a significant reduction in survival after surgery, but even after adjustment for these variables social deprivation remains a significant independent predictor of increased risk of mortality.

Chest pain and hypertension in an 18 year old girl.

We describe the case of an 18 year old lady who presented with chest pain, breathlessness and hypertension. The initial diagnosis of renal artery stenosis, while correct, was incomplete. The finding of a reduced right radial pulse suggested the possibility of a large vessel vasculitis. She was also found to have critical coronary artery disease that required stenting and aortic incompetence. Renal artery stenting was also performed. Additional investigations confirmed Takayasu's arteritis. With immunosuppressive therapy and stenting she is now well and normotensive but may require aortic valve replacement in the future.

Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation.

BACKGROUND AND PURPOSES: Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol-3 kinase (PI3K)/Akt and ERK1/2. However these pro-survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non-diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia-reoxygenation injury. EXPERIMENTAL APPROACH: Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed. KEY RESULTS: EPO improved the force of contraction in tissue from non-diabetic patients (46.7+/-1.7% vs. 30.2+/-2.2% in control, p<0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non-diabetic and diabetic patients, relative to their respective untreated controls. CONCLUSIONS AND IMPLICATIONS: EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.

Monitoring the occurrence of wound infections after cardiac surgery.

The aim of this study was to demonstrate the use of a graphical method for real-time monitoring of the occurrence of surgical wound infection following cardiac surgery. This included developing and incorporating a risk scoring system so that variations in case-mix could be duly accounted for in the monitoring process. We analysed routinely collected data from a London teaching hospital. These data consisted of records for 2146 patients who had undergone cardiac surgery between April 2000 and March 2004 and whose surgical wounds were followed up as part of the local surveillance programme. The risk model was developed using logistic regression analysis with surgical wound infection diagnosed before hospital discharge as the outcome measure. Factors included in the model were the number of surgical wounds, patient age, operations that combined bypass surgery and valve replacement, renal disease and the number of days between hospital admission and surgery. The model was a good predictor of outcomes recorded within an independent data set (Chi-squared=3.81, P=0.58) and we incorporated it into a graphical tool for monitoring outcomes. The risk model and the associated graphical monitoring method could be valuable tools to assist with infection management. If used in real-time, problems with the care process can be quickly identified allowing timely remedial action to be taken.

Logistic, additive or historical: is EuroSCORE an appropriate model for comparing individual surgeons' performance?

Both versions of the EuroSCORE, the complex logistic and the simpler additive, have been used for comparing institutional performance, but they are no longer robust enough to be used for comparing individual surgeons. It is now time to tighten the standard and add additional data to obtain a more holistic picture of the quality of cardiac surgical care in the UK.

Functional brain imaging using a long intravenous half-life gadolinium-based contrast agent.

PURPOSE: We describe a technique for functional MR imaging (fMRI) with high spatial and temporal resolution using a long intravascular half-life gadolinium-based contrast agent, MS-325. METHODS: All fMRI measurements used a rat model of sensory cortex activation with forepaw electrical stimulation under alpha-chloralose anesthesia. Standard blood oxygen level-dependent (BOLD) fMRI measurement was initially performed. MS-325 was then intravenously administered and a MS-325 fMRI measurement was performed by using a 3D gradient-echo sequence. RESULTS: We found that a dose of 0.1 mmol/kg MS-325 produced adequate signal intensity changes in rat sensory cortex to demonstrate activations. Using a boxcar stimulation pattern with a standard correlation analysis, the locations of the most significantly activated voxels (ie, highest Z score) in the MS-325 and BOLD fMRI measurements were not significantly different. CONCLUSIONS: MS-325 fMRI has the advantage of using a T1-weighted sequence, rather than the highly T2*-weighted sequences used in other common fMRI techniques. This could reduce the susceptibility artifacts associated with fMRI.

Molecular epidemiologic investigation of tuberculosis in an area of increasing incidence in inner-city Dublin.

In 2002 the tuberculosis (TB) incidence in Dublin was 13.1 cases per 100,000 persons. In inner city Dublin, the TB incidence was > 20 per 100,000 persons. TB notification rates have remained elevated. The objective of the study is to characterize the population affected in this inner city area and to investigate transmission patterns and potential risk factors for TB disease. This hospital-based molecular epidemiologic study included all culture positive cases of TB between January 1, 1998 and December 31, 2002 from the Mater Misericordiae University Hospital. 142 cases were analyzed. 84 (59%) had clustered Mycobacterium tuberculosis (Mtb) isolates, 58 (41%) had unique isolates by molecular typing. There were 13 clusters; the largest two clusters had 26 cases each, one linked to pubs, the other linked through family contact. In multivariate logistic regression analysis, birth in Ireland, pulmonary TB, and younger age were significantly associated with recent transmission. Dublin is a developed city with persistent areas of high rates of TB in the native population. Despite a functioning public health system and lack of predisposing risk factors such as HIV, immigration, and extreme poverty, TB can persist in pockets of the younger, native population.