Effects of TNF receptor blockade on in vitro cell survival and response to negative energy balance in dairy cattle.

BACKGROUND: Associative data and some controlled studies suggest that the inflammatory cytokine tumor necrosis factor (TNF) α can induce fatty liver in dairy cattle. However, research demonstrating that TNFα is a necessary component in the etiology of bovine fatty liver is lacking. The aim of this work was to evaluate whether blocking TNFα signaling with a synthetic cyclic peptide (TNF receptor loop peptide; TRLP) would improve liver metabolic function and reduce triglyceride accumulation during feed restriction. RESULTS: Capability of TRLP to inhibit TNFα signaling was confirmed on primary bovine hepatocytes treated with recombinant bovine TNFα and 4 doses of TRLP (0, 1, 10, 50 µmol/L) over 24 h. Next, 4 lactating Holstein cows (parity 1.4 ± 0.5, 433 ± 131 d in milk) in an incomplete Latin rectangle design (3 × 2) were subcutaneously administered with different TRLP doses (0, 1.5, 3.0 mg/kg BW) every 4 h for 24 h, followed by an intravenous injection of TNFα (5 µg/kg BW). Before and for 2 h after TNFα injection, TRLP decreased plasma non-esterified fatty acid (NEFA) concentration (P ≤ 0.05), suggesting an altered metabolic response to inflammation. Finally, 10 non-pregnant, non-lactating Holstein cows (3.9 ± 1.1 yr of age) were randomly assigned to treatments: control (carrier: 57% DMSO in PBS) or TRLP (1.75 mg TRLP /kg BW per day). Treatments were administrated every 4 h for 7 d by subcutaneous injection to feed-restricted cows fed 30% of maintenance energy requirements. Daily blood samples were analyzed for glucose, insulin, ß-hydroxybutyrate, NEFA, and haptoglobin concentrations, with no treatment effects detected. On d 7, cows completed a glucose tolerance test (GTT) by i.v. administration of a dextrose bolus (300 mg glucose/kg BW). Glucose, insulin, and NEFA responses failed to demonstrate any significant effect of treatment during the GTT. However, plasma and liver analyses were not indicative of dramatic lipolysis or hepatic lipidosis, suggesting that the feed restriction protocol failed to induce the metabolic state of interest. Injection site inflammation, assessed by a scorer blinded to treatment, was enhanced by TRLP compared to control. CONCLUSIONS: Although the TRLP inhibited bovine TNFα signaling and altered responses to i.v. administration of TNFα, repeated use over 7 d caused apparent local allergic responses and it failed to alter metabolism during a feed restriction-induced negative energy balance. Although responses to feed restriction seemed atypical in this study, side effects of TRLP argue against its future use as a tool for investigating the role of inflammation in metabolic impacts of negative energy balance.

The impact of active stakeholder involvement on recruitment, retention and engagement of schools, children and their families in the cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP): a school-based intervention to prevent obesity.

BACKGROUND: Recruitment and retention of participants is crucial for statistical power and internal and external validity and participant engagement is essential for behaviour change. However, many school-based interventions focus on programme content rather than the building of supportive relationships with all participants and tend to employ specific standalone strategies, such as incentives, to improve retention. We believe that actively involving stakeholders in both intervention and trial design improves recruitment and retention and increases the chances of creating an effective intervention. METHODS: The Healthy Lifestyles Programme, HeLP (an obesity prevention programme for children 9-10 years old) was developed using intervention mapping and involved extensive stakeholder involvement in both the design of the trial and the intervention to ensure that: (i) delivery methods were suitably engaging, (ii) deliverers had the necessary skills and qualities to build relationships and (iii) the intervention dovetailed with the National Curriculum. HeLP was a year-long intervention consisting of 4 multi-component phases using a range of delivery methods. We recruited 1324 children from 32 schools from the South West of England to a cluster-randomised controlled trial to determine the effectiveness of HeLP in preventing obesity. The primary outcome was change in body mass index standard deviation score (BMI SDS) at 24 months post randomisation. Secondary outcomes included additional anthropometric and behavioural (physical activity and diet) measures at 18 and 24 months. RESULTS: Anthropometric and behavioural measures were taken in 99%, 96% and 94% of children at baseline, 18 and 24 months, respectively, with no differential follow up between the control and intervention groups at each time point. All children participated in the programme and 92% of children and 77% of parents across the socio-economic spectrum were considered to have actively engaged with HeLP. CONCLUSIONS: We attribute our excellent retention and engagement results to the high level of stakeholder involvement in both trial and intervention design, the building of relationships using appropriate personnel and creative delivery methods that are accessible to children and their families across the social spectrum. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Register, ISRCTN15811706 . Registered on 1 May 2012.

Cost-effectiveness of outpatient parenteral antibiotic therapy: a simulation modelling approach.

Objectives: In the UK, patients who require intravenous antimicrobial (IVA) treatment may receive this in the community through outpatient parenteral antimicrobial therapy (OPAT) services. Services include: IVA administration at a hospital outpatient clinic (HO); IVA administration at home by a general nurse (GN) or a specialist nurse (SN); or patient self-administered (SA) IVA administration following training. There is uncertainty regarding which OPAT services represent value for money; this study aimed to estimate their cost-effectiveness. Methods: A cost-effectiveness decision-analytic model was developed using a simulation technique utilizing data from hospital records and a systematic review of the literature. The model estimates cost per QALY gained from the National Health Service (NHS) perspective for short- and long-term treatment of infections and service combinations across these. Results: In short-term treatments, HO was estimated as the most effective (0.7239 QALYs), but at the highest cost (£973). SN was the least costly (£710), producing 0.7228 QALYs. The combination between SN and HO was estimated to produce 0.7235 QALYs at a cost of £841. For long-term treatments, SN was the most effective (0.677 QALYs), costing £2379, while SA was the least costly at £1883, producing 0.666 QALYs. A combination of SA and SN was estimated to produce 0.672 QALYs at a cost of £2128. Conclusions: SN and SA are cost-effective for short- and long-term treatment of infections, while combining services may represent the second-best alternative for OPAT in the UK.

Clinical and cost-effectiveness, safety and acceptability of community intravenous antibiotic service models: CIVAS systematic review.

OBJECTIVE: Evaluate evidence of the efficacy, safety, acceptability and cost-effectiveness of outpatient parenteral antimicrobial therapy (OPAT) models. DESIGN: A systematic review. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Library, National Health Service (NHS) Economic Evaluation Database (EED), Research Papers in Economics (RePEc), Tufts Cost-Effectiveness Analysis (CEA) Registry, Health Business Elite, Health Information Management Consortium (HMIC), Web of Science Proceedings, International Pharmaceutical Abstracts, British Society for Antimicrobial Chemotherapy website. Searches were undertaken from 1993 to 2015. STUDY SELECTION: All studies, except case reports, considering adult patients or practitioners involved in the delivery of OPAT were included. Studies combining outcomes for adults and children or non-intravenous (IV) and IV antibiotic groups were excluded, as were those focused on process of delivery or clinical effectiveness of 1 antibiotic over another. Titles/abstracts were screened by 1 reviewer (20% verified). 2 authors independently screened studies for inclusion. RESULTS: 128 studies involving >60 000 OPAT episodes were included. 22 studies (17%) did not indicate the OPAT model used; only 29 involved a comparator (23%). There was little difference in duration of OPAT treatment compared with inpatient therapy, and overall OPAT appeared to produce superior cure/improvement rates. However, when models were considered individually, outpatient delivery appeared to be less effective, and self-administration and specialist nurse delivery more effective. Drug side effects, deaths and hospital readmissions were similar to those for inpatient treatment, but there were more line-related complications. Patient satisfaction was high, with advantages seen in being able to resume daily activities and having greater freedom and control. However, most professionals perceived challenges in providing OPAT. CONCLUSIONS: There were no systematic differences related to the impact of OPAT on treatment duration or adverse events. However, evidence of its clinical benefit compared with traditional inpatient treatment is lacking, primarily due to the dearth of good quality comparative studies. There was high patient satisfaction with OPAT use but the few studies considering practitioner acceptability highlighted organisational and logistic barriers to its delivery.

Explaining trends in alcohol-related harms in Scotland 1991-2011 (II): policy, social norms, the alcohol market, clinical changes and a synthesis.

OBJECTIVE: To provide a basis for evaluating post-2007 alcohol policy in Scotland, this paper tests the extent to which pre-2007 policy, the alcohol market, culture or clinical changes might explain differences in the magnitude and trends in alcohol-related mortality outcomes in Scotland compared to England & Wales (E&W). STUDY DESIGN: Rapid literature reviews, descriptive analysis of routine data and narrative synthesis. METHODS: We assessed the impact of pre-2007 Scottish policy and policy in the comparison areas in relation to the literature on effective alcohol policy. Rapid literature reviews were conducted to assess cultural changes and the potential role of substitution effects between alcohol and illicit drugs. The availability of alcohol was assessed by examining the trends in the number of alcohol outlets over time. The impact of clinical changes was assessed in consultation with key informants. The impact of all the identified factors were then summarised and synthesised narratively. RESULTS: The companion paper showed that part of the rise and fall in alcohol-related mortality in Scotland, and part of the differing trend to E&W, were predicted by a model linking income trends and alcohol-related mortality. Lagged effects from historical deindustrialisation and socio-economic changes exposures also remain plausible from the available data. This paper shows that policy differences or changes prior to 2007 are unlikely to have been important in explaining the trends. There is some evidence that aspects of alcohol culture in Scotland may be different (more concentrated and home drinking) but it seems unlikely that this has been an important driver of the trends or the differences with E&W other than through interaction with changing incomes and lagged socio-economic effects. Substitution effects with illicit drugs and clinical changes are unlikely to have substantially changed alcohol-related harms: however, the increase in alcohol availability across the UK is likely to partly explain the rise in alcohol-related mortality during the 1990s. CONCLUSIONS: Future policy should ensure that alcohol affordability and availability, as well as socio-economic inequality, are reduced, in order to maintain downward trends in alcohol-related mortality in Scotland.

Explaining trends in alcohol-related harms in Scotland, 1991-2011 (I): the role of incomes, effects of socio-economic and political adversity and demographic change.

OBJECTIVE: This paper tests the extent to which differing trends in income, demographic change and the consequences of an earlier period of social, economic and political change might explain differences in the magnitude and trends in alcohol-related mortality between 1991 and 2011 in Scotland compared to England & Wales (E&W). STUDY DESIGN: Comparative time trend analyses and arithmetic modelling. METHODS: Three approaches were utilised to compare Scotland with E&W: 1. We modelled the impact of changes in income on alcohol-related deaths between 1991-2001 and 2001-2011 by applying plausible assumptions of the effect size through an arithmetic model. 2. We used contour plots, graphical exploration of age-period-cohort interactions and calculation of Intrinsic Estimator coefficients to investigate the effect of earlier exposure to social, economic and political adversity on alcohol-related mortality. 3. We recalculated the trends in alcohol-related deaths using the white population only to make a crude approximation of the maximal impact of changes in ethnic diversity. RESULTS: Real incomes increased during the 1990s but declined from around 2004 in the poorest 30% of the population of Great Britain. The decline in incomes for the poorest decile, the proportion of the population in the most deprived decile, and the inequality in alcohol-related deaths, were all greater in Scotland than in E&W. The model predicted less of the observed rise in Scotland (18% of the rise in men and 29% of the rise in women) than that in E&W (where 60% and 68% of the rise in men and women respectively was explained). One-third of the decline observed in alcohol-related mortality in Scottish men between 2001 and 2011 was predicted by the model, and the model was broadly consistent with the observed trends in E&W and amongst women in Scotland. An age-period interaction in alcohol-related mortality was evident for men and women during the 1990s and 2000s who were aged 40-70 years and who experienced rapidly increasing alcohol-related mortality rates. Ethnicity is unlikely to be important in explaining the trends or differences between Scotland and E&W. CONCLUSIONS: The decline in alcohol-related mortality in Scotland since the early 2000s and the differing trend to E&W were partly described by a model predicting the impact of declining incomes. Lagged effects from historical social, economic and political change remain plausible from the available data.

Auditing HIV Testing Rates across Europe: Results from the HIDES 2 Study.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Community IntraVenous Antibiotic Study (CIVAS): protocol for an evaluation of patient preferences for and cost-effectiveness of community intravenous antibiotic services.

INTRODUCTION: Outpatient parenteral antimicrobial therapy (OPAT) is used to treat a wide range of infections, and is common practice in countries such as the USA and Australia. In the UK, national guidelines (standards of care) for OPAT services have been developed to act as a benchmark for clinical monitoring and quality. However, the availability of OPAT services in the UK is still patchy and until quite recently was available only in specialist centres. Over time, National Health Service (NHS) Trusts have developed OPAT services in response to local needs, which has resulted in different service configurations and models of care. However, there has been no robust examination comparing the cost-effectiveness of each service type, or any systematic examination of patient preferences for services on which to base any business case decision. METHODS AND ANALYSIS: The study will use a mixed methods approach, to evaluate patient preferences for and the cost-effectiveness of OPAT service models. The study includes seven NHS Trusts located in four counties. There are five inter-related work packages: a systematic review of the published research on the safety, efficacy and cost-effectiveness of intravenous antibiotic delivery services; a qualitative study to explore existing OPAT services and perceived barriers to future development; an economic model to estimate the comparative value of four different community intravenous antibiotic services; a discrete choice experiment to assess patient preferences for services, and an expert panel to agree which service models may constitute the optimal service model(s) of community intravenous antibiotics delivery. ETHICS AND DISSEMINATION: The study has been approved by the NRES Committee, South West-Frenchay using the Proportionate Review Service (ref 13/SW/0060). The results of the study will be disseminated at national and international conferences, and in international journals.

Worker Injuries Involving the Interaction of Cattle, Cattle Handlers, and Farm Structures or Equipment.

Cattle have been identified as leading sources of injuries to agricultural workers. The present study focused on worker injuries that involved the interaction of cattle, cattle handlers, and farm structures or equipment. The goal of the study was to identify opportunities for injury prevention. We examined 221 reports of injury to cattle handlers from the Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS). Expected interactions led to many of the cattle-handling injuries reported in the NEISS database. In almost 30% of cases, cattle pushed workers into structures such as fences, gates, posts, and walls. In another 16% to 19% of injuries, cattle struck gates and other objects, propelling them at the victims. The present research makes several important contributions to the study of cattle-handling injuries. First, the research supports an increased emphasis on the development of safer gate designs (e.g., gates that are remotely operated or that absorb energy to limit the speed at which they may be propelled by animals). Second, the research suggests a need for additional study of energy-absorbing fence and wall structures. We view these two points to be of significance because gates and associated structures (e.g., posts, fences, and walls) accounted for 45% of the injuries in the dataset, based on the associated injury narrative. Finally, the research identifies a previously unexplored source of agricultural injury data, namely the NEISS database.

Continuous low-dose infusion of tumor necrosis factor alpha in adipose tissue elevates adipose tissue interleukin 10 abundance and fails to alter metabolism in lactating dairy cows.

Repeated bolus doses of tumor necrosis factor-α (TNFα) alters systemic metabolism in lactating cows, but whether chronic release of inflammatory cytokines from adipose tissue has similar effects is unclear. Late-lactation Holstein cows (n=9-10/treatment) were used to evaluate the effects of continuous adipose tissue TNFα administration on glucose and fatty acid (FA) metabolism. Cows were blocked by feed intake and milk yield and randomly assigned within block to control or TNFα treatments. Treatments (4mL of saline or 14µg/kg of TNFα in 4mL of saline) were infused continuously over 7d via 2 osmotic pumps implanted in a subcutaneous adipose depot. Plasma, milk samples, milk yield, and feed intake data were collected daily, and plasma glucose turnover rate was measured on d 7. At the end of d 7, pumps were removed and liver and contralateral tail-head adipose biopsies were collected. Results were modeled with the fixed effect of treatment and the random effect of block. Treatment with TNFα increased plasma concentrations of the acute phase protein haptoglobin, but did not alter plasma TNFα, IL-4, IL-6, or IFN-γ concentrations, feed intake, or rectal temperature. Milk yield and composition were unchanged, and treatments did not alter the proportion of short- versus long-chain FA in milk on d 7. Treatments did not alter plasma free FA concentration, liver triglyceride content, or plasma glucose turnover rate. Surprisingly, TNFα infusion tended to decrease liver TNFα and IL-1 receptor 1 mRNA abundance and significantly increased adipose tissue IL-10 protein concentration. Continuous infusion of TNFα did not induce the metabolic responses previously observed following bolus doses delivered at the same rate per day. Metabolic homeostasis may have been protected by an adaptive anti-inflammatory response to control systemic inflammation.

Home delivery of medication - the role of a patient information leaflet on maximising service uptake.

There are currently over 30,000 HIV-positive individuals in London and over 25,000 on anti-retroviral therapy. In 2009/2010, this equated to £170m spent by London's NHS on anti-retroviral drugs. Ways employed to reduce this cost include standardising the drugs patients are on and delivering medication to patients at home. Home delivery (HD) medication is exempt from value-added tax. The savings made from 10 patients using the home delivery service would free up resources to provide anti-retroviral therapy to one further patient. Studies have shown that concerns surrounding potential breaches of confidentiality are a potential barrier to some people using the home delivery service. In order to challenge these concerns, a leaflet was devised highlighting the major benefits to both the patient and the NHS of home delivery and addressing concerns over confidentiality. The leaflet was handed out to patients at the Mortimer Market Centre who were currently on anti-retroviral medication but not on home delivery. They were asked to complete a survey on their views of the service before and after reading the leaflet, whether they had been previously aware of the service and whether their concerns had been addressed. Some 79% felt that the patient information leaflet addressed all of their concerns, and it helped 11% decide whether to consider using home delivery. However, as more patients were opposed to the service after reading the patient information leaflet than those considering it, more work needs to be done to explore patients' concerns and other factors influencing home delivery service uptake.

Sodium salicylate treatment in early lactation increases whole-lactation milk and milk fat yield in mature dairy cows.

Multiple lines of inquiry have suggested that a high degree of inflammation in early lactation cows is associated with low productivity and increased disease incidence. In addition, some small studies have suggested that milk production increases in response to antiinflammatory treatment in the first week of lactation. Our objective was to determine if administration of sodium salicylate (SS), a nonsteroidal antiinflammatory drug (NSAID), in the first week of lactation changes whole-lactation productivity and retention in the herd. At calving, 78 cows [n=39 primiparous (1P); n=24 second parity (2P); n=15 third parity or greater (3P)] were alternately assigned to either control (CON) or SS treatments for 7 d postpartum. Sodium salicylate treatment was administered via individual water bowls at a concentration of 1.95 g/L, delivering a mean of 123.3±5.5 g of salicylate/d during the 7-d treatment. For the first 21 d of lactation, dry matter intake, water intake, milk yield, and health were monitored daily, and milk samples were collected twice weekly for milk component analysis. Monthly milk yield and component testing through the rest of the lactation provided data to assess long-term responses, and the effects of treatment on the risk of leaving the herd and on 305-d milk, fat, and protein yields were assessed. During the first 21 d of lactation, we observed no differences in morbidity, except for increased risk of metritis in 3P SS cows. Treatment interacted with parity to influence both 305-d milk and milk fat yields, and a tendency for an interaction was detected for 305-d milk protein yield. Milk yield was 2,469±646 kg greater over the lactation in 3P SS cows compared with 3P CON cows (21% increase) and tended to decrease by 8% in 1P cows treated with SS; no effects were detected in 2P cows. Furthermore, 3P SS cows produced 130±23 kg more milk fat over the lactation (30% increase), with no effects detected for 1P or 2P. Treatment with SS tended to increase 305-d milk protein yield in 3P cows by 14%, with no effects in 1P or 2P cows. A tendency for a treatment × parity interaction was also observed for the risk of leaving the herd. First-parity cows treated with SS tended to have greater risk of leaving the herd than controls (30 vs. 6% risk); however, treatment did not alter herd retention in 2P or 3P groups, and SS had no effect on the risk of leaving the herd overall. Results indicate that SS has long-term effects on lactation of mature dairy cows, particularly on fat yield, but may have negative effects for primiparous cows.

Echocardiography in newly diagnosed atrial fibrillation patients: a systematic review and economic evaluation.

OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of transthoracic echocardiography (TTE) in all patients who are newly diagnosed with atrial fibrillation (AF). DESIGN: Narrative synthesis reviews were conducted on the prognostic and diagnostic accuracy of TTE for, and prevalence of, pathologies in patients with AF. Databases were searched from inception. MEDLINE searches were conducted from March to August 2010, and reference lists of articles checked. There were 44 diagnostic accuracy studies, five prognostic studies, and 16 prevalence studies accepted into the review. Given the complexity of the many pathologies identified by TTE, the variety of potential changes to clinical management, and paucity of data, the model focused on changes to oral anticoagulation (OAC). The mathematical model assessed the cost-effectiveness of TTE for patients with AF who were not routinely given OAC, assuming, if left atrial abnormality was detected, that the higher risk of stroke warranted OAC; this meant that patients with a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke doubled) score of 0 [dabigatran etexilate (Pradaxa, Boehringer Ingelheim)/rivaroxaban (Xarelto, Bayer Schering)] or 0/1 (warfarin) were included. A simplified approach evaluated the additional quality-adjusted life-years (QALYs) required in order for TTE to be perceived as cost-effective at a threshold of £20,000 per QALY. SETTING: Transthoracic echocardiography is usually performed in cardiology clinics but may be used in primary or non-specialist secondary care. PARTICIPANTS: Patients with newly diagnosed AF. INTERVENTION: Transthoracic echocardiography. MAIN OUTCOME MEASURES: Prognosis, diagnostic sensitivity or specificity of TTE, prevalence of pathologies in patients with AF, cost-effectiveness and QALYs. RESULTS: Prognostic studies indicated that TTE-diagnosed left ventricular dysfunction, increased left atrial diameter and valvular abnormality were significantly associated with an increased risk of stroke, mortality or thromboembolism. There was a high prevalence (around 25-30%) of ischaemic heart disease, valvular heart disease and heart failure in patients with AF. Diagnostic accuracy of TTE was high, with most pathologies having specificity of ≥ 0.8 and sensitivity of ≥ 0.6. The mathematical model predicted that when the CHADS2 tool is used the addition of TTE in identifying patients with left atrial abnormality appears to be cost-effective for informing some OAC decisions. In the simplified approach a threshold of 0.0033 was required for a TTE to be cost-effective. CONCLUSIONS: When CHADS2 was used, the addition of TTE in identifying patients with left atrial abnormality was cost-effective for informing some OAC decisions. A simple analysis indicates that the number of QALYs required for TTE to be cost-effective is small, and that if benefits beyond those associated with a reduction in stroke are believed probable then TTE is likely to be cost-effective in all scenarios. Our findings suggest that further research would be useful, following up newly diagnosed patients with AF who have undergone TTE, to study treatments given as a result of TTE diagnoses and subsequent cardiovascular events. This could identify additional benefits of routine testing, beyond stroke prevention. Studies assessing the proportion of people with a CHADS2 score of 0 or 1 that have left atrial abnormality would provide better estimates of the cost-effectiveness of TTE, and allow more accurate estimates of the sensitivity and specificity of TTE for identifying left atrial abnormality in AF to be obtained. STUDY REGISTRATION: PROSPERO CRD42011001354. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle.

Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation.

The clinical effectiveness and cost-effectiveness of technologies used to visualise the seizure focus in people with refractory epilepsy being considered for surgery: a systematic review and decision-analytical model.

BACKGROUND: For patients who continue to have seizures despite ongoing treatment, surgical resection of the epileptic focus may be considered, and can result in seizure-freedom. Currently, non-invasive tests provide information to inform the scope and positioning of invasive electroencephalography (EEG) electrodes. However, these technologies could replace intracranial EEG in at least some patients if their ability to accurately locate a seizure focus could be established. In order to inform clinical practice, studies need to investigate the clinical value of a test, and the impact of the results of that test on the decision-making process and subsequently on clinical outcomes. OBJECTIVES: The aims of this systematic review were to determine the diagnostic accuracy of non-invasive technologies, how these technologies impact on the decision-making process, associations with surgical outcome, and the gaps in the current evidence base. In addition, a decision-analytical model was designed to consider the potential use of existing data to determine the cost-effectiveness of options for presurgical work-up. DATA SOURCES: Eighteen electronic databases were searched without language restrictions [including MEDLINE, EMBASE, BIOSIS Previews, PASCAL, ClinicalTrials.gov, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Register of Diagnostic Studies] from 2003 to July 2010. A prior, wider-ranging HTA review in this area conducted by the Centre for Reviews and Dissemination was used as the source for studies prior to 2003. Reference lists of included studies and relevant reviews were also searched, and a citation search of key papers undertaken. REVIEW METHODS: Systematic reviews of the diagnostic accuracy, clinical utility and cost-effectiveness of non-invasive technologies used to define the seizure focus in patients with refractory epilepsy being considered for surgery were undertaken according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Thirteen diagnostic accuracy studies, seven outcome prediction studies and one study reporting the impact of test results on the decision-making process ('decision study') were included. The decision study was used to aid the development of a decision-analytical model to illustrate how data from appropriately designed clinical studies can be utilised. RESULTS: Data from the diagnostic accuracy studies could not determine the contribution of the tests to the decision-making process. The number of index tests that could not be classified as correctly, non- or wrongly localising as indicated by a surgical outcome was high, up to 53%. The decision study reported fluorodeoxyglucose positron emission tomography influencing the decision for or against surgery in 78 of the 110 patients. The constructed decision-analytical model provided provisional cost-effectiveness results from the included diagnostic strategies. It demonstrated the feasibility of extending such analysis to all diagnostic strategies if suitable data were to become available. LIMITATIONS: There were a number of limitations of the available evidence, and overall, the quality of the available evidence was poor; only one study met the inclusion criteria that evaluated the use an index test on the decision-making process. Most of the available data was from the diagnostic accuracy studies; those currently available did not provide information on either the diagnostic accuracy or clinical utility of the tests being evaluated. Further limitations were the generally small study sizes, patient selection bias and the substantial clinical heterogeneity across the studies. CONCLUSIONS: The current evidence base is abundant but not adequately informative; there is no acceptable reference standard, reporting of clinical outcomes tends to be only following surgery, and decision level and clinical effectiveness studies are lacking. The additional value of diagnostic technologies for the localisation of epileptic foci is related to the impact on treatment decisions and the value of the treatments themselves; this needs to be considered fully in informing cost-effectiveness. Appropriately designed studies are needed to determine the added value of diagnostic regimens. Ultimately, how research informs the actual decision problem(s) faced by clinicians and the NHS needs to be considered; decision modelling is central to this issue. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Novel GLIS3 mutations demonstrate an extended multisystem phenotype.

INTRODUCTION: Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism. SUBJECTS: We report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1-2 (case 1) or exons 1-4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2. CONCLUSIONS: Our results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

Interaction of Bacillus species and Salmonella enterica serovar Typhimurium in immune or inflammatory signaling from swine intestinal epithelial cells.

Previous research evaluated a laboratory strain of Bacillus licheniformis (BL) in a model swine epithelium and found it exerted antiinflammatory effects on Salmonella enterica serovar Typhimurium (Sal)-induced secretion of IL-8. The current investigation evaluated the antiinflammatory actions of Bacillus bacteria available commercially as feed additives for the swine industry. Three isolates were obtained from the product, 2 Bacillus subtilis (BS1 and BS3) and 1 BL (BL2). Swine jejunal epithelial IPEC-J2 cells were seeded into wells on permeable membrane supports and allowed to form confluent monolayers. Treatments included apical pretreatment with BL, BS1, BL2, or BS3 for 17 h without Sal, and the same Bacillus treatments but with 10(8) cfu of Sal added in the final hour of Bacillus incubation. Two additional treatments included negative control wells receiving no bacteria (control) and positive control wells receiving only Sal (10 total treatments). After bacterial incubation, wells were washed and fresh medium containing gentamicin was added. Cells were incubated for an additional 5 h, after which apical and basolateral media were recovered for determination of IL-8 and bacitracin. In addition, inserts with epithelial cells that had received Sal were lysed and lysates were cultured to determine treatment effects on Sal invasion. Exposure to Sal alone provoked an increase in IL-8 secretion from IPEC-J2 cells compared with control wells (P < 0.001 for both the apical and basolateral directions). Pretreatment with each Bacillus isolate followed by challenge with Sal reduced Sal-induced IL-8 secretion in both the apical and basolateral compartments compared with wells receiving only Sal (P < 0.001; except for BS3 apical, P < 0.01). The residual presence of bacitracin could be detected only in BL2 and BL2+Sal. Fewer Sal colonies could be cultured from lysates of BL2+Sal than from the Sal, BS1+Sal, and BS3+Sal treatments (P < 0.001). Results indicate that B. subtilis and BL have the ability to intervene in secretion of the neutrophil chemoattractant IL-8 from swine intestinal epithelial cells. This effect on chemokine secretion by gastrointestinal epithelial cells in vitro could not be explained solely by reduced invasion of epithelial cells by Sal.

Oral inoculation with Salmonella enterica serovar Typhimurium or Choleraesuis promotes divergent responses in the somatotropic growth axis of swine.

Enteric disease and immune challenge are processes that have detrimental effects on the growth performance of young swine. The current study tested the hypothesis that salmonella-induced enteric disease would perturb the endocrine growth axis in a serovar-dependent fashion. Specifically, we evaluated the effects of Salmonella enterica serovar Typhimurium (Typhimurium) and serovar Choleraesuis (Choleraesuis) on critical regulatory components of growth in young swine. Weaned pigs were housed 2 per pen with ad libitum access to feed and water in a 14-d experiment. Pigs were then repeatedly fed 10(8) cfu of either Choleraesuis or Typhimurium in dough balls, with control pigs receiving dough without bacteria. Bacteria were refed twice weekly. Rectal temperatures were monitored daily from d 0 to 7 and ADFI was measured through d 14. Pigs were weighed and samples of serum were obtained for circulating IGF-I on d 0, 7, and 14. At the conclusion of the study, samples of semitendinosus muscle and liver were obtained and subsequently assayed for IGF-I, IGFBP-3, and IGFBP-5 mRNA. Rectal temperatures were elevated in pigs given Choleraesuis from d 2 through 7 (P < 0.05) when compared with control pigs and pigs fed Typhimurium. Pigs receiving Choleraesuis had a substantially decreased feed intake on d 2, 3, 4, 7, 8, 9, and 10 (P < 0.01), with a trend for a reduction on d 5 (P = 0.08), and they experienced an approximately 25% reduction in BW compared with control pigs and pigs given Typhimurium by the conclusion of the study. Pigs given Choleraesuis also experienced marked reductions in circulating IGF-I on d 7 (P < 0.01 vs. control and Typhimurium), with reductions of lesser magnitude on d 14 (P = 0.07 vs. control and P < 0.05 vs. Typhimurium). Inoculation tended to affect liver IGFBP-3 mRNA (P = 0.08), for which expression tended to be elevated in pigs given Typhimurium and Choleraesuis. In contrast, IGFBP-3 mRNA relative abundance was increased (P < 0.03) in pigs given Typhimurium compared with control pigs. Muscle IGF-I mRNA was reduced in pigs given Choleraesuis compared with control pigs and pigs given Typhimurium (P < 0.05). Treatment tended to affect muscle IGFBP-3 mRNA (P = 0.10). Oral inoculation of growing pigs with Choleraesuis disrupted feed intake and BW gain, and this was accompanied by decreases in circulating IGF-I and reduced muscle expression of mRNA for IGF-I and IGFBP-3.

Daily injection of tumor necrosis factor-{alpha} increases hepatic triglycerides and alters transcript abundance of metabolic genes in lactating dairy cattle.

To determine whether inflammation can induce bovine fatty liver, we administered recombinant bovine tumor necrosis factor-alpha (rbTNF) to late-lactation Holstein cows. Cows (n = 5/treatment) were blocked by feed intake and parity and randomly assigned within block to control (CON; saline), rbTNF at 2 microg/(kg.d), or pair-fed control (saline, intake matched) treatments. Treatments were administered once daily by subcutaneous injection for 7 d. Plasma samples were collected daily for analysis of glucose and FFA and a liver biopsy was collected on d 7 for triglyceride (TG) and quantitative RT-PCR analyses. Data were analyzed using treatment contrasts to assess effects of tumor necrosis factor-alpha (TNFalpha) and decreased feed intake. By d 7, feed intake of both rbTNF and pair-fed cows was approximately 15% less than CON (P < 0.01). Administration of rbTNF resulted in greater hepatic TNFalpha mRNA and protein abundance and 103% higher liver TG content (P < 0.05) without affecting the plasma FFA concentration. Hepatic carnitine palmitoyltransferase 1 transcript abundance tended to be lower (P = 0.09) and transcript abundance of fatty acid translocase and 1-acyl-glycerol-3-phosphate acyltransferase was higher (both P < 0.05) after rbTNF treatment, consistent with increased FFA uptake and storage as TG. Transcript abundance of glucose-6-phosphatase (P < 0.05) and phosphoenolpyruvate carboxykinase 1 (P = 0.09), genes important for gluconeogenesis, was lower for rbTNF-treated cows. These findings indicate that TNFalpha promotes liver TG accumulation and suggest that inflammatory pathways may also be responsible for decreased glucose production in cows with fatty liver.

Devolving of statin prescribing to general practitioners for HIV-infected patients receiving antiretroviral therapy.

Serious adverse events and medication errors are common in clinical practice and are associated with significant morbidity and mortality. Management of HIV-positive patients is likely to become more complex as people age, developing multiple medical conditions and thus requiring polypharmacy. We undertook a casenote review and interview of patients on antiretroviral therapy (ART) to audit the safety of devolving statin prescribing to general practitioners (GPs). Of 26 patients only 50% had their statin prescribing successfully been devolved to GPs. Many experienced significant difficulties and two of 26 (8%) were switched to simvastatin while receiving a protease inhibitor. We demonstrate that prescribing ART and non-ART medication by different practitioners on different sites can potentially expose patients to serious life-threatening adverse events. We make recommendations to minimize these risks and suggest that care pathways are reviewed to ensure they remain both convenient and user-friendly without compromising patient safety.