A luminous fast radio burst that probes the Universe at redshift 1.

Fast radio bursts (FRBs) are millisecond-duration pulses of radio emission originating from extragalactic distances. Radio dispersion is imparted on each burst by intervening plasma, mostly located in the intergalactic medium. In this work, we observe the burst FRB 20220610A and localize it to a morphologically complex host galaxy system at redshift 1.016 ± 0.002. The burst redshift and dispersion measure are consistent with passage through a substantial column of plasma in the intergalactic medium and extend the relationship between those quantities measured at lower redshift. The burst shows evidence for passage through additional turbulent magnetized plasma, potentially associated with the host galaxy. We use the burst energy of 2 × 1042 erg to revise the empirical maximum energy of an FRB.

The presence or absence of midsagittal tissue bridges and walking: a retrospective cohort study in spinal cord injury.

STUDY DESIGN: Cohort study. Retrospective analysis of T2-weighted magnetic resonance images (MRIs) and clinical documentation. OBJECTIVES: To evaluate the relationship between the presence/absence and widths of midsagittal tissue bridges and walking ability among veterans with cervical, predominantly chronic SCI. SETTING: University research and hospital setting. METHODS: T2-weighted midsagittal MRIs of 22 United States veterans with cervical spinal cord injuries were examined. The presence/absence of midsagittal tissue bridges were determined, and the widths of present ventral and dorsal tissue bridges were measured. Midsagittal tissue bridge characteristics were related to each participant's ability to walk based off examination of clinical documentation. RESULTS: Fourteen of the analyzed participant images revealed the presence of midsagittal tissue bridges. Ten of those individuals (71%) possessed overground walking ability. The 8 individuals with no apparent tissue bridges were all unable to walk. There was a significant correlation between walking and widths of ventral midsagittal tissue bridges (r = 0.69, 95%CI: 0.52, 0.92, p < 0.001), as well as dorsal midsagittal tissue bridges (r = 0.44, 95%CI: 0.15, 0.73, p = 0.039). CONCLUSION: The evaluation of midsagittal tissue bridges may be useful in various rehabilitation settings to help inform patients' plan of care, allocation of neuromodulatory resources, and appropriate stratification into research cohorts.

A census of baryons in the Universe from localized fast radio bursts.

More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy clusters1,2. Censuses of the nearby Universe have used absorption line spectroscopy3,4 to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas4-6 in denser regions near galaxies7. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses8,9 can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters9,10. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon11-13. We augment the sample of reported arcsecond-localized14-18 fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments11, and we derive a cosmic baryon density of [Formula: see text] (95 per cent confidence; h70 = H0/(70 km s-1 Mpc-1) and H0 is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis19,20.

A single fast radio burst localized to a massive galaxy at cosmological distance.

Fast radio bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Nonrepeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single-pulse FRB 180924 to a position 4 kiloparsecs from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from those of the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.

Short-term changes observed in multiparametric liver MRI following therapy with direct-acting antivirals in chronic hepatitis C virus patients.

METHODS: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). RESULTS: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. CONCLUSION: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. KEY POINTS: • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

A dust-enshrouded tidal disruption event with a resolved radio jet in a galaxy merger.

Tidal disruption events (TDEs) are transient flares produced when a star is ripped apart by the gravitational field of a supermassive black hole (SMBH). We have observed a transient source in the western nucleus of the merging galaxy pair Arp 299 that radiated >1.5 × 1052 erg at infrared and radio wavelengths but was not luminous at optical or x-ray wavelengths. We interpret this as a TDE with much of its emission reradiated at infrared wavelengths by dust. Efficient reprocessing by dense gas and dust may explain the difference between theoretical predictions and observed luminosities of TDEs. The radio observations resolve an expanding and decelerating jet, probing the jet formation and evolution around a SMBH.

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

BACKGROUND: Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. AIM: To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. METHODS: The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. RESULTS: Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). CONCLUSIONS: The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers. RESULTS: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany. CONCLUSIONS: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses.

Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy.

OBJECTIVES: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. METHODS: This was a hospital-based clinical trial (EudraCT 2013-004535-72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. RESULTS: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC48-72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC48-72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours. CONCLUSIONS: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

Prevention of progression to cirrhosis in hepatitis C with fibrosis: effectiveness and cost effectiveness of sequential therapy with new direct-acting anti-virals.

BACKGROUND: The new direct-acting anti-virals (DAAs) for hepatitis C virus (HCV) infection offer higher cure rates, but at a much higher cost than the standard interferon-based treatments. AIM: To identify the cost-effective treatment for patients with HCV infection with F3 liver fibrosis who are at high risk of progression to cirrhosis. METHODS: A decision-analytic Markov model compared the health benefits and costs of all currently licensed treatments as single treatments and in sequential therapy of up to three lines. Costs were expressed in pound sterling from the perspective of the UK National Health Service. Health benefits were expressed in quality-adjusted life years. RESULTS: Treatment before progression to cirrhosis always offers the most health benefits for the least costs. Sequential therapy with multiple treatment lines cures over 89% of patients across all HCV genotypes while ensuring a cost-effective use of resources. Cost-effective regimes for HCV genotype 1 patients include first-line oral therapy with sofosbuvir-ledipasvir while peginterferon continues to have a role in other genotypes. CONCLUSIONS: The cost-effective treatment for HCV can be established using decision analytic modelling comparing single and sequential therapies. Sequential therapy with DAAs is effective and cost-effective in HCV patients with F3 fibrosis. This information is of significant benefit to health care providers with budget limitations and provides a sound scientific basis for drug treatment choices.

Ledipasvir-Sofosbuvir for Treating Chronic Hepatitis C: A NICE Single Technology Appraisal-An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited Gilead, the company manufacturing ledipasvir-sofosbuvir (LDV/SOF), to submit evidence for the clinical effectiveness and cost effectiveness of LDV/SOF for treating chronic hepatitis C. The School of Health and Related Research (ScHARR) Technology Assessment Group was commissioned as the Evidence Review Group (ERG). This paper describes the company's submission (CS), the ERG review and the subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical effectiveness and cost-effectiveness evidence of LDV/SOF based upon the CS. The clinical effectiveness data for LDV/SOF were taken from ten trials: three phase III trials and seven phase II trials. Trials compared different durations of LDV/SOF, with and without ribavirin (RBV). There were no head-to-head trials comparing LDV/SOF with any comparator listed in the NICE scope. Data from the trials were mostly from populations with genotype 1 (GT1) disease, although some limited data were available for populations with genotypes 3 and 4. For GT1 treatment-naïve patients, sustained viral response for 12 weeks (SVR12) rates for LDV/SOF ranged from 93.1 to 99.4 % for subgroups of patients with non-cirrhotic disease, whilst SVR rates of 94.1 to 100 % were reported for subgroups of patients with compensated cirrhosis. For GT1 treatment-experienced patients, SVR12 rates ranging from 95.4 to 100 % were reported for subgroups of non-cirrhotic patients, and SVR rates ranging from 81.8 to 100 % were reported within subgroups of patients with compensated cirrhosis. Comparator data were not searched systematically as part of the submission, but were based on the company's previous NICE submission of sofosbuvir, with additional targeted searches. The ERG's critical appraisal of the company's economic evaluation highlighted a number of concerns. The ERG's base case analyses suggested that the incremental cost-effectiveness ratios (ICERs) for LDV/SOF (+RBV) are dependent on (a) treatment durations, (b) whether patients have been previously treated and (c) whether patients have liver cirrhosis or not. The AC concluded that it was appropriate to use the approach taken in the ERG's exploratory analyses, in line with the marketing authorisation, which considered people with and without cirrhosis separately, and estimated the cost effectiveness for each recommended treatment duration of LDV/SOF.

An audit of prescribing practices for benzodiazepines and Z-drugs.

Concerns persist over the use of benzodiazepines and Z-drugs in Ireland. A prospective prescription audit was conducted in 81 community pharmacies across Ireland over a four week period. The study sought to assess the level of prescription compliance with key components of benzodiazepine and Z-drug prescribing guidelines. 28% of audit booklets issued were returned, yielding data on 4,418 prescriptions. The findings suggest that little progress has been made in improving the prescribing of benzodiazepines and Z-drugs in Ireland in the decade since publication of the Benzodiazepine Committee's report. Fewer than one fifth of prescriptions (18.8%) were fully compliant with the assessment criteria and the majority (53.7%) had multiple discrepancies. This study highlights the importance of monitoring and auditing benzodiazepine and Z-drug prescribing practices. Interventions involving patients, prescribers and pharmacists are required to improve the prescribing and use of these medications in Ireland.

HCV treatment rates and sustained viral response among people who inject drugs in seven UK sites: real world results and modelling of treatment impact.

Hepatitis C virus (HCV) antiviral treatment for people who inject drugs (PWID) could prevent onwards transmission and reduce chronic prevalence. We assessed current PWID treatment rates in seven UK settings and projected the potential impact of current and scaled-up treatment on HCV chronic prevalence. Data on number of PWID treated and sustained viral response rates (SVR) were collected from seven UK settings: Bristol (37-48% HCV chronic prevalence among PWID), East London (37-48%), Manchester (48-56%), Nottingham (37-44%), Plymouth (30-37%), Dundee (20-27%) and North Wales (27-33%). A model of HCV transmission among PWID projected the 10-year impact of (i) current treatment rates and SVR (ii) scale-up with interferon-free direct acting antivirals (IFN-free DAAs) with 90% SVR. Treatment rates varied from <5 to over 25 per 1000 PWID. Pooled intention-to-treat SVR for PWID were 45% genotypes 1/4 [95%CI 33-57%] and 61% genotypes 2/3 [95%CI 47-76%]. Projections of chronic HCV prevalence among PWID after 10 years of current levels of treatment overlapped substantially with current HCV prevalence estimates. Scaling-up treatment to 26/1000 PWID annually (achieved already in two sites) with IFN-free DAAs could achieve an observable absolute reduction in HCV chronic prevalence of at least 15% among PWID in all sites and greater than a halving in chronic HCV in Plymouth, Dundee and North Wales within a decade. Current treatment rates among PWID are unlikely to achieve observable reductions in HCV chronic prevalence over the next 10 years. Achievable scale-up, however, could lead to substantial reductions in HCV chronic prevalence.

Review article: 2014 UK consensus guidelines - hepatitis C management and direct-acting anti-viral therapy.

BACKGROUND: Therapeutic options for the management of hepatitis C virus (HCV) infection have evolved rapidly over the past two decades, with a consequent improvement in cure rates. Novel therapeutic agents are an area of great interest in the research community, with a number of these agents showing promise in the clinical setting. AIMS: To assess and present the available evidence for the use of novel therapeutic agents for the treatment of HCV, updating previous guidelines. METHODS: All Phase 2 and 3 studies, as well as abstract presentations from international Hepatology meetings were identified and reviewed for suitable inclusion, based on studies of new therapies in HCV. Treatment-naïve and experienced individuals, as well as cirrhotic and co-infected individuals were included. RESULTS: Sofosbuvir, simeprevir and faldaprevir, along with pegylated interferon and ribavirin, have a role in the treatment of chronic HCV infection. The precise regimens are largely dependent on the patient characteristics, patient and physician preferences, and cost implication. CONCLUSIONS: Therapies for chronic HCV have evolved dramatically in recent years. Interferon-free regimens are now possible without compromise in the rate of sustained viral response. The decision as to which regimen is most appropriate is multifactorial, and based on efficacy, safety and cost.

Historical epidemiology of hepatitis C virus (HCV) in selected countries.

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Extended duration therapy with pegylated interferon and ribavirin for patients with genotype 3 hepatitis C and advanced fibrosis: final results from the STEPS trial.

BACKGROUND & AIMS: Patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have poor response rates after 24 weeks treatment with pegylated interferon and ribavirin. Treatment for 48 weeks is therefore recommended, although the benefits of this are untested. We examined extended therapy in patients with genotype 3 HCV and advanced fibrosis. METHODS: Multicentre, open labelled randomized trial comparing therapy with 24 weeks pegylated interferon and ribavirin to 48 weeks of the same therapy. RESULTS: 136 patients completed the study. 67 received 24 weeks therapy and the SVR rate (48%) did not differ from that seen in the 69 patients who received 48 weeks therapy (42%). The response rates in patients with biopsy proven cirrhosis (13 patients treated for 24 weeks, 18 patients treated for 48 weeks) or cirrhosis proven on imaging (28 patients treated for 24 weeks and 25 patients treated for 48 weeks) were 46% in those treated for 24 weeks and 40% in those treated for 48 weeks. The differences were not significantly different. Treatment failure was due to relapse in the majority of patients. CONCLUSIONS: Patients with genotype 3 HCV and advanced fibrosis do not benefit from extended therapy with pegylated interferon and ribavirin.

SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis.

BACKGROUND: The principal diagnosis/indication for this assessment is chronic diarrhoea due to bile acid malabsorption (BAM). Diarrhoea can be defined as the abnormal passage of loose or liquid stools more than three times daily and/or a daily stool weight > 200 g per day and is considered to be chronic if it persists for more than 4 weeks. The cause of chronic diarrhoea in adults is often difficult to ascertain and patients may undergo several investigations without a definitive cause being identified. BAM is one of several causes of chronic diarrhoea and results from failure to absorb bile acids (which are required for the absorption of dietary fats and sterols in the intestine) in the distal ileum. OBJECTIVE: For people with chronic diarrhoea with unknown cause and in people with Crohn's disease and chronic diarrhoea with unknown cause (i.e. before resection): (1) What are the effects of selenium-75-homocholic acid taurine (SeHCAT) compared with no SeHCAT in terms of chronic diarrhoea, other health outcomes and costs? (2) What are the effects of bile acid sequestrants (BASs) compared with no BASs in people with a positive or negative SeHCAT test? (3) Does a positive or negative SeHCAT test predict improvement in terms of chronic diarrhoea, other health outcomes and costs? DATA SOURCES: A systematic review was conducted to summarise the evidence on the clinical effectiveness of SeHCAT for the assessment of BAM and the measurement of bile acid pool loss. Search strategies were based on target condition and intervention, as recommended in the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. The following databases were searched up to April 2012: MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; EMBASE; the Cochrane Databases; Database of Abstracts of Reviews of Effects; Health Technology Assessment (HTA) Database; and Science Citation Index. Research registers and conference proceedings were also searched. REVIEW METHODS: Systematic review methods followed the principles outlined in the CRD guidance for undertaking reviews in health care and the National Institute for Health and Care Excellence (NICE) Diagnostic Assessment Programme interim methods statement. In the health economic analysis, the cost-effectiveness of SeHCAT for the assessment of BAM, in patients with chronic diarrhoea, was estimated in two different populations. The first is the population of patients with chronic diarrhoea with unknown cause and symptoms suggestive of diarrhoea-predominant irritable bowel syndrome (IBS-D) and the second population concerns patients with Crohn's disease without ileal resection with chronic diarrhoea. For each population, three models were combined: (1) a short-term decision tree that models the diagnostic pathway and initial response to treatment (first 6 months); (2) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving BAS; and (3) a long-term Markov model that estimates the lifetime costs and effects for patients initially receiving regular treatment (IBS-D treatment in the first population and Crohn's treatment in the second population). Incremental cost-effectiveness ratios were estimated as additional cost per additional responder in the short term (first 6 months) and per additional quality-adjusted life-year (QALY) in the long term (lifetime). RESULTS: We found three studies assessing the relationship between the SeHCAT test and response to treatment with cholestyramine. However, the studies had small numbers of patients with unknown cause chronic diarrhoea, and they used different cut-offs to define BAM. For the short term (first 6 months), when trial of treatment is not considered as a comparator, the optimal choice depends on the willingness to pay for an additional responder. For lower values (between £1500 and £4600) the choice will be no SeHCAT in all scenarios; for higher values either SeHCAT 10% or SeHCAT 15% becomes cost-effective. For the lifetime perspective, the various scenarios showed widely differing results: in the threshold range of £20,000-30,000 per QALY gained we found as optimal choice either no SeHCAT, SeHCAT 5% (only IBS-D) or SeHCAT 15%. When trial of treatment is considered a comparator, the analysis showed that for the short term, trial of treatment is the optimal choice across a range of scenarios. For the lifetime perspective with trial of treatment, again the various scenarios show widely differing results. Depending on the scenario, in the threshold range of £20,000-30,000 per QALY gained, we found as optimal choice either trial of treatment, no SeHCAT or SeHCAT 15%. CONCLUSIONS: In conclusion, the various analyses show that for both populations considerable decision uncertainty exists and that no firm conclusions can be formulated about which strategy is optimal. Standardisation of the definition of a positive SeHCAT test should be the first step in assessing the usefulness of this test. As there is no reference standard for the diagnosis of BAM and SeHCAT testing provides a continuous measure of metabolic function, diagnostic test accuracy (DTA) studies are not the most appropriate study design. However, in studies where all patients are tested with SeHCAT and all patients are treated with BASs, response to treatment can provide a surrogate reference standard; further DTA studies of this type may provide information on the ability of SeHCAT to predict response to BASs. A potentially more informative option would be multivariate regression modelling of treatment response (dependent variable), with SeHCAT result and other candidate clinical predictors as covariates. Such a study design could also inform the definition of a positive SeHCAT result. STUDY REGISTRATION: The study is registered as PROSPERO CRD42012001911. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Tumour vasculature targeting agents in hybrid/conjugate drugs.

Tumour vasculature targeting has been a very active area of cancer drug discovery over the last decade. Growth of solid tumours beyond a certain point requires a sufficient blood supply in order for them to develop and metastasise. While novel anti-angiogenic and vascular disrupting agents represent an important contribution to the armoury of anti-cancer agents they nevertheless usually require combination with standard cytotoxic therapy in order to demonstrate positive clinical outcomes. In line with this consensus, a new concept has arisen, namely the design of functional hybrids where at least one component of the design targets a tumour angiogenic/vasculature pathway. This review will outline examples of such hybrid/conjugate-based approaches. Emphasis will be placed on their preclinical evaluation with particular focus on the RGD/NGR-conjugates, heparin-related hybrids and antibody-drug conjugates. In conclusion, the benefits and shortcomings of hybrids under development will be discussed in the context of future directions and applications.

UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients.

BACKGROUND: The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs. AIMS: To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection. METHODS: These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers. RESULTS: We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients. CONCLUSIONS: These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

Profiling harmful medication errors in an acute Irish teaching hospital.

BACKGROUND: Medication error reporting systems in hospitals are faced with the challenge of processing vast numbers of reports which identify a myriad of safety issues. With such large volumes of data and limited resources it makes sense to adopt a prioritisation approach. Several published studies have focused solely on the subset of errors which cause patient harm. The majority of such research has concerned the individual analysis of criteria associated with medication errors. However, the research described here used an alternative approach which involved linking the three criteria of medication class, patient outcome, and type of error, in order to describe the medication-related scenarios presenting greatest risk to the organisation. AIMS: To identify the highest-priority medication-related risks in an acute teaching hospital. To profile harmful medication errors submitted to a voluntary reporting system in a tertiary healthcare setting in Ireland. METHODS: A database of medication errors, reported via an internal voluntary reporting system over a 5-year period, was analysed. The criteria of medication class, patient outcome and type of error were analysed separately and then cross-tabulated. RESULTS: The medication classes, error types and adverse patient outcomes most frequently associated with harm were identified. The cross-tabulation highlighted ten priority risk areas which accounted for the majority of patient harm. CONCLUSIONS: A cross-tabulation strategy for prioritising medication-associated risks was successfully applied to a hospital database comprising medication errors. The profile developed for harmful medication errors in this acute tertiary healthcare setting was broadly in line with that published for error reporting systems internationally.