Integrating a newly developed BAC-based physical mapping resource for Lolium perenne with a genome-wide association study across a L. perenne European ecotype collection identifies genomic contexts associated with agriculturally important traits.

BACKGROUND AND AIMS: Lolium perenne (perennial ryegrass) is the most widely cultivated forage and amenity grass species in temperate areas worldwide and there is a need to understand the genetic architectures of key agricultural traits and crop characteristics that deliver wider environmental services. Our aim was to identify genomic regions associated with agriculturally important traits by integrating a bacterial artificial chromosome (BAC)-based physical map with a genome-wide association study (GWAS). METHODS: BAC-based physical maps for L. perenne were constructed from ~212 000 high-information-content fingerprints using Fingerprint Contig and Linear Topology Contig software. BAC clones were associated with both BAC-end sequences and a partial minimum tiling path sequence. A panel of 716 L. perenne diploid genotypes from 90 European accessions was assessed in the field over 2 years, and genotyped using a Lolium Infinium SNP array. The GWAS was carried out using a linear mixed model implemented in TASSEL, and extended genomic regions associated with significant markers were identified through integration with the physical map. KEY RESULTS: Between ~3600 and 7500 physical map contigs were derived, depending on the software and probability thresholds used, and integrated with ~35 k sequenced BAC clones to develop a resource predicted to span the majority of the L. perenne genome. From the GWAS, eight different loci were significantly associated with heading date, plant width, plant biomass and water-soluble carbohydrate accumulation, seven of which could be associated with physical map contigs. This allowed the identification of a number of candidate genes. CONCLUSIONS: Combining the physical mapping resource with the GWAS has allowed us to extend the search for candidate genes across larger regions of the L. perenne genome and identified a number of interesting gene model annotations. These physical maps will aid in validating future sequence-based assemblies of the L. perenne genome.

Comparison of biomechanical characteristics between male and female elite fast bowlers.

This study investigated ball release speed and performance kinematics between elite male and female cricket fast bowlers. Fifty-five kinematic parameters were collected for 20 male and 20 female elite fast bowlers. Group means were analysed statistically using an independent samples approach to identify differences. Significant differences were found between: ball release speed; run-up speed; the kinematics at back foot contact (BFC), front foot contact (FFC), and ball release (BR); and the timings between these key instants. These results indicate that the female bowlers generated less whole body linear momentum during the run-up than the males. The male bowlers also utilised a technique between BFC and FFC which more efficiently maintained linear momentum compared to the females. As a consequence of this difference in linear momentum at FFC, the females typically adopted a technique more akin to throwing where ball release speed was contributed to by both the whole body angular momentum and the large rotator muscles used to rotate the pelvis and torso segments about the longitudinal axis. This knowledge is likely to be useful in the coaching of female fast bowlers although future studies are required to understand the effects of anthropometric and strength constraints on fast bowling performance.

Cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as an add-on to Metformin in the Treatment of Type 2 Diabetes Mellitus from a UK Healthcare System Perspective.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic, progressive condition where the primary treatment goal is to maintain control of glycated haemoglobin (HbA1c). In order for healthcare decision makers to ensure patients receive the highest standard of care within the available budget, the clinical benefits of each treatment option must be balanced against the economic consequences. The aim of this study was to assess the cost-effectiveness of dapagliflozin, the first-in-class sodium-glucose co-transporter 2 (SGLT2) inhibitor, compared with a dipeptidyl peptidase-4 inhibitor (DPP-4i), when added to metformin for the treatment of patients with T2DM inadequately controlled on metformin alone. METHODS: The previously published and validated Cardiff diabetes model was used as the basis for this economic evaluation, with treatment effect parameters sourced from a systematic review and network meta-analysis. Costs, derived from a UK healthcare system perspective, and quality-adjusted life years (QALYs), were used to present the final outcome as an incremental cost-effectiveness ratio (ICER) over a lifetime horizon. Univariate and probabilistic sensitivity analyses (PSA) were carried out to assess uncertainty in the model results. RESULTS: Compared with DPP-4i, dapagliflozin was associated with a mean incremental benefit of 0.032 QALYs (95% confidence interval [CI]: -0.022, 0.140) and with an incremental cost of £216 (95% CI: £-258, £795). This resulted in an ICER point estimate of £6,761 per QALY gained. Sensitivity analysis determined incremental costs to be insensitive to variation in most parameters, with only the treatment effect on weight having a notable impact on the incremental QALYs; however, there were no scenarios which raised the ICER above £15,000 per QALY. The PSA estimated that dapagliflozin had an 85% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option from a UK healthcare system perspective for patients with T2DM who are inadequately controlled on metformin alone.

The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus.

AIMS: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. METHODS: Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. RESULTS: The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy.

Living with osteoarthritis: a systematic review and meta-ethnography.

OBJECTIVES: To review and synthesize the existing literature on the experience of living with a diagnosis of hip and/or knee osteoarthritis (OA). METHOD: A systematic review was undertaken using meta-ethnography. A search of both published (AMED, CINAHL, EMBASE, PsychINFO, SportsDisc, MEDLINE, Cochrane Clinical Trials Registry, PubMed) and unpublished/trial registry databases [World Health Organization (WHO) International Clinical Trials Registry Platform, Current Controlled Trials, the United States National Institute of Health Trials Registry, National Institute for Health Research (NIHR) Clinical Research Portfolio Database] was undertaken from their inception to 5 June 2013. RESULTS: Thirty-two studies formed the meta-ethnography of the lived experiences of people with OA. In total, 1643 people with OA were sampled, the majority diagnosed with knee OA. The evidence base was weak to moderate in quality. The majority of studies indicated that people viewed living with OA negatively. Four key factors influenced their attitudes to the condition: the severity of their symptoms; the impact of these symptoms on their functional capability; their attitude towards understanding their disease; and their perceptions of other people's beliefs towards their disease. CONCLUSIONS: The current literature suggests that greater knowledge of the pathology of OA, management of symptoms, promotion of functional activity for patients and their family/friends networks, and understanding to better inform OA patient's role in society are all important elements that affect a person's attitude to OA. By better understanding these factors during future consultations, clinicians may forge stronger relationships with their patients to more effectively manage this long-term disabling condition.

Muon-spin rotation measurements of an unusual vortex-glass phase in the layered superconductor Bi2.15Sr1.85CaCu2O8+δ.

Muon-spin rotation measurements, performed on the mixed state of the classic anisotropic superconductor Bi(2.15)Sr(1.85)CaCu(2)O(8+δ), obtain quantities directly related to two- and three-body correlations of vortices in space. A novel phase diagram emerges from such local probe measurements of the bulk, revealing an unusual glassy state at intermediate fields which appears to freeze continuously from the equilibrium vortex liquid but differs both from the lattice and the conventional high-field vortex glass state in its structure.

Rehabilitation implications during the development of the Norwich Enhanced Recovery Programme (NERP) for patients following total knee and total hip arthroplasty.

BACKGROUND/HYPOTHESIS: To report the analysis of the initial rehabilitation results of the Norwich Enhanced Recovery Programme (NERP), regime with increased post-operative physiotherapy input following total hip arthroplasty (THA) and total knee arthroplasty (TKA) performed under spinal anaesthetic with wound catheter infiltration. MATERIALS AND METHODS: A secondary analysis of a service improvement programme was undertaken from an acute National Health Service Hospital in the United Kingdom. Ninety-five patients listed for THA (n=67) or TKA (n=28) were reviewed during the first six post-operative weeks. All received an enhanced post-operative programme including commencement of mobilisation four hours post-operatively and physiotherapy interventions a minimum of twice daily during hospital admission. The primary outcome measure was the Iowa Level of Assistance Score at discharge. Secondary outcomes included length of hospital stay (LOS), visual analogue scale pain at discharge and complications during the initial six post-operative weeks. RESULTS: The NERP is a successful rehabilitation regime for patients following THA and TKA, facilitating early safe discharge (mean LOS=3.5 days) with minimal complications. Patients who commenced mobilisation on the day of the operation reported significantly reduced pain score (p=0.02) and length of stay (p<0.01) compared to those who did not. Thirty-four percent of patients were discharged with rollator frames. CONCLUSIONS: Whilst the early results of the NERP allow patients who have undergone THA or TKA surgery a short hospital length of stay, its demand on out-reach physiotherapy suggests that the availability of such community services is imperative to ensure the appropriate progression of rehabilitation. LEVEL OF EVIDENCE: Level IV - retrospective series.

Ground reaction force analysis of unilateral coxofemoral denervation for the treatment of canine hip dysplasia.

Coxofemoral denervation has success rates of 90-96% reported retrospectively for palliative treatment of hip dysplasia. The aim of this study was to objectively evaluate ground reaction forces (GRF) in dysplastic dogs after unilateral denervation. Unilateral coxofemoral denervation was performed by means of a previously reported technique on 10 dogs with asymmetric gait. GRF were measured at zero, one and three months. Statistical analysis was performed using repeated measures analysis of variance and paired t-tests, with p< or =0.05. There was a lack of significant difference in mean peak vertical force (PVF) or vertical impulse (VI) in the operated limb (TX) over time. For the unoperated limb (UnTX), mean PVF and VI significantly decreased over time. The dogs were significantly more lame in the TX limb initially and at one month, however, there was no significant difference between limbs by three months. In the UnTX limb, 40% of dogs decreased PVF by >5%, by three months. Over time, there was no significant difference in mean average rise or mean average fall for TX or UnTX limbs. Between limbs, mean rise in the TX limb was significantly less at zero months, but not at one or three months. Decreased compensatory load shifting to the UnTX limb due to procedural efficacy could explain decreases in the UnTX limb. Worsening disease could also explain decreases in the UnTX limb, and may indicate a protective effect denoted by a lack of change in the TX limb. Longer follow-up would be required in improved dogs in order to document continued efficacy.

Gastroprotection in patients prescribed non-selective NSAIDs, and the risk of related hospitalization.

OBJECTIVE: To assess co-prescription of gastroprotective agents (GPAs) for non-selective NSAID (nsNSAID)-treated patients in UK primary care, and the rate of gastrointestinal (GI)-related hospitalizations occurring with varying levels of GPA use in patients at high Gl risk. RESEARCH DESIGN AND METHODS: A retrospective, observational study was conducted using the DIN-LINK UK primary care database, on patients prescribed nsNSAIDs alone or concomitantly with GPAs between September 2003 and August 2005. Patients were stratified by GI risk, frequency of nsNSAID use and level of GPA use. Rates and odds ratios of GI-related hospitalizations were calculated for high GI-risk patients. RESULTS: In August 2005, 26 371 patients with nsNSAID prescriptions were identified, of whom 55% were frequent users. In the overall and frequent nsNSAID-user populations, 74% and 71%, respectively, were co-prescribed none or few GPAs (0-19% level of use), and only 18% and 20%, respectively, received complete gastroprotection. GI risk factors were identified in 76% of all patients. Overall, 70% of patients with serious co-morbidity, 44% with GI event history, and 56% of aspirin users received little or no gastroprotection (0-19%). Data for previous months of the analysis period were similar. In patients with a GI-event history, based on data over the 2-year study period, hospitalization rates ranged from 2.4% (with full gastroprotection) to 8.0% (20-39% GPA use). Odds of a GI-related hospitalization were up to 3.5 times higher with low GPA use. CONCLUSION: This study revealed low levels of GPA co-prescription for nsNSAID users in UK primary care, even among high-risk patients. Lower levels of GPA co-therapy were associated with increasing rates of GI-related hospitalization.

Digital measurement of radiographic tibial plateau angle. A comparison to measurement on printed digital images.

Pre-operative digital radiographs from 50 dogs undergoing a tibial plateau leveling osteotomy were evaluated. Tibial plateau angles were measured directly on printed films and measured on digital images using two different commercial DICOM viewers. The radiographs were scored for osteoarthritis and positioning. Using pooled results, the mean TPA from the digital images employing Web1000 (26.47 degrees +/- 3.90) was significantly higher then the mean TPA using film radiographs (25.41 degrees +/- 3.51), or IQ-View Pro (25.48 degrees +/- 3.89). There was not a significant difference between mean TPA using radiographs or IQ-view. Digital TPA measurement using built-in angle calipers in the clinical setting is a valid technique compared to measurements from film radiographs, and produces reproducible results. However, before changing to digital measurements, the chosen software programme should be validated against measurements using film radiographs to determine the magnitude of differences.

Formation of a nematic fluid at high fields in Sr3Ru2O7.

In principle, a complex assembly of strongly interacting electrons can self-organize into a wide variety of collective states, but relatively few such states have been identified in practice. We report that, in the close vicinity of a metamagnetic quantum critical point, high-purity strontium ruthenate Sr3Ru2O7 possesses a large magnetoresistive anisotropy, consistent with the existence of an electronic nematic fluid. We discuss a striking phenomenological similarity between our observations and those made in high-purity two-dimensional electron fluids in gallium arsenide devices.

Coupled magnetic excitations in single crystal PrBa(2)Cu(3)O(6.2).

The dispersion of the low-energy magnetic excitations of the Pr sublattice in PrBa(2)Cu(3)O(6.2) is determined by inelastic neutron scattering measurements on a single crystal. The dispersion, which shows the effect of interactions with the Cu spin waves, is well described by a model of the coupled Cu-Pr magnetic system. This model enables values for the principal exchange constants to be determined. The results suggest that both Pr-Pr and Cu-Pr interactions are important in producing the anomalously high ordering temperature of the Pr sublattice. Measurements of the Cu optic spin wave mode show that the interlayer Cu-Cu exchange is significantly lower than in YBa(2)Cu(3)O(6.2).

Potential utilisation of sewage sludge and paper mill waste for biosorption of metals from polluted waterways.

The adsorption of cadmium, copper(II), lead and zinc ions from aqueous solution by sewage sludge, paper mill waste (PMW) and composted PMW was investigated along with the influence of pre-treatment on composted PMW. Langmuir adsorption isotherms were fitted where appropriate. Sewage sludge was the most effective biosorbent of the waste products for all metal ions examined, adsorbing, for example, up to 39.3 mg/g of Pb at an initial concentration of 77.8 mg/l. PMW was a less effective biosorbent than sewage sludge. However, it was found that composting the PMW resulted in an increase in metal uptake capacity and both sewage sludge and composted PMW have potential for low-cost remediation of high leachate wastewaters. The desorption of metal ions from PMW compost was most effective using 0.1 N H2SO4 and 1 mM nitrilotriacetic acid (NTA).

Localized 4f states and dynamic Jahn-Teller effect in PrO2.

Neutron spectroscopic measurements of the magnetic excitations in PrO2 reveal (1) sharp peaks characteristic of transitions between levels of the 4f(1) configuration of Pr4+ split by the cubic crystal field, and (2) broad bands of scattering centered near 30 and 160 meV. We present a simple model based on a vibronic Hamiltonian that accounts for these contrasting features of the data. The analysis shows that 90%+/-10% of the Pr ions have a localized 4f(1) configuration and provides strong evidence for a dynamic Jahn-Teller effect in the gamma(8) electronic ground state.

'Scaling-up' in emergencies: British NGOs after Hurricane Mitch.

This article examines research on NGO 'scaling-up' in a disaster context and links it to a broader discussion on whether scaling-up is a useful concept for understanding NGO processes in an emergency. Using concepts of scaling-up from development literature, research findings from a study of the responses of British NGOs to Hurricane Mitch in Central America are presented. The article assesses the extent and type of scaling-up that occurred, constraints faced by the agencies and the impact of scaling-up on support to partners. Broader issues relating to scaling-up post-Mitch are also explored. The conclusion suggests that while the concept of scaling-up is useful, the tendency for its use to refer to organisational growth has limited a wider understanding and evaluation of the role of Northern NGOs in humanitarian crises.

Serological approaches to subtyping of HIV-1 in injecting drug users in Russia: evidence of subtype homogeneity at the main sites of the epidemic.

The aim of this study was to develop and evaluate a simple V3 peptide-based enzyme immunoassay (PEIA) for large-scale serotyping of HIV-1 specimens derived from injecting drug users (IDUs) in the Russian Federation. Two synthetic peptides were evaluated, named P1 (RKSIHIGPGRAFYATGD) and P2 (RTSVRIGPGQVFYKTGD), in an PEIA on 63 HIV-1 IDUs sera for which genotypes had been determined by heteroduplex mobility assay (HMA) and sequencing. The sensitivities of P1 (subtype B) and P2 (subtype A) were 87% and 75% respectively. Specificity of the assay was 100% for both peptides, with 100% predictive values of a monoreactive positive test for both peptides. Using the PEIA with peptides P1 and P2, we have serotyped 375 of 477 serum samples derived from IDUs in 4 main sites of the HIV-1 epidemic in Russia. The results demonstrated a high level of subtype homogeneity in all regions studied. In 3 of 4 territories, Tver' (n=345), and Rostov-on-Don (n=61) regions, and Krasnodar Kray (n=27), 100% of typable sera were found to belong to env subtype A. On the other hand, all specimens serotyped in the Kaliningrad region (n=38) belonged to env subtype B, and there is strong evidence that the recombinant gagAenvB virus which has caused the largest outbreak of HIV-1 in Russia is located in this region. At the present time another parental strain with gagBenvB genotype is of minor importance in the IDUs HIV-1 epidemic in Russia.

February asthma outbreaks in NSW: a case control study.

OBJECTIVES: To investigate individual factors associated with an asthma outbreak among children aged one to 14 years in Sydney in February 1999. METHODS: A case control study was undertaken with cases (n=92) defined as all children admitted to Sydney Children's Hospital for asthma in February 1999. Unmatched controls (n=76) were all children admitted for asthma in the previous three months. We obtained information by a structured telephone survey of parents. Logistic regression analyses were used to determine odds ratios for risk factors for hospital admission. RESULTS: Mean age for hospital admission of 4.7 years for cases and 4.4 years for controls. The presence of one or more siblings reduced the risk of admission during an asthma outbreak (OR=0.59, 95% CI 0.37 to 0.93). Children with older siblings aged 10 to 14 years were also less likely to be admitted (OR=0.3, 95% CI 0.12 to 0.74). An age effect was observed. Other demographic, clinical and environmental characteristics, including smoking, were not associated with admission during the outbreak. CONCLUSIONS: The main findings of this study are the protective effect of siblings and an age-dependent effect in risk of hospital admission during an asthma outbreak. These findings are consistent with an infective cause of the outbreak. IMPLICATIONS: Children without siblings, particularly older siblings, appear to be at highest risk of hospital admission during an asthma outbreak. Environmental and other factors need to be examined to further explain the episodicity of such outbreaks and to determine means of predicting and preventing future episodes.

The pharmacology of latent inhibition as an animal model of schizophrenia.

The nature of the primary symptoms of schizophrenia and our lack of knowledge of its underlying cause both contribute to the difficulty of generating convincing animal models of schizophrenia. A more recent approach to investigating the biological basis of schizophrenia has been to use information processing models of the disease to link psychotic phenomena to their neural basis. Schizophrenics are impaired in a number of experimental cognitive tasks that support this approach, including sensory gating tasks and models of selective attention such as latent inhibition (LI). LI refers to a process in which noncontingent presentation of a stimulus attenuates its ability to enter into subsequent associations, and it has received much attention because it is widely considered to relate to the cognitive abnormalities that characterise acute schizophrenia. Several claims have been made for LI having face and construct validity for schizophrenia. In this review of the pharmacological studies carried out with LI we examine its claim to predictive validity and the role of methodological considerations in drug effects. The data reviewed demonstrate that facilitation of low levels of LI is strongly related to demonstrated antipsychotic activity in man and all major antipsychotic drugs, both typical and atypical, have been shown to potentiate LI using a variety of protocols. Very few compounds without antipsychotic activity are active in this model. In contrast, disruption of LI occurs with a wide range of drugs and the relationship with psychotomimetic potential is less clear. Although reversal of disrupted LI has also been used as a model for antipsychotic acticity, mostly using amphetamine-induced disruption, insufficient studies have been carried out to evaluate its claim to predictive validity. However, like facilitation, it is sensitive to both typical and atypical antipsychotic agents. The data we have reviewed here demonstrate that facilitation of LI and, perhaps to a lesser extent, reversal of disrupted LI fulfil the criteria for predictive validity.