Cost-effectiveness of the Manchester approach to identifying Lynch syndrome in women with endometrial cancer

This is the final version. Available on open access from MDPI via the DOI in this recordLynch syndrome (LS) is a hereditary cancer syndrome responsible for 3% of all endometrial cancer and 5% in those aged under 70 years. It is unclear whether universal testing for LS in endometrial cancer patients would be cost-effective. The Manchester approach to identifying LS in endometrial cancer patients uses immunohistochemistry (IHC) to detect mismatch repair (MMR) deficiency, incorporates testing for MLH1 promoter hypermethylation, and genetic testing for pathogenic MMR variants. We aimed to assess the cost-effectiveness of the Manchester approach based on primary research data from clinical practice in Manchester. The PETALS study informed estimates of diagnostic performances for a number of different strategies. A recent microcosting study was adapted and used to estimate diagnostic costs. A Markov model was used to predict long-term costs and health outcomes (measured in quality-adjusted life years, QALYs) for individuals and their relatives. Bootstrapping and probabilistic sensitivity analysis were used to estimate the uncertainty in cost-effectiveness. The Manchester approach dominated other reflex testing strategies when considering diagnostic costs and Lynch syndrome cases identified. When considering long-term costs and QALYs the Manchester approach was the optimal strategy, costing £5459 per QALY gained (compared to thresholds of £20,000 to £30,000 per QALY commonly used in the NHS). Cost-effectiveness is not an argument for restricting testing to younger patients or those with a strong family history. Universal testing for Lynch syndrome in endometrial cancer patients is expected to be cost-effective in the UK NHS, and the Manchester approach is expected to be the optimal testing strategy.Medical Research Council (MRC)National Institute for Health Research (NIHR

Cyclic hypoxia exposure accelerates the progression of amoebic gill disease

Amoebic gill disease (AGD), caused by the amoeba Neoparamoeba perurans, has led to considerable economic losses in every major Atlantic salmon producing country, and is increasing in frequency. The most serious infections occur during summer and autumn, when temperatures are high and poor dissolved oxygen (DO) conditions are most common. Here, we tested if exposure to cyclic hypoxia at DO saturations of 40–60% altered the course of infection with N. perurans compared to normoxic controls maintained at ≥90% DO saturation. Although hypoxia exposure did not increase initial susceptibility to N. perurans, it accelerated progression of the disease. By 7 days post-inoculation, amoeba counts estimated from qPCR analysis were 1.7 times higher in the hypoxic treatment than in normoxic controls, and cumulative mortalities were twice as high (16 ± 4% and 8 ± 2%), respectively. At 10 days post-inoculation, however, there were no differences between amoeba counts in the hypoxic and normoxic treatments, nor in the percentage of filaments with AGD lesions (control = 74 ± 2.8%, hypoxic = 69 ± 3.3%), or number of lamellae per lesion (control = 30 ± 0.9%, hypoxic = 27.9 ± 0.9%) as determined by histological examination. Cumulative mortalities at the termination of the experiment were similarly high in both treatments (hypoxic = 60 ± 2%, normoxic = 53 ± 11%). These results reveal that exposure to cyclic hypoxia in a diel pattern, equivalent to what salmon are exposed to in marine aquaculture cages, accelerated the progression of AGD in post-smolts

A randomized controlled trial of a passive accessory joint mobilization on acute ankle inversion sprains

AbstractBackground and Purpose. Passive joint mobilization is commonly used by physical therapists as an intervention for acute ankle inversion sprains. A randomized controlled trial with blinded assessors was conducted to investigate the effect of a specific joint mobilization, the anteroposterior glide on the talus, on increasing pain-free dorsiflexion and 3 gait variables: stride speed (gait speed), step length, and single support time. Subjects. Forty-one subjects with acute ankle inversion sprains (&amp;lt;72 hours) and no other injury to the lower limb entered the trial. Methods. Subjects were randomly assigned to 1 of 2 treatment groups. The control group received a protocol of rest, ice, compression, and elevation (RICE). The experimental group received the anteroposterior mobilization, using a force that avoided incurring any increase in pain, in addition to the RICE protocol. Subjects in both groups were treated every second day for a maximum of 2 weeks or until the discharge criteria were met, and all subjects were given a home program of continued RICE application. Outcomes were measured before and after each treatment. Results. The results showed that the experimental group required fewer treatment sessions than the control group to achieve full pain-free dorsiflexion. The experimental group had greater improvement in range of movement before and after each of the first 3 treatment sessions. The experimental group also had greater increases in stride speed during the first and third treatment sessions. Discussion and Conclusion. Addition of a talocrural mobilization to the RICE protocol in the management of ankle inversion injuries necessitated fewer treatments to achieve pain-free dorsiflexion and to improve stride speed more than RICE alone. Improvement in step length symmetry and single support time was similar in both groups.</jats:p

Tincurrin : a new biscuit wheat

Although a demand has existed both locally and overseas for soft wheat suitable for biscuits, cakes and various confectioneries, production has been very limited. In 1978 farmers in the soft wheat area will be able to grow the higher yielding variety Tincurrin. It is recommended for general sowing to replace all varieties grown at present in the soft wheat areas as defined.Exceptions may prevail in areas prone to rust snd septoria problems

Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

BackgroundDuchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy.Methods and resultsSSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix.ConclusionsSSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy

Climatic controls on diffuse groundwater recharge across Australia

Reviews of field studies of groundwater recharge have attempted to investigate how climate characteristics control recharge, but due to a lack of data have not been able to draw any strong conclusions beyond that rainfall is the major determinant. This study has used numerical modelling for a range of Köppen-Geiger climate types (tropical, arid and temperate) to investigate the effect of climate variables on recharge for different soil and vegetation types. For the majority of climate types, the correlation between the modelled recharge and total annual rainfall is weaker than the correlation between recharge and the annual rainfall parameters reflecting rainfall intensity. Under similar soil and vegetation conditions for the same annual rainfall, annual recharge in regions with winter-dominated rainfall is greater than in regions with summer-dominated rainfall. The importance of climate parameters other than rainfall in recharge estimation is highest in the tropical climate type. Mean annual values of solar radiation and vapour pressure deficit show a greater importance in recharge estimation than mean annual values of the daily mean temperature. Climate parameters have the lowest relative importance in recharge estimation in the arid climate type (with cold winters) and the temperate climate type. For 75% of all soil, vegetation and climate types investigated, recharge elasticity varies between 2 and 4 indicating a 20% to 40% change in recharge for a 10% change in annual rainfall. Understanding how climate controls recharge under the observed historical climate allows more informed choices of analogue sites if they are to be used for climate change impact assessments

Quantitative immuno-mass spectrometry imaging of skeletal muscle dystrophin

Emerging and promising therapeutic interventions for Duchenne muscular dystrophy (DMD) are confounded by the challenges of quantifying dystrophin. Current approaches have poor precision, require large amounts of tissue, and are difficult to standardize. This paper presents an immuno-mass spectrometry imaging method using gadolinium (Gd)-labeled anti-dystrophin antibodies and laser ablation-inductively coupled plasma-mass spectrometry to simultaneously quantify and localize dystrophin in muscle sections. Gd is quantified as a proxy for the relative expression of dystrophin and was validated in murine and human skeletal muscle sections following k-means clustering segmentation, before application to DMD patients with different gene mutations where dystrophin expression was measured up to 100 µg kg−1 Gd. These results demonstrate that immuno-mass spectrometry imaging is a viable approach for pre-clinical to clinical research in DMD. It rapidly quantified relative dystrophin in single tissue sections, efficiently used valuable patient resources, and may provide information on drug efficacy for clinical translation

Response Inhibition and ADHD Traits: Correlates and Heritability in a Community Sample

Endophenotypes or intermediate phenotypes are of great interest in neuropsychiatric genetics because of their potential for facilitating gene discovery. We evaluated response inhibition, latency and variability measures derived from the stop task as endophenotypes of ADHD by testing whether they were related to ADHD traits in the general population, heritable and shared genetic risk with ADHD traits. Participants were 16,099 children and adolescents, ages 6 to 18æyears who visited a local science center. We measured ADHD traits using the Strengths and Weaknesses of ADHD-symptoms and Normal-Behavior (SWAN) rating scale and performance on the stop signal task (SST)?response inhibition (SSRT), response latency (GoRT), and response variability (GoRTSD). Regression analysis was used to assess the relationship of cognitive measures and ADHD traits while controlling for family, age, sex, ethnicity, socioeconomic status and treatment status. Heritability of ADHD and cognitive traits was estimated using SOLAR in 7,483 siblings from 3,507 families that included multiple siblings. Bivariate relationships between pairs of variables were examined. Individuals with greater ADHD trait scores had worse response inhibition, slower response latency, and greater variability. Younger participants and girls had inferior performance although the gender effects were minimal and evident in youngest participants. Inhibition, latency, variability, total ADHD traits, inattention and hyperactivity-impulsivity scores were significantly heritable. ADHD traits and inhibition, but not latency or variability were coheritable. In the largest study in the general population, we found support for the validity of response inhibition as an endophenotype of ADHD. Electronic supplementary material The online version of this article (doi:10.1007/s10802-012-9693-9) contains supplementary material, which is available to authorized users