Economic Evaluation alongside a Randomised Controlled Crossover Trial of Modified Group Cognitive Behavioural Therapy for Anxiety Compared to Treatment-as-Usual in Adults with Asperger Syndrome

Background: There is a growing interest in using group cognitive behavioural therapy (CBT) with people who have Asperger Syndrome (AS) and comorbid mental health problems. This study aims to assess the cost-effectiveness of modified group CBT for adults with AS experiencing co-occurring anxiety compared to treatment-as-usual. Methods: Economic evaluation alongside a pilot, multi-centre, single-blind, randomised controlled trial. Costs from the UK public sector (National Health Service and Social Services) and societal perspectives, quality-adjusted life-years (QALYs), incremental net (monetary) benefit (INB), expected value of perfect information, expected value of sample information, expected net gain of sampling, and efficient sample size of a future trial are reported. Results: Over 48 weeks, from the societal perspective, CBT results in additional costs of £6647, with only a 0.015 gain in QALYs, leading to a negative INB estimate of £6206 and a 23% probability of cost-effectiveness at a threshold of £30,000/QALY. Results from sensitivity analyses support the unlikely cost-effectiveness of CBT, but indicate the potential for cost-effectiveness over longer time horizons. Eliminating decision uncertainty is valued at £277 million and the efficient sample size for a future trial is estimated at 1,200 participants per arm. Limitations: Relatively small sample size and prevalence of missing data present challenges to the interpretation of the results. Conclusions: Current evidence from this small pilot study suggests that on average, modified group CBT is not cost-effective. However, there is much decision uncertainty so such a conclusion could be wrong. A large, full scale trial to reduce uncertainty would be an efficient investment for the UK health economy

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Oral Treatment with Cu[superscript II](atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper[superscript II] [Cu[superscript II](atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu[superscript II](atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched ⁶⁵Cu[superscript II](atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu[superscript II](atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu[superscript II](atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu[superscript II](atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by the Society for Neuroscience. The published article can be found at: http://www.jneurosci.org/

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer

BACKGROUND The comparative effectiveness of treatments for prostate cancer that is detected by prostatespecific antigen (PSA) testing remains uncertain. METHODS We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P = 0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P = 0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P = 0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.) a bs tr ac

Review of Kaon Physics at CERN and in Europe

The Kaon physics program at CERN and in Europe will be presented. I will first give a short review of recent results form the NA48/2 and NA62 experiments, with special emphasis to the measurement of RK , the ratio of Kaon leptonic decays rates, K → eν and K → μν, using the full minimum bias data sample collected in 2007-2008. The main subject of the talk will be the study of the highly suppressed decay K → πνν. While its rate can be predicted with minimal theoretical uncertainty in the Standard Model (BR ∼ 8 × 10−11), the smallness of BR and the challenging experimental signature make it very difficult to measure. The branching ratio for this decay is thus a sensitive probe of the flavour sector of the SM. The aim of NA62 is the measurement of the K → πνν BR with ∼ 10% precision in two years of data taking. This will require the observation of 10K decays in the experiment's fiducial volume, as well as the use of high-performance systems for precision tracking, particle identification, and photon vetoing. These aspects of the experiment will also allow NA62 to carry out a rich program of searches for lepton flavour and/or number violating K decays. Data taking will start in October 2014. The physics prospects and the status of the construction and commissioning of the NA62 experiment will be presented. In the last part of the talk I will report on Kaon physics results and prospects from other experiments at CERN (e.g. LHCb) and in Europe (e.g. KLOE and KLOE-2) and briefly mention the status in US

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Rollover of apparent wave attenuation in ice covered seas

Wave attenuation from two field experiments in the ice‐covered Southern Ocean is examined. Instead of monotonically increasing with shorter waves, the measured apparent attenuation rate peaks at an intermediate wave period. This “rollover” phenomenon has been postulated as the result of wind input and nonlinear energy transfer between wave frequencies. Using WAVEWATCH III®, we first validate the model results with available buoy data, then use the model data to analyze the apparent wave attenuation. With the choice of source parameterizations used in this study, it is shown that rollover of the apparent attenuation exists when wind input and nonlinear transfer are present, independent of the different wave attenuation models used. The period of rollover increases with increasing distance between buoys. Furthermore, the apparent attenuation for shorter waves drops with increasing separation between buoys or increasing wind input. These phenomena are direct consequences of the wind input and nonlinear energy transfer, which offset the damping caused by the intervening ice.MOE (Min. of Education, S’pore)Published versio