Initial Results of a Silicon Sensor Irradiation Study for ILC Extreme Forward Calorimetry

Detectors proposed for the International Linear Collider (ILC) incorporate a tungsten sampling calorimeter (`BeamCal') intended to reconstruct showers of electrons, positrons and photons that emerge from the interaction point of the collider with angles between 5 and 50 milliradians. For the innermost radius of this calorimeter, radiation doses at shower-max are expected to reach 100 MRad per year, primarily due to minimum-ionizing electrons and positrons that arise in the induced electromagnetic showers of e+e- `beamstrahlung' pairs produced in the ILC beam-beam interaction. However, radiation damage to calorimeter sensors may be dominated by hadrons induced by nuclear interactions of shower photons, which are much more likely to contribute to the non-ionizing energy loss that has been observed to damage sensors exposed to hadronic radiation. We report here on the results of SLAC Experiment T-506, for which several different types of silicon diode sensors were exposed to doses of radiation induced by showering electrons of energy 3.5-10.6 GeV. By embedding the sensor under irradiation within a tungsten radiator, the exposure incorporated hadronic species that would potentially contribute to the degradation of a sensor mounted in a precision sampling calorimeter. Depending on sensor technology, efficient charge collection was observed for doses as large as 220 MRad.Comment: Talk presented at the International Workshop on Future Linear Colliders (LCWS13), Tokyo, Japan, 11-15 November 201

Prognostic factors for chronic headache: A systematic review

OBJECTIVE: To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache. METHODS: This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists. RESULTS: We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review-17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features. CONCLUSIONS: This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache

Assessment of the molecular mechanisms of action of novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one allosteric modulators at the M1 muscarinic acetylcholine receptors

Positive allosteric modulators (PAMs) that target the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) are potential treatments for cognitive deficits in conditions such as Alzheimer's disease and schizophrenia. We recently reported novel 4-phenylpyridine-2-one and 6-phenylpyrimidin-4-one M1 mAChR PAMs with the potential to display different modes of positive allosteric modulation and/or agonism (Mistry et al., 2016), but their molecular mechanisms of action remain undetermined. The current study compared the pharmacology of three such novel PAMs with the prototypical first-generation PAM, BQCA, in a recombinant Chinese hamster ovary (CHO) cell line stably expressing the human M1 mAChR. Interactions between the orthosteric agonists and the novel PAMs or BQCA suggested their allosteric effects were solely governed by modulation of agonist affinity. The greatest degree of positive co-operativity was observed with higher efficacy agonists, whereas minimal potentiation was observed when the modulators were tested against the lower efficacy agonist, xanomeline. Each PAM was investigated for its effects on the endogenous agonist, ACh, on three different signalling pathways, (ERK1/2 phosphorylation, IP1 accumulation and β-arrestin-2 recruitment), revealing that the allosteric potentiation generally tracked with the efficiency of stimulus-response coupling and that there was little pathway bias in the allosteric effects. Thus, despite the identification of novel allosteric scaffolds targeting the M1 mAChR, the molecular mechanism of action of these compounds is largely consistent with a model of allostery previously described for BQCA, suggesting that this may be a more generalized mechanism for M1 mAChR PAM effects than previously appreciated

Non-pharmacological self-management for people living with migraine or tension-type headache:a systematic review including analysis of intervention components

ObjectivesTo assess the effect of non-pharmacological self-management interventions against usual care, and to explore different components and delivery methods within those interventionsParticipantsPeople living with migraine and/or tension-type headacheInterventionsNon-pharmacological educational or psychological self-management interventions; excluding biofeedback and physical therapy. We assessed the overall effectiveness against usual care on headache frequency, pain intensity, mood, headache related disability, quality of life, and medication consumption in meta-analysis. We also provide preliminary evidence on the effectiveness of intervention components and delivery methods.Results We found a small overall effect for the superiority of self-management interventions over usual care, with a SMD of-0.36 (-0.45 to -0.26) for pain intensity; -0.32 (-0.42 to -0.22) for headache related disability, 0.32 (0.20 to 0.45) for quality of life and a moderate effect on mood (SMD = 0.53 (-0.66 to -0.40)). We did not find an effect on headache frequency (SMD = -0.07 (-0.22 to 0.08). Assessment of components and characteristics suggests a larger effects on pain intensity in interventions that included explicit educational components (-0.51 (-0.68 to -0.34) versus -0.28 (-0.40 to -0.16)); mindfulness components (-0.50 (-0.82 to -0.18) versus 0.34 (-0.44 to -0.24) and in interventions delivered in groups versus one-to-one delivery (0.56 (-0.72 to -0.40) versus -0.39 (-0.52 to -0.27) and larger effects on mood in interventions including a CBT component with a SMD of -0.72 (-0.93 to -0.51) compared to those without CBT -0.41 (-0.58 to -0.24). Conclusion Overall we found that self-management interventions for migraine and tension-type headache are more effective than usual care in reducing pain intensity, mood, and headache related disability. Preliminary findings also suggest that including CBT, mindfulness and educational components in interventions, and delivery in groups may increase effectiveness.RegistrationPROSPERO 2016:CRD4201604129

Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients

<br>Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.</br> <br>Methods: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.</br><br>Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.</br> <br>Conclusion: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.</br&gt

The clinical and cost effectiveness of steroid injection compared with night splints for carpal tunnel syndrome: the INSTINCTS randomised clinical trial study protocol.

BACKGROUND: Patients diagnosed with idiopathic mild to moderate carpal tunnel syndrome (CTS) are usually managed in primary care and commonly treated with night splints and/or corticosteroid injection. The comparative effectiveness of these interventions has not been reliably established nor investigated in the medium and long term. The primary objective of this trial is to investigate whether corticosteroid injection is effective in reducing symptoms and improving hand function in mild to moderate CTS over 6 weeks when compared with night splints. Secondary objectives are to determine specified comparative clinical outcomes and cost effectiveness of corticosteroid injection over 6 and 24 months. METHOD/DESIGN: A multicentre, randomised, parallel group, clinical pragmatic trial will recruit 240 adults aged ≥18 years with mild to moderate CTS from GP Practices and Primary-Secondary Care Musculoskeletal Interface Clinics. Diagnosis will be by standardised clinical assessment. Participants will be randomised on an equal basis to receive either one injection of 20 mg Depo-Medrone or a night splint to be worn for 6 weeks. The primary outcome is the overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks. Secondary outcomes are the BCTQ symptom severity and function status subscales, symptom intensity, interrupted sleep, adherence to splinting, perceived benefit and satisfaction with treatment, work absence and reduction in work performance, EQ-5D-5L, referral to surgery and health utilisation costs. Participants will be assessed at baseline and followed up at 6 weeks, 6, 12 and 24 months. The primary analysis will use an intention to treat (ITT) approach and multiple imputation for missing data. The sample size was calculated to detect a 15 % greater improvement in the BTCQ overall score in the injection group compared to night-splinting at approximately 90 % power, 5 % two-tailed significance and allows for 15 % loss to follow-up. DISCUSSION: The trial makes an important contribution to the evidence base available to support effective conservative management of CTS in primary care. No previous trials have directly compared these treatments for CTS in primary care populations, reported on clinical effectiveness at more than 6 months nor compared cost effectiveness of the interventions. TRIAL REGISTRATION: Trial registration: EudraCT 2013-001435-48 (registered 05/06/2013), ClinicalTrials.gov NCT02038452 (registered 16/1/2014), and Current Controlled Trials ISRCTN09392969 (retrospectively registered 01/05/2014)

The clinical and cost-effectiveness of corticosteroid injection versus night splints for carpal tunnel syndrome (INSTINCTS trial): an open-label, parallel group, randomised controlled trial

Background To our knowledge, the comparative effectiveness of commonly used conservative treatments for carpal tunnel syndrome has not been evaluated previously in primary care. We aimed to compare the clinical and cost-effectiveness of night splints with a corticosteroid injection with regards to reducing symptoms and improving hand function in patients with mild or moderate carpal tunnel syndrome. Methods We did this randomised, open-label, pragmatic trial in adults (≥18 years) with mild or moderate carpal tunnel syndrome recruited from 25 primary and community musculoskeletal clinics and services. Patients with a new episode of idiopathic mild or moderate carpal tunnel syndrome of at least 6 weeks' duration were eligible. We randomly assigned (1:1) patients (permutated blocks of two and four by site) with an online web or third party telephone service to receive either a single injection of 20 mg methylprednisolone acetate (from 40 mg/mL) or a night-resting splint to be worn for 6 weeks. Patients and clinicians could not be masked to the intervention. The primary outcome was the overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks. We used intention-to-treat analysis, with multiple imputation for missing data, which was concealed to treatment group allocation. The trial is registered with the European Clinical Trials Database, number 2013-001435-48, and ClinicalTrial.gov, number NCT02038452. Findings Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2·02 [SD 0·81]) than the night splint group (2·29 [0·75]; adjusted mean difference −0·32; 95% CI −0·48 to −0·16; p=0·0001). No adverse events were reported. Interpretation A single corticosteroid injection shows superior clinical effectiveness at 6 weeks compared with night-resting splints, making it the treatment of choice for rapid symptom response in mild or moderate carpal tunnel syndrome presenting in primary care