Parent support advisor pilot : first interim report from the evaluation

The Parent Support Adviser (PSA) pilot is a government funded initiative to support 20 Local Authorities (LAs) to introduce PSAs into their workforce. The Department for Children, Schools and Families (DCSF) commissioned the Centre for Educational Development, Appraisal and Research (CEDAR) to evaluate the PSA pilot programme from September 2006 – August 2008. A government grant (£40 million) has been made available to fund employment of PSAs over this period. To date, 717 PSAs are in place, supporting parents in 1167 schools. This first Interim Report is based on semi-structured interviews with 97 PSAs, 85 line managers and 23 other professionals in 12 case study LAs during Phase 1 of the evaluation, which was carried out between April and June 2007. Phase 2 of the study will take place during the period October to December 2007; phase 3 will take place during March to June 2008. In addition to these interview-based studies with the 12 case study LAs, an analysis will be made of the data collected by all 20 LAs over the period of the pilot using a standard database devised by CEDAR. Data are being collected on the PSAs’ work with parents and, where this occurs, with children. Finally, a cost effectiveness study will be undertaken. The findings from these phases of the project will be reported in the final report

Lamin A Δexon9 mutation leads to telomere and chromatin defects but not genomic instability

Over 300 mutations in the LMNA gene, encoding A-type lamins, are associated with 15 human degenerative disorders and premature aging syndromes. Although genomic instability seems to contribute to the pathophysiology of some laminopathies, there is limited information about what mutations cause genomic instability and by which molecular mechanisms. Mouse embryonic fibroblasts depleted of A-type lamins or expressing mutants lacking exons 8–11 (Lmna(Δ8–11/Δ8–11)) exhibit alterations in telomere biology and DNA repair caused by cathepsin L-mediated degradation of 53BP1 and reduced expression of BRCA1 and RAD51. Thus, a region encompassing exons 8–11 seems essential for genome integrity. Given that deletion of lamin A exon 9 in the mouse (Lmna(Δ9/Δ9)) results in a progeria phenotype, we tested if this domain is important for genome integrity. Lmna(Δ9/Δ9) MEFs exhibit telomere shortening and heterochromatin alterations but do not activate cathepsin L-mediated degradation of 53BP1 and maintain expression of BRCA1 and RAD51. Accordingly, Lmna(Δ9/Δ9) MEFs do not present genomic instability, and expression of mutant lamin A Δexon9 in lamin-depleted cells restores DNA repair factors levels and partially rescues nuclear abnormalities. These data reveal that the domain encoded by exon 9 is important to maintain telomere homeostasis and heterochromatin structure but does not play a role in DNA repair, thus pointing to other exons in the lamin A tail as responsible for the genomic instability phenotype in Lmna(Δ8–11/Δ8–11) mice. Our study also suggests that the levels of DNA repair factors 53BP1, BRCA1 and RAD51 could potentially serve as biomarkers to identify laminopathies that present with genomic instability

Scenario of Accelerating Universe from the Phenomenological \Lambda- Models

Dark matter, the major component of the matter content of the Universe, played a significant role at early stages during structure formation. But at present the Universe is dark energy dominated as well as accelerating. Here, the presence of dark energy has been established by including a time-dependent $\Lambda$ term in the Einstein's field equations. This model is compatible with the idea of an accelerating Universe so far as the value of the deceleration parameter is concerned. Possibility of a change in sign of the deceleration parameter is also discussed. The impact of considering the speed of light as variable in the field equations has also been investigated by using a well known time-dependent $\Lambda$ model.Comment: Latex, 9 pages, Major change

A Simple & Convenient Solid Phase Synthesis of Bacterial Origin Octapeptide Sequence, Glu-Asp-Gly-Asn-Lys-Pro-Gly-Lys-OH

The repeating octapeptide sequence, Glu-Asp-Gly-Asn-Lys-Pro-Gly-Lys-OH derived from the glycoprotein found in Staphylococcus aureus cell wall is assembled by simple solid phase peptide synthesis methodology using a base labile linker

Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany

Метафизическое значение категорий предмета и непредмета в логике, поясняемое примерами решения антиномии Рассела в теории типов и аксиоматической системе NBG

Метафизическое значение категорий предмета и непредмета в логике, поясняемое примерами решения антиномии Рассела в теории типов и аксиоматической системе NB

Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

The purpose of this study was to determine whether metformin promotes weight loss in overweight out-patients with chronic schizophrenia or schizoaffective disorder