COSTMODL: An automated software development cost estimation tool

The cost of developing computer software continues to consume an increasing portion of many organizations' total budgets, both in the public and private sector. As this trend develops, the capability to produce reliable estimates of the effort and schedule required to develop a candidate software product takes on increasing importance. The COSTMODL program was developed to provide an in-house capability to perform development cost estimates for NASA software projects. COSTMODL is an automated software development cost estimation tool which incorporates five cost estimation algorithms including the latest models for the Ada language and incrementally developed products. The principal characteristic which sets COSTMODL apart from other software cost estimation programs is its capacity to be completely customized to a particular environment. The estimation equations can be recalibrated to reflect the programmer productivity characteristics demonstrated by the user's organization, and the set of significant factors which effect software development costs can be customized to reflect any unique properties of the user's development environment. Careful use of a capability such as COSTMODL can significantly reduce the risk of cost overruns and failed projects

Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers

Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.United States. National Institutes of Health (R01GM107536)Alex's Lemonade Stand FoundationHoward Hughes Medical InstituteBoston Children's Hospital. Manton Center for Orphan Disease ResearchNational Institute of General Medical Sciences (U.S.) (T32GM007753

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Patient Satisfaction with Private Physiotherapy for Musculoskeletal Pain

Despite emphasis on patient centred healthcare, healthcare professionals have been slow to use validated measurements of patient satisfaction in physiotherapy practice. This cross sectional survey measured patient satisfaction with private physiotherapy in Ireland, for patients with musculoskeletal pain, using a multidimensional patient satisfaction questionnaire (PTOPS). The 'PTOPS' questionnaire categorised and scored satisfaction items under four domains, Enhancer, Detractor, Location and Cost. 55% (n = 131/240) of questionnaires were returned. The most common site of musculoskeletal pain was spinal (51.5% n = 66) and the mean (SD) number of treatments attended was 8.3 (8.3), at a mean total cost (SD) of €350.2 (€322.8). Overall satisfaction with physiotherapy experience was scored on a five-point scale "excellent to poor", with a modal response of "Very Good" (42%; n = 55). Results demonstrated high levels of satisfaction with all components of physiotherapy treatment, except cost, and provided valuable patient feedback regarding their physiotherapy treatment for musculoskeletal pain.Peer reviewedFinal Published versio

Quality of meta-analyses for randomized trials in the field of hypertension: a systematic review.

OBJECTIVES: Doubling on average every 6 years, hypertension-related meta-analyses are now published twice weekly and are often considered the highest level of evidence for clinical practice. However, some hypertension specialists and guideline authors view meta-analyses with skepticism. This article evaluates the quality of hypertension-related meta-analyses of clinical trials. METHODS: A systematic search was conducted for meta-analyses of clinical trials recently published over 3.3 years. Specific criteria reproducibly assessed 26 features in the four domains of meta-analysis quality, domains justified by fundamental analytics and extensive research: analyzing trial quality, analyzing heterogeneity, analyzing publication bias, and providing transparency. RESULTS: A total of 143 meta-analyses were identified. A total of 44% had 8+ deficient features with no relation to journal impact factor: odds ratio relating 8+ deficient features to the upper third versus lower third of impact factor = 1.3 (95% confidence limit 0.6-2.9). A total of 56% had all four domains deficient. Quality did not improve over time. Thirty articles (21%) reported statistically significant results (P \u3c 0.05) from inappropriate DerSimonian-Laird models, whereas unreported, appropriate, Knapp-Hartung models gave statistical nonsignificance; 88% of these 30 articles reported the incorrect results in their abstracts. A total of 60% of all meta-analyses failed to conduct analyses in subgroups of quality when indicated, 63% failed to report Tau and Tau, 57% omitted testing for publication bias, none conducted a cumulative analysis for publication bias, and 71-77% omitted mentioning in their abstracts problems of trial quality, heterogeneity, and publication bias. CONCLUSION: Although widespread, deficiencies in hypertension-related meta-analyses are readily corrected and do not represent flaws inherent in the meta-analytic method