Design Parameterization for Concurrent Design and Manufacturing of Mechanical Systems

Design changes are frequently encountered in the product development process. The complexity of the design changes is multiplied when the product design involves multiple engineering disciplines. Very often, a simple change in one part may propagate to its neighboring parts, therefore, affects the entire product assembly. Both parts and assembly must be regenerated for a physically valid product model, at the same time, the regenerated product model must meet designer's expectations.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The ABCD of usability testing

We introduce a methodology for tracking and auditing feedback, errors and suggestions for software packages. This short paper describes how we innovate on the evaluation mechanism, introducing an (Antecedent, Barrier, Consequence and Development) ABCD form, embedded within an eParticipation platform to enable end users to easily report on any usability issues. This methodology will be utilised to improve the STEP cloud eParticipation platform (part of the current STEP Horizon2020 project http://step4youth.eu. The platform is currently being piloted in real life contexts, with the participation of public authorities that are integrating the eParticipation platform into their regular decision-making practices. The project is involving young people, through engagement and motivation strategies and giving them a voice in Environmental decision making at the local level. The pilot evaluation aims to demonstrate how open engagement needs to be embedded within public sector processes and the usability methodology reported here will help to identify the key barriers for wide scale deployment of the platform

A self-rating scale for patient-perceived side effects of inhaled corticosteroids

BACKGROUND: Patient-reported side effect questionnaires offer a simple method for the systematic measurement of drug-related side effects. In order to measure patients' inhaled corticosteroids (ICS) related side effect perceptions the 14-day retrospective Inhaled Corticosteroid Questionnaire (ICQ) was developed. In this research we aim to assess the construct validity and reliability of the ICQ and test its responsiveness to dose changes in adult asthma patients. METHODS: In a cross-sectional study, current inhaler users with asthma completed the ICQ (27 with non ICS inhaler; 61 BDP equivalent daily ICS low dose ≤400 μg; 62 mid dose 401–800 μg; and 105 with high dose >800 μg). We generated 3 construct validity hypotheses: 1) a hierarchical dose-response pattern for scoring of the individual items on the ICQ, and statistically significant differences in the scores of each of the 15 ICQ domains by ICS dose group 2) an association between ICS dose and ICQ scoring after adjusting for appropriate confounders in multiple regression; 3) greater convergence between local side effect domains than between systemic and local domains of the scale. Test-retest reliability was assessed on a randomly selected subgroup of patients (n = 73) who also completed the ICQ a second time after 7 days. In a separate longitudinal study, 61 patients with asthma completed the ICQ at baseline and after changing their daily ICS dose, at 2- and 6- months, in order to test the ICQ's responsiveness. RESULTS: All three construct validity hypotheses were well supported: 1) a statistically significant difference existed in scores for 14 domains, the high ICS dose group scoring highest; 2) ICS dose independently predicted ICQ scoring after adjusting for confounders; 3) greater convergence existed between local ICQ domains than between local and systemic domains. The ICQ had good reproducibility: test-retest intraclass correlation coefficients were ≥0.69 for all but the 'Facial Oedema' domain. In the longitudinal study, ICQ scores for 'Voice Problems' changed significantly at 2- and 6-months from baseline and other ICQ domains displayed trends in scoring change accordant with dose modulation at 6-months. CONCLUSION: The ICQ has good dose-related discriminative properties, is valid, reliable, and shows potential responsiveness to ICS dose change

Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients

Pexa-Vec is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to Pexa-Vec include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.e., an immunologically ‘cold’ tumour microenvironment is transformed into a ‘hot’ tumour. However, as with all immunotherapies, not all patients respond in a uniformly favourable manner. Our study herein, shows a differential immune response by patients to intravenous Pexa-Vec therapy, whereby some patients responded to the virus in a typical and expected manner, demonstrating a significant IFN induction and subsequent peripheral immune activation. However, other patients experienced a markedly subdued immune response and appeared to exhibit an exhausted phenotype at baseline, characterised by higher baseline immune checkpoint expression and regulatory T cell (Treg) levels. This differential baseline immunological profile accurately predicted the subsequent response to Pexa-Vec and may, therefore, enable the development of predictive biomarkers for Pexa-Vec and OV therapies more widely. If confirmed in larger clinical trials, these immunological biomarkers may enable a personalised approach, whereby patients with an exhausted baseline immune profile are treated with immune checkpoint blockade, with the aim of reversing immune exhaustion, prior to or alongside OV therapy

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

Abstract Introduction Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines. Methods Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response. Results Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade. Conclusions These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991

A review of wearable motion tracking systems used in rehabilitation following hip and knee replacement

Clinical teams are under increasing pressure to facilitate early hospital discharge for total hip replacement and total knee replacement patients following surgery. A wide variety of wearable devices are being marketed to assist with rehabilitation following surgery. A review of wearable devices was undertaken to assess the evidence supporting their efficacy in assisting rehabilitation following total hip replacement and total knee replacement. A search was conducted using the electronic databases including Medline, CINAHL, Cochrane, PsycARTICLES, and PubMed of studies from January 2000 to October 2017. Five studies met the eligibility criteria, and all used an accelerometer and a gyroscope for their technology. A review of the studies found very little evidence to support the efficacy of the technology, although they show that the use of the technology is feasible. Future work should establish which wearable technology is most valuable to patients, which ones improve patient outcomes, and the most economical model for deploying the technolog

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

There was no funding support for this study. Disclosure. The authors declare no conflict of interest.Peer reviewedPublisher PD