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An experimental investigation is presented of an oscillating disk submerged in water. The system is adapted from one modeled by the Bagley-Torvik equation, being modified to more closely approximate idealizations in the derivation. The modified system eliminates alignment problems that would violate the assumption of fluid forces being due only to shear in the fluid. An implicit finite difference model based on the Riemann-Liouville fractional derivative was used to model the observed oscillatory free response resulting from a non-homogeneous initial condition. The numerical model accounted for motion well until the amplitude was small. MSC 2010 : 26A33, 34A08, 76A99, 34K11

Collaborative Product Design and Realization in Mechanical Engineering Technology Curricula Abstract Mechanical and manufacturing engineers are working in a global environment which requires new skills. New term developed over the last decade for them: the “knowledge workers”. Those engineers need a new skill set to work successfully on collaborative projects involving people located not only at different companies, but also potentially on different continents. This new skill set can be developed using secure web sites for storing product related data, virtual chat rooms which would enable students to share presentations and applications. Those tools could enable faster collaboration on those projects. They could save that information as knowledge for their future capstone projects and alike. Working around the clock has recently become the goal of every company. Collaboration needs to be facilitated by digital means such as web portals, voice over internet protocol, and video and audio conferencing. Mechanical Engineering Technology students should be able to adapt quickly into this new working environment after their graduation. The student projects should involve working on web-based collaborative projects. Midwest Coalition for Comprehensive Design Education, National Science Foundation founded project, various projects were developed in the web based collaborative environment.

Natural Killer (NK) cells are innate immune cells that secrete lytic granules to directly kill virus-infected or transformed cells across an immune synapse. However, a major gap in understanding this process is in establishing how lytic granules pass through the mesh of cortical actin known to underlie the NK cell membrane. Research has been hampered by the resolution of conventional light microscopy, which is too low to resolve cortical actin during lytic granule secretion. Here we use two high-resolution imaging techniques to probe the synaptic organisation of NK cell receptors and filamentous (F)-actin. A combination of optical tweezers and live cell confocal microscopy reveals that microclusters of NKG2D assemble into a ring-shaped structure at the centre of intercellular synapses, where Vav1 and Grb2 also accumulate. Within this ring-shaped organisation of NK cell proteins, lytic granules accumulate for secretion. Using 3D-structured illumination microscopy (3D-SIM) to gain super-resolution of ~100 nm, cortical actin was detected in a central region of the NK cell synapse irrespective of whether activating or inhibitory signals dominate. Strikingly, the periodicity of the cortical actin mesh increased in specific domains at the synapse when the NK cell was activated. Two-colour super-resolution imaging revealed that lytic granules docked precisely in these domains which were also proximal to where the microtubule-organising centre (MTOC) polarised. Together, these data demonstrate that remodelling of the cortical actin mesh occurs at the central region of the cytolytic NK cell immune synapse. This is likely to occur for other types of cell secretion and also emphasises the importance of emerging super-resolution imaging technology for revealing new biology.

Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. Cancer Research UK.

BackgroundMany high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear.MethodsWe conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted.ResultsOf 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0–5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59–2.85), CML (n = 61) = 1.77 (95% CI 0.38–4.50), and ALL (n = 71) = 6.65 (95% CI 2.79–14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards.DiscussionWe found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

We conduct an analysis of over 60,000 dwarf galaxies ( 7≲logM*/M⊙≲10 ) in search of photometric variability indicative of active galactic nuclei (AGNs). Using data from the Young Supernova Experiment, a time domain survey on the Pan-STARRS telescopes, we construct light curves for each galaxy in up to four bands (griz) where available. We select objects with AGN-like variability by fitting each light curve with a damped random walk (DRW) model. After quality cuts and removing transient contaminants, we identify 1100 variability-selected AGN candidates (representing 2.4% of the available sample). We analyze their spectra to measure various emission lines and calculate black hole (BH) masses, finding general agreement with previously found mass scaling relations and nine potential intermediate-mass BH candidates. Furthermore, we reanalyze the light curves of our candidates to calculate the dampening timescale τDRW associated with the DRW and see a similar correlation between this value and the BH mass. Finally, we estimate the active fraction as a function of stellar mass and see evidence that the active fraction increases with host mass.

Studies evaluating titration of antihypertensive medication using self-monitoring give contradictory findings and the precise place of telemonitoring over self-monitoring alone is unclear. The TASMINH4 trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care. This study was a parallel randomised controlled trial done in 142 general practices in the UK, and included hypertensive patients older than 35 years, with blood pressure higher than 140/90 mm Hg, who were willing to self-monitor their blood pressure. Patients were randomly assigned (1:1:1) to self-monitoring blood pressure (self-montoring group), to self-monitoring blood pressure with telemonitoring (telemonitoring group), or to usual care (clinic blood pressure; usual care group). Randomisation was by a secure web-based system. Neither participants nor investigators were masked to group assignment. The primary outcome was clinic measured systolic blood pressure at 12 months from randomisation. Primary analysis was of available cases. The trial is registered with ISRCTN, number ISRCTN 83571366. 1182 participants were randomly assigned to the self-monitoring group (n=395), the telemonitoring group (n=393), or the usual care group (n=394), of whom 1003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137·0 [SD 16·7] mm Hg and telemonitoring, 136·0 [16·1] mm Hg vs usual care, 140·4 [16·5]; adjusted mean differences vs usual care: self-monitoring alone, −3·5 mm Hg [95% CI −5·8 to −1·2]; telemonitoring, −4·7 mm Hg [–7·0 to −2·4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference −1·2 mm Hg [95% CI −3·5 to 1·2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups. Self-monitoring, with or without telemonitoring, when used by general practitioners to titrate antihypertensive medication in individuals with poorly controlled blood pressure, leads to significantly lower blood pressure than titration guided by clinic readings. With most general practitioners and many patients using self-monitoring, it could become the cornerstone of hypertension management in primary care. National Institute for Health Research via Programme Grant for Applied Health Research (RP-PG-1209-10051), Professorship to RJM (NIHR-RP-R2-12-015), Oxford Collaboration for Leadership in Applied Health Research and Care, and Omron Healthcare UK.

In some colorectal cancers, a loss of DNA-repair function causes a defect called microsatellite instability. This study unexpectedly found that adjuvant treatment with fluorouracil did not benefit patients whose tumors had high-frequency microsatellite instability, whereas such treatment did benefit patients with microsatellite-stable tumors. The results may affect future trials of therapy for colorectal cancer. Colorectal cancer is the fourth most common type of cancer in Western society and the second leading cause of cancer-related death in North America. 1 Although surgical resection alone is potentially curative, local or distant recurrences develop in many patients, and those with the highest risk of recurrence are advised to receive fluorouracil-based systemic adjuvant chemotherapy, which has been shown to be beneficial in a number of cooperative-group trials and analyses. 2 – 12 Traditional pathological staging systems have been useful in predicting the outcome of colorectal cancer, but it is now evident that these cancers are heterogeneous. The natural history of colorectal . . .

Precision diagnostic testing (PDT) employs appropriate biomarkers to identify cancer patients that may optimally respond to precision medicine (PM) approaches, such as treatments with targeted agents and immuno‐oncology drugs. To date, there are no published systematic appraisals evaluating the cost‐effectiveness of PDT in non‐small‐cell lung cancer (NSCLC). To address this gap, we conducted Preferred Reporting Items for Systematic Reviews and Meta‐Analyses searches for the years 2009–2019. Consolidated Health Economic Evaluation Reporting Standards were employed to screen, assess and extract data. Employing base costs, life years gained or quality‐adjusted life years, as well as willingness‐to‐pay (WTP) threshold for each country, net monetary benefit was calculated to determine cost‐effectiveness of each intervention. Thirty‐seven studies (50%) were included for analysis; a further 37 (50%) were excluded, having failed population‐, intervention‐, comparator‐, outcomes‐ and study‐design criteria. Within the 37 studies included, we defined 64 scenarios. Eleven scenarios compared PDT‐guided PM with non‐guided therapy [epidermal growth factor receptor (EGFR), n = 5; programmed death‐ligand 1 (PD‐L1), n = 6]. Twenty‐eight scenarios compared PDT‐guided PM with chemotherapy alone (anaplastic lymphoma kinase, n = 3; EGFR, n = 17; PD‐L1, n = 8). Twenty‐five scenarios compared PDT‐guided PM with chemotherapy alone, while varying the PDT approach. Thirty‐four scenarios (53%) were cost‐effective, 28 (44%) were not cost‐effective, and two were marginal, dependent on their country’s WTP threshold. When PDT‐guided therapy was compared with a therapy‐for‐all patients approach, all scenarios (100%) proved cost‐effective. Seven of 37 studies had been structured appropriately to assess PDT‐PM cost‐effectiveness. Within these seven studies, all evaluated scenarios were cost‐effective. However, 81% of studies had been poorly designed. Our systematic analysis implies that more robust health economic evaluation could help identify additional approaches towards PDT cost‐effectiveness, underpinning value‐based care and enhanced outcomes for patients with NSCLC. Precision diagnostic testing guides therapy to non‐small‐cell lung carcinoma (NSCLC) patients who will best respond, increasing both quantity and quality of life. Our analysis demonstrates the inherent value of precision medicines for NSCLC patients in over half of cases. However, to build the health economic evidence base further, cost‐effectiveness analyses should be appropriately designed to maximise the potential of precision diagnostic testing.