Particle dynamics associated with the space environment

A major factor in dust dynamics in a microgravity environment is the absence of settling; hence, Spacelab air will contain larger particles than a comparable laboratory on earth. In addition, the presence of low level acceleration fluctuations (thruster firings, crew motions, etc.) could inhibit dust removal by surface scavenging. Because of the presence of larger particles, aerosol dynamics at larger Reynolds numbers must be considered. An accurate drag coefficient for spherical particles was developed for the higher Reynolds number phenomena. A general graphic correlation for the drag coefficient as a function of Reynolds and Knudsen numbers was developed based on currently available drag data for spheres. The general equations that govern dust dynamics were reviewed

Correlation between the outer flow and the turbulent production in a boundary layer

Space-time velocity correlation measurements between fluctuations occurring in the convoluting outer edge of a flat boundary layer with fluctuations occurring near the viscous subregion were made. The correlations indicate that information is propagated from the outer region to the inner region. The migration of turbulence away from the wall was previously studied in the open literature. The results presented here along with the migration results lend support to the limit cycle model for turbulence production

Evaluation of mean and turbulent velocity measurements in subsonic accelerated boundary layers

Exploratory measurements of the mean and turbulent flow in the wall boundary layer of a 15.5- by 10.2-cm channel were obtained as part of an instrumentation development program for measurements in compressible flow. Mean surface and flow-field surveys were obtained at channel Mach numbers ranging from 0.2 to 0.9. The mean velocity distributions were obtained with total pressure probes and a laser velocimeter. At a channel Mach number of 0.2, several types of hot-wire probes were used to obtain both velocity fluctuations and Reynolds shear-stress results

Measurements and a model for convective velocities in the turbulent boundary layer

A physical model is presented which describes convective velocities within a flat plate turbulent boundary layer. A production zone concept is used as a basis for the physical model. The production zone concept employs the idea that packets of turbulent fluid are generated near the viscous sublayer. These packets are found to be discernible from the mean motion and may move either outward from the production zone or inward depending on their circulation relative to the fluid surrounding the packet. The packets are predicted to travel with a convective velocity different from the local mean velocity throughout most of the boundary layer. The model also predicts that the convective velocities will be functions of wave number outside the production zone

Evaluation of high Reynolds number flow in a 180 degree turn-around-duct

Mean and turbulent velocities were measured for the flow in a 180 degree turn-around-duct over a Reynolds number range from 600,000 to greater than 900,000. The measurements were made in water using a forward scattering laser velocimeter. A duct of 100 x 10 cm constant cross-section, with a mean radius of curvature (centerline) of 10 cm was employed for the study. The measurements are in agreement with previous studies in that the use of local bulk velocity to nondimensionalize the mean and turbulent velocities reduce the Reynolds number variations. The basic phenomenon of relaminarization along the inner surface at the exit of the turn are similar to the flow observed at low Reynolds numbers. The separation bubble region shows a systematic variation with Reynolds number, however the Reynolds number effect may be of second order in the calculation of the overall flow. Large tangential, radial, and lateral turbulent velocities are measured along the outer surface of the turn

Market Access Analysis of Biologics and Small-Molecule Inhibitors for Inflammatory Bowel Disease Among US Health Insurance Policies.

BACKGROUND AND AIMS:Treatment pathways for ulcerative colitis (UC) and Crohn's disease (CD) are shifting to a more individualized, risk-stratified approach. The perception is that insurance policies may not have implemented this paradigm shift, particularly regarding access to newer agents. We evaluated patient access to advanced therapies by analyzing policy information from the Managed Markets Insight and Technology database. METHODS:Coverage status as of December 2018 for all US lives was queried for adalimumab, infliximab, infliximab-dyyb, tofacitinib, ustekinumab, and vedolizumab by indication (UC and/or CD) and medical or pharmacy coverage benefit. Coverage status was classified by the number of biologic steps before access to specified drug as "No Biologic," "1 Prior Biologic," "2+ Prior Biologics," "Not Covered." Unknown lives were excluded from the analyses. RESULTS:Coverage analysis was available for approximately 302 million lives under each medical and pharmacy benefit. Our analysis indicates that approximately half of covered lives had access to all agents (except tofacitinib) as first-line therapy; two-thirds had access after one biologic exposure. Among newer agents, vedolizumab had the widest coverage. For indications of UC and CD, 81% of known lives had access to vedolizumab with no prior biologic exposure required ("No Biologic"), 95% after "No Biologic" + "1 prior Biologic." Geographic variations were identified for coverage patterns. CONCLUSIONS:This US-based healthcare policy analysis points to an increased access to advanced therapies for UC and CD. An individualized, risk-stratified treatment approach integrating advanced therapies, including those recently approved, into treatment pathways for UC and CD is feasible

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BackgroundBudesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.AimThe aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.MethodsData from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.ResultsA similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.ConclusionsThis integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion