Luncheon address : the Greenspan era : lessons for the future

Greenspan, Alan ; Monetary policy

Visualization of hydrogen injection in a scramjet engine by simultaneous PLIF imaging and laser holographic imaging

Flowfield characterization has been accomplished for several fuel injector configurations using simultaneous planar laser induced fluorescence (PLIF) and laser holographic imaging (LHI). The experiments were carried out in the GASL-NASA HYPULSE real gas expansion tube facility, a pulsed facility with steady test times of about 350 microsec. The tests were done at simulated Mach numbers 13.5 and 17. The focus of this paper is on the measurement technologies used and their application in a research facility. The HYPULSE facility, the models used for the experiments, and the setup for the LHI and PLIF measurements are described. Measurement challenges and solutions are discussed. Results are presented for experiments with several fuel injector configurations and several equivalence ratios

Supreme Court Amicus Brief Regarding Wyeth v. Diana Levine

Prominent in arguments opposing preemption of state tort law liability for alleged inadequacies in prescription drug labeling is the argument that such liability can complement FDA regulation by improving on a regulatory scheme that fails to provide adequate deterrence against the marketing of unsafe or inadequately labeled drugs. The premise of this argument is faulty. Fundamental principles of economics and numerous studies of FDA drug regulation reveal that FDA in fact errs on the side of overregulation of prescription drugs. Product liability litigation focused solely on one side of the prescription drug public health equation leads to further distortions of the drug approval and labeling process and exacerbates FDA's inherent overly cautious approach. Preemption of state tort law where it conflicts with FDA requirements will minimize these distortions and thereby maximize public health.Health and Safety, Other Topics

On the Perceptual Organization of Speech

A general account of auditory perceptual organization has developed in the past 2 decades. It relies on primitive devices akin to the Gestalt principles of organization to assign sensory elements to probable groupings and invokes secondary schematic processes to confirm or to repair the possible organization. Although this conceptualization is intended to apply universally, the variety and arrangement of acoustic constituents of speech violate Gestalt principles at numerous junctures, cohering perceptually, nonetheless. The authors report 3 experiments on organization in phonetic perception, using sine wave synthesis to evade the Gestalt rules and the schematic processes alike. These findings falsify a general auditory account, showing that phonetic perceptual organization is achieved by specific sensitivity to the acoustic modulations characteristic of speech signals

Impact of the SPOP Mutant Subtype on the Interpretation of Clinical Parameters in Prostate Cancer.

Purpose: Molecular characterization of prostate cancer, including The Cancer Genome Atlas, has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes, SPOP (speckle-type POZ protein) mutant prostate cancer, has previously only been identifiable via DNA sequencing, which has made the impact on prognosis and routinely used risk stratification parameters unclear. Methods: We have developed a novel gene expression signature, classifier (Subclass Predictor Based on Transcriptional Data), and decision tree to predict the SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Results: The subclass predictor based on transcriptional data model showed high sensitivity and specificity in multiple cohorts across both RNA sequencing and microarray gene expression platforms. We predicted approximately 8% to 9% of cases to be SPOP mutant from both retrospective and prospective cohorts. We found that the SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy; however, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pretreatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with high-risk preoperative PSA levels. Conclusion: Using a novel gene expression model and a decision tree algorithm to define prostate cancer molecular subclasses, we found that the SPOP mutant subclass is associated with higher preoperative PSA, less adverse pathologic features, and favorable prognosis. These findings suggest a paradigm in which the interpretation of common risk stratification parameters, particularly PSA, may be influenced by the underlying molecular subtype of prostate cancer

Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia–thalamic communication

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source

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

Human prostate sphere-forming cells represent a subset of basal epithelial cells capable of glandular regeneration in vivo.

BackgroundProstate stem/progenitor cells function in glandular development and maintenance. They may be targets for tumor initiation, so characterization of these cells may have therapeutic implications. Cells from dissociated tissues that form spheres in vitro often represent stem/progenitor cells. A subset of human prostate cells that form prostaspheres were evaluated for self-renewal and tissue regeneration capability in the present study.MethodsProstaspheres were generated from 59 prostatectomy specimens. Lineage marker expression and TMPRSS-ERG status was determined via immunohistochemistry and fluorescence in situ hybridization (FISH). Subpopulations of prostate epithelial cells were isolated by cell sorting and interrogated for sphere-forming activity. Tissue regeneration potential was assessed by combining sphere-forming cells with rat urogenital sinus mesenchyme (rUGSM) subcutaneously in immunocompromised mice.ResultsProstate tissue specimens were heterogeneous, containing both benign and malignant (Gleason 3-5) glands. TMPRSS-ERG fusion was found in approximately 70% of cancers examined. Prostaspheres developed from single cells at a variable rate (0.5-4%) and could be serially passaged. A basal phenotype (CD44+CD49f+CK5+p63+CK8-AR-PSA-) was observed among sphere-forming cells. Subpopulations of prostate cells expressing tumor-associated calcium signal transducer 2 (Trop2), CD44, and CD49f preferentially formed spheres. In vivo implantation of sphere-forming cells and rUGSM regenerated tubular structures containing discreet basal and luminal layers. The TMPRSS-ERG fusion was absent in prostaspheres derived from fusion-positive tumor tissue, suggesting a survival/growth advantage of benign prostate epithelial cells.ConclusionHuman prostate sphere-forming cells self-renew, have tissue regeneration capability, and represent a subpopulation of basal cells

Factors associated with nonessential workplace attendance during the Covid-19 pandemic in the UK in early 2021

Objectives: Working from home where possible is important in reducing spread of Covid-19. In early 2021, a quarter of people in England who believed they could work entirely from home reported attending their workplace. To inform interventions to reduce this, this study examined associated factors. / Study design: Data from the ongoing CORSAIR survey series of nationally representative samples of people in the UK aged 16+ years in January-February 2021 were used. / Methods:. The study sample was 1422 respondents who reported that they could work completely from home. The outcome measure was self-reported workplace attendance at least once during the preceding week. Factors of interest were analysed in three blocks: 1) sociodemographic variables, 2) variables relating to respondents’ circumstances, and 3) psychological variables. / Results: 26.8% (95%CI=24.5%-29.1%) of respondents reported having attended their workplace at least once in the preceding week. Sociodemographic variables and living circumstances significantly independently predicted non-essential workplace attendance: male gender (OR=1.85,95%CI=1.33-2.58), dependent children in the household (OR=1.65,95%CI=1.17-2.32), financial hardship (OR=1.14,95%CI=1.08-1.21), socio-economic grade C2DE (OR=1.74, 95%CI=1.19-2.53), working in sectors such as health or social care (OR=4.18, 95%CI=2.56-6.81), education and childcare (OR=2.45, 95%CI=1.45-4.14) and key public service (OR=3.78, 95%CI=1.83-7.81), and having been vaccinated (OR=2.08,95%CI=1.33-3.24). / Conclusions: Non-essential workplace attendance in the UK in early 2021 during the Covid-19 pandemic was significantly independently associated with a range of sociodemographic variables and personal circumstances. Having been vaccinated, financial hardship, socio-economic grade C2DE, having a dependent child at home, working in certain key sectors were associated with higher likelihood of workplace attendance

Factors associated with wearing a facemask in shops in England following removal of a legal requirement to do so during the COVID-19 pandemic

OBJECTIVES: We aimed to identify psychological factors associated with the use of facemasks in shops in England following removal of legal requirements to do so, and to compare associations with and without legal restrictions. DESIGN: Repeated cross-sectional online surveys (n ≈ 2000 adults) between August 2020 and April 2022 (68,716 responses from 45,682 participants) using quota sampling. METHODS: The outcome measure was whether those who had visited a shop for essentials in the previous seven days reported always having worn a facemask versus sometimes or not at all. Psychological predictor variables included worry, perceived risk and severity of COVID-19 and the perceived effectiveness of facemasks. Socio-demographic variables and measures of clinical vulnerability were also measured. For the period following removal of legal restrictions, multivariable regression was used to assess associations between the primary outcome variable and predictors adjusting for socio-demographic and clinical vulnerability measures. The analysis was repeated including interactions between psychological predictors and presence versus absence of legal restrictions. RESULTS: Worry about COVID-19, beliefs about risks and severity of COVID-19 and effectiveness of facemasks were substantially and independently associated with the use of facemasks. Removal of legal obligations to wear facemasks was associated with a 25% decrease in wearing facemasks and stronger associations between psychological predictors and wearing facemasks. CONCLUSIONS: Legal obligations increase rates of wearing a facemask. Psychological factors associated with wearing a facemask could be targets for interventions aiming to alter rates of wearing a facemask. These interventions may be more effective when there are no legal obligations to wear a face covering in place