Wavelet analysis of variance box plot.

Functional box plots satisfy two needs; visualization of functional data, and the calculation of important box plot statistics. Data visualization illuminates key characteristics of functional sets missed by statistical tests and summary statistics. The calculation of box plot statistics for functional sets permits a novel comparison more suited to functional data. The functional box plot uses a depth method to visualize and rank smooth functional curves in terms of a mean, box, whiskers, and outliers. The functional box plot improves upon other classic functional data analysis tools such as functional principal components and discriminant analysis for outlier detection. This research adds wavelet analysis as a generating mechanism along with depth for functional box plots to visualize functional data and calculate relevant statistics. The wavelet analysis of variance box plot tool gives competitive error rates in Gaussian test cases with magnitude outliers, and outperforms the functional box plot, for Gaussian test cases with shape outliers. Further, we show wavelet analysis is well suited at approximating irregular and noisy functional data and show the enhanced capability of WANOVA box plots to classify shape outliers which follow a different pattern than other functional data for both simulated and real data instances.

Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; An fMRI study.

BACKGROUND: Opiate addiction is a major health challenge with substantial societal cost. Though harm minimisation strategies have been effective, there is a growing need for new treatments for detoxification and relapse prevention. Preclinical research has found neurokinin 1 (NK1) receptors have prominent effects on opiate reward and reinforcement, and human studies have found NK1 antagonism led to reductions in craving and withdrawal. However, its effect on brain mechanisms in opiate addiction has not yet been examined. METHODS: This study aims to assess the impact of NK1 antagonist aprepitant on heroin cue-elicited changes in blood-oxygenation level dependent (BOLD) signal in opiate dependent individuals undergoing detoxification. Participants will attend two scanning sessions and receive a single dose of aprepitant (320 mg) and a placebo in a randomised, cross-over design. During functional magnetic resonance imaging participants will undergo two runs of a cue reactivity task, which consists of passive viewing of drug cues or neutral cues in a block design fashion. We hypothesise that NK1 antagonism will attenuate the BOLD response to drug cues in the caudate nucleus and amygdala. Regions of interest were selected based on NK1 receptor density and their role in cue reactivity and craving.

Understanding the UK Psychoactive Substances Act.

This review paper is based on a talk given at the British Pharmaceutical Society Winter Meeting in 2018 derived from the Home Office Report on the workings of the UK Psychoactive Substances Act (PSA) published in November 2018. The review deals with the context in which the PSA 2016 arose and how this piece of legislation differs from other UK drug regulations. It attempts to put the PSA in context with other control schemes being instituted around the world and to assess the success of the Act in its first 2 years of implementation. For more details the reader is referred to Review of the Psychoactive Substances Act 2016, Home Office, November 2018.

Modeling training effects using a human performance taxonomy.

OBJECTIVE: The aim of this study was to characterize skill acquisition during training and skill retention as a function of training strategy, retention period, and task type in the form of a numerical model and then apply that model to make predictions of performance on an unknown task. BACKGROUND: Complex systems require efficient and effective training programs for the humans who operate them in discontinuous fashion. Although there are several constructs for learning theory, models that enable analysts to predict training outcomes are needed during the design of training programs. METHOD: This study involved 60 participants who were trained on five tasks relevant to RQ-I Predator unmanned aircraft system sensor operators by one of three strategies that represented a continuum of instructor interactivity. After training, performance data for all five tasks were collected. Participants completed the same tasks 30 or 60 days later to determine skill retention and the rate at which task proficiency was reacquired. RESULTS: Models built from tasks that isolate human performance channels adequately predicted performance on a task that combined those channels. CONCLUSION: Models that predict performance on tasks that isolate human performance channels can be used to make predictions on tasks that draw on multiple channels.This model provided a distribution of performance data that was statistically similar to actual performance data. APPLICATION: System designers trained with human performance data on a set of tasks can apply those tasks' characteristics to future tasks to make reasonably accurate performance predictions, thereby allowing the designers to make early decisions regarding training strategy to teach those tasks.

Diffraction imaging in a He+ ion beam scanning transmission microscope.

The scanning helium ion microscope has been used in transmission mode to investigate both the feasibility of this approach and the utility of the signal content and the image information available. Operating at 40 keV the penetration of the ion beam, and the imaging resolution achieved, in MgO crystals was found to be in good agreement with values predicted by Monte Carlo modeling. The bright-field and annular dark-field signals displayed the anticipated contrasts associated with beam absorption and scattering. In addition, the diffraction of the He ion beam within the sample gave rise to crystallographic contrast effects in the form of thickness fringes and dislocation images. Scanning transmission He ion microscopy thus achieves useful sample penetration and provides nanometer scale resolution, high contrast images of crystalline materials and crystal defects even at modest beam energies.

Does higher surgical volume predict better patient outcomes?

OBJECTIVE: To measure the relationship between procedural volume and quality by examining the association between hospital procedural volume and mortality in coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA). METHODS: A retrospective quantitative analysis was conducted of Kentucky hospital discharge database for patients who underwent CABG and PTCA from 2000 through 2005. Hospitals were classified into three categories based on annual number of procedures--low (12-249), medium (250-499), and high-volume (> or = 500) CABG and PTCA facilities. This study employed a multiple logistic regression model to compare the odds for fatal outcome for patients treated in high, medium, and low-volume facilities, while controlling for patient age, gender, admission urgency, hospital length-of-stay, case severity, and pre-existing clinical conditions. RESULTS: From 2000 through 2005, 24 facilities performed 47,972 CABGs, while 30 facilities performed 75,869 PTCAs across the state of Kentucky. In non-emergent CABG and PTCA patients between the ages of 18 to 65 years, there was no statistically significant difference in the odds for fatal outcomes between low-, medium-, and high-volume hospitals. However, older (> or = 65 years old) emergent CABG and PTCA patients were more likely to die at high-volume and low-volume hospitals than medium-volume hospitals (odds ratio for CABG surgery--1.260 [1.004-1.580], 1.753 [1.266-2.4261, and odds ratio for PTCA--1.106 [1.207-2.163], 1.616 [1.207-2.163]). CONCLUSIONS: This study indicates that in hospital procedural volume Kentucky, is an imprecise predictor of quality as measured by CABG and PTCA outcomes, and should not be used by purchasers and policy makers as the only index of hospital quality.

Cost-benefit analysis on the HPV vaccine in Medicaid-enrolled females of the Appalachian region of Kentucky.

OBJECTIVE: The objective of this study was to determine the cost-efficiency of vaccinating against Human Papillomavirus (HPV) in Medicaid enrolled females of the Appalachian region of Kentucky (n = 49,411 females) aged 12 to 25 years, versus paying for the treatment of cervical cancer cases (n = 643 cases) within this population later in life. METHODS: In order to determine the cost of vaccination and cervical cancer treatment, the use of data acquired from the Kentucky Department of Medicaid Services (DMS) and Kentucky Cancer Registry (KCR) was necessary. RESULTS: Relative Risk of Appalachian Kentuckian females developing cervical cancer compared to their non-Appalachian counterparts is 1.23. The total cost DMS paid to treat cervical cancer in 2005 in Appalachian counties was $5.95 million. The direct cost DMS paid in 2005 to treat cervical cancer was $960,910.95. The direct cost for the vaccine for the 2005 Medicaid-enrolled population aged 12 to 25 in Appalachian Kentucky counties is $17.8 million (price of $360 for the three-dose vaccine). The cost to vaccinate the subsequent 12-year-old cohort (n = 4,137 females, born in 1995) in the next year is $1.5 million. Each year similar additional costs would accrue. CONCLUSIONS: Implementing a prevention plan for cervical cancer that includes annually vaccinating Medicaid-enrolled adolescent females of the Appalachian region of Kentucky against HPV infection is cost-efficient for the Medicaid system when considering the total expenditures associated with the illness. Recognition of an actual cost savings would not occur for several decades as the vaccinated population ages.

The forgotten instrument: analysis of the national public health performance standards program governance instrument.

This study examines the use of, and results from, the National Public Health Performance Standards Program Local Governance Instrument. It includes a compilation and analysis of 173 local governance instruments completed by local boards of health from 2003 to 2006. Only 24 of the 173 scored instruments are used because of exclusion of data from New Jersey. The study compares results from the instruments based upon demographic data reported by the local boards of health, and data on performance compiled by the National Public Health Performance Standards Program Local Public Health System Instrument. Local boards of health perform well on Essential Public Health Services #6 (78.85%), #2 (71.41%), and #7 (70.75%). Performance is far from optimal on Essential Public Health Services #10 (45.42%) and #9 (41.30%). Comparing groups based on demographic data yielded deviations too large and power too low to form any significant conclusions about local boards of health performance. It is important to note that individuals with varying levels of knowledge may have completed the governance instruments, and this may affect the results of any comparison between individual boards of health. Local boards of health need encouragement from national and state associations of local boards of health to complete the local governance instrument. This would allow local boards of health to use these data to compare performance with other boards around the nation. Identification of weak performing areas may lead to changes to improve service to the community. This instrument could also prove a useful tool in health department accreditation.

The Kentucky plan revisited: lessons learned from an innovative doctoral education program.

In the first doctoral education special issue of the Journal of Health Administration Education, the authors presented the University of Kentucky College of Public Health's plans for an innovative new Doctor of Public Health (Dr. P.H.) degree. The degree as designed, prepares graduates for professional practice, and included extensive supervised field experience as part of the academic training linking theory with practice. Based upon the interest that the Kentucky Dr.P.H. degree program received, the authors will share the experience of the degree's initial years of operation through a "lessons learned" paper. As the program evolved there have been many lessons related to trends, curriculum design, admissions, prerequisite requirements, curriculum innovations, scheduling, the comprehensive examination, and attrition. In addition, there are many questions for the future. "In theory, theory and practice are the same. In practice, they are not."-- Lawrence Peter "Yogi" Berra.

Partnership between small biotech and big pharma.

The process involved in the identification and development of novel breakthrough medicines at big pharma has recently undergone significant changes, in part because of the extraordinary complexity that is associated with tackling diseases of high unmet need, and also because of the increasingly demanding requirements that have been placed on the pharmaceutical industry by investors and regulatory authorities. In addition, big pharma no longer have a monopoly on the tools and enabling technologies that are required to identify and discover new drugs, as many biotech companies now also have these capabilities. As a result, researchers at biotech companies are able to identify credible drug leads, as well as compounds that have the potential to become marketed medicinal products. This diversification of companies that are involved in drug discovery and development has in turn led to increased partnering interactions between the biotech sector and big pharma. This article examines how Merck and Co Inc, which has historically relied on a combination of internal scientific research and licensed products, has poised itself to become further engaged in partnering with biotech companies, as well as academic institutions, to increase the probability of success associated with identifying novel medicines to treat unmet medical needs--particularly in areas such as central nervous system disorders, obesity/metabolic diseases, atheroma and cancer, and also to cultivate its cardiovascular, respiratory, arthritis, bone, ophthalmology and infectious disease franchises.

New treatments for neuropathic pain.

Existing treatments for neuropathic pain deliver inadequate pain relief, unacceptable side effects, or both. The unmet medical need for more effective treatment is driving a large volume of research to discover new drugs. Most existing treatments are drugs introduced to treat other pain conditions or other medical conditions, such as antidepressants and anticonvulsants, which were found empirically to be effective for neuropathic pain. Only recently have drug discovery efforts have become mechanistically driven, addressing targets identified by a molecular neurobiological approach to the pathophysiology of neuropathic states.

The bradykinin B1 receptor antagonist B9858 inhibits a nociceptive spinal reflex in rabbits.

There are two bradykinin receptor subtypes, designated B1 and B2. Whilst both have been implicated in nociception, it is believed that there is a low level of constitutive expression of B1 receptors and that their expression is induced by inflammation or tissue damage. The present study investigated the role of B1 receptors in spinal nociceptive processing using an in vivo electrophysiological assay in decerebrate, spinalized rabbits, a species that shares close B1 receptor homology with the human receptor. Inflammation was induced in the paw by an injection of complete Freund's adjuvant at least 1 h before recording single motor unit activity of the semitendinous/biceps femoris muscle in response to a noxious pinch of the foot. Control animals received an intraplantar injection of saline. The peptide B1 receptor antagonist B9858 was administered i.v. and caused dose-dependent and complete inhibition of the nociceptive spinal reflex (ID50 = 1 mg x kg(-1)). In control animals without paw inflammation, B9858 had no effect. These findings are consistent with other evidence that peptide B1 receptor antagonists inhibit spinal nociceptive reflexes only after induction of B1 receptors by inflammation and support the potential therapeutic utility of B1 receptor antagonists as analgesic and anti-inflammatory drugs.

Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature.

Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein-coupled receptor, the calcitonin receptor-like receptor (CRLR), whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP binds calcitonin gene-related peptide with high affinity, whereas CRLR coexpression with RAMP2 or -3 confers high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral, pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel types. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine, and may lead to possible ways in which future synthetic ligands may be applied to manage these disorders.

Enantioselective inhibition of the formalin paw late phase by the NK1 receptor antagonist L-733,060 in gerbils.

Intravenous administration of the NK1 receptor antagonist L-733,060 to gerbils 3 h before intraplantar injection of formalin caused a dose-dependent and complete inhibition of the late, but not early, phase nociceptive response (paw licking). The ID50 for L-733,060 (0.17 mg/kg) revealed a greater than 50-fold separation in potency over its less active enantiomer L-733,061 (ID50 > or = 10 mg/kg). In contrast, the non-brain penetrant quaternary ketone NK1 receptor antagonist, L-743,310 (3 mg/kg), did not attenuate the response to formalin, indicating that the antinociceptive effect of blockade of NK1 receptors by L-733,060 in this assay is centrally-mediated. These findings add to the preclinical evidence that NK1 receptor antagonists may be of therapeutic use as centrally-acting analgesics.