Death Anxiety in Huntington Disease: Longitudinal Heath-Related Quality-of-Life Outcomes.

Objective: Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD. Methods: HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates. Results: Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being. Interpretation: Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.

Meaning and purpose in Huntington's disease: a longitudinal study of its impact on quality of life.

OBJECTIVE: Previous work in Huntington's disease (HD) has shown that a sense of meaning and purpose (M&P) is positively associated with positive affect and well-being (PAW); however, it was unknown whether HD-validated patient-reported outcomes (PROs) influence this association and how M&P impacts PROs in the future. Our study was designed to examine if HD-validated PROs moderate the relationship between M&P and PAW and to evaluate if baseline M&P predicts 12- and 24-month changes in HD-validated PROs. METHODS: This was a longitudinal, multicenter study to develop several PROs (e.g., specific for the physical, emotional, cognitive, and social domains) for people with HD (HDQLIFE). The sample consisted of 322 people with HD (n = 50 prodromal, n = 171 early-stage manifest, and n = 101 late-stage manifest HD). A single, multivariate linear mixed-effects model was performed with PAW as the outcome predicted by main effects for M&P and several moderators (i.e., an HD-validated PRO) and interactions between M&P and a given PRO. Linear-mixed models were also used to assess if baseline M&P predicted HD-validated PROs at 12 and 24 months. RESULTS: Higher M&P was positively associated with higher PAW regardless of the magnitude of symptom burden, as represented by HD-validated PROs, and independent of disease stage. In our primary analysis, baseline M&P predicted increased PAW and decreased depression, anxiety, anger, emotional/behavioral disruptions, and cognitive decline at 12 and 24 months across all disease stages. INTERPRETATION: These findings parallel those seen in the oncology population and have implications for adapting and developing psychotherapeutic and palliative HD interventions.

The Effects of Radiation and Emitted Light Transport on the Positional Response of 11 cm × 42.5 cm × 5.5 cm NaI(Tl) Detectors.

Experiments were performed with 30 11 cm × 42.5 cm × 5.5 cm NaI(Tl) detectors to better understand their positional response. Spectra were collected using 0.02 to 0.15 MBq point sources of Am, Cs, Co, and Ba positioned on lines parallel and perpendicular to the long axis of the crystal along both the narrow and wide detector faces as well as at different distances from them. A greater density of positions was sampled at the ends of the detector, and repeated measurements were made to examine potential gain drifts during the experiment. Spectroscopic peak counts, spectroscopic pulse heights, and net counts were analyzed. Empirical equations were fit to the aforementioned data for each specific source energy as a function of source position. In addition, a Monte Carlo radiation transport code was used to simulate the expected positionally variable response based solely upon radiation absorption. The simulated radiation transport efficiency functions were compared to the experimental data. The effects of the geometric radiation efficiency, the attenuation and scattering of emitted light within the scintillation crystal, and combined effects such as nonuniformity of the photomultiplier tube, photocathode response, and crystal irregularities were then distinguished. Functions describing each effect were derived. The results suggest potential new corrections to data obtained with large scintillation detectors as well as a novel approach to partial positional gamma-ray detection with minimal collimation, given that the energy resolution is within reason for particular photopeaks.

A Radiation Weather Station: Development of a Continuous Monitoring System for the Collection, Analysis, and Display of Environmental Radiation Data.

Due to heightened fear surrounding the possibility of future terrorism involving nuclear weapons and radiological dispersive devices, compounded by nonroutine nuclear power plant releases such as from emergencies or accidents, interest in contamination levels of environmental radiation has spiked. This project sought to develop a continuously operational radiation-monitoring system, with graphically visualized data easily accessible to the public. Because this continuing project is housed at a university facility, it bears no connection to perceived political or commercial interests, generally increasing the credibility of the endeavor. Outdoor weather and radiation parameters were gathered by sensors installed on the rooftop of a two-story building. A display and cloud service website was used to project the live data in an understandable format. A correlation was observed between weather and visibly heightened levels of gamma radiation. The goal of this paper is to share and highlight the overall hardware selection and the unique software challenges encountered when developing a robust collection and analysis system, along with the challenges of displaying meteorological and radiological data in a clear and concise fashion.

New symptomatic therapies for Huntington disease.

Huntington disease (HD), an inherited neurodegenerative disease, results from a CAG repeat expansion creating mutant huntingtin protein and widespread neuronal damage. Motor symptoms such as chorea are often preceded by cognitive and behavioral changes. Tetrabenazine and deutetrabebenazine are the two drugs approved by the Federal Food and Drug Administrationfor HD symptoms, is an effective therapy for chorea. However, there is still a large need for other symptomatic therapies impacting functional issues, including impaired gait, behavioral, and cognitive symptoms. A number of pharmacologic agents are under investigation. Additionally, other mechanisms are being targeted in motor symptom drug development, including phosphodiesterase 10 enzyme inhibition, dopamine modulation, and inhibition of deacetylation. There is perhaps the greatest unmet need in treating nonmotor effects, such as cognition and change in disease course. PBT2, a metal chaperone, and latrepirdine, a mitochondrial stabilizer, are under investigation specifically for the possibility of cognitive benefit. Unfortunately, there is a lack of HD-specific evidence on effective treatments for behavioral and psychiatric symptoms. Further investigation of nonmedication interventions such as physical therapy is necessary. As our understanding of molecular and cellular mechanisms underlying HD broadens, a new set of mechanistic targets will become the focus of HD symptomatic therapies.

Design of Interrogation Protocols for Radiation Dose Measurements Using Optically-Stimulated Luminescent Dosimeters.

Optically-stimulated luminescent dosimeters are capable of being interrogated multiple times post-irradiation. Each interrogation removes a fraction of the signal stored within the optically-stimulated luminescent dosimeter. This signal loss must be corrected to avoid systematic errors in estimating the average signal of a series of optically-stimulated luminescent dosimeter interrogations and requires a minimum number of consecutive readings to determine an average signal that is within a desired accuracy of the true signal with a desired statistical confidence. This paper establishes a technical basis for determining the required number of readings for a particular application of these dosimeters when using certain OSL dosimetry systems.

Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer: EGFR and beyond.

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non-small cell lung cancer (NSCLC). EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers. However, it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies. For instance, in addition to EGFR genotype, genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase (RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies. In this review, we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways. Specifically, the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors: cetuximab and erlotinib. The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors. Furthermore, they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.

Are therapeutic motivation and having one's own doctor as researcher sources of therapeutic misconception?

BACKGROUND: Desire for improvement in one's illness and having one's own doctor functioning as a researcher are thought to promote therapeutic misconception (TM), a phenomenon in which research subjects are said to conflate research with treatment. PURPOSE: To examine whether subjects' therapeutic motivation and own doctor functioning as researcher are associated with TM. METHODS: We interviewed 90 persons with advanced Parkinson's disease (PD) enrolled or intending to enrol in sham surgery controlled neurosurgical trials, using qualitative interviews. Subjects were compared by motivation (primarily therapeutic vs primarily altruistic or dually motivated by altruistic and therapeutic motivation), and by doctor status (own doctor as site investigator vs not) on the following: understanding of purpose of study; understanding of research procedures; perception of chance of direct benefit; and recollection and perceptions concerning the risks. RESULTS: 60% had primarily therapeutic motivation and 44% had their own doctor as the site investigator, but neither were generally associated with increased TM responses. Overall level of understanding of purpose and procedures of research were high. Subjects responded with generally high estimates of probability of direct benefit, but their rationales were personal and complex. The therapeutic-motivation group was more sensitive to risks. Five (5.6%) subjects provided incorrect answers to the question about purpose of research, and yet, showed excellent understanding of research procedures. CONCLUSIONS: In persons with PD involved in sham surgery clinical trials, being primarily motivated by desire for direct benefit to one's illness or having one's own doctor as the site investigator were not associated with greater TM responses.

Noninvasive image texture analysis differentiates K-ras mutation from pan-wildtype NSCLC and is prognostic.

BACKGROUND: Non-invasive characterization of a tumor's molecular features could enhance treatment management. Quantitative computed tomography (CT) based texture analysis (QTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in non-small cell lung cancer (NSCLC) and other cancers. In this study, we examined the potential of tumoral QTA to differentiate K-ras mutant from pan-wildtype tumors and its prognostic potential using baseline pre-treatment non-contrast CT imaging in NSCLC. METHODS: Tumor DNA from patients with early-stage NSCLC was analyzed on the LungCarta Panel. Cases with a K-ras mutation or pan-wildtype for 26 oncogenes and tumor suppressor genes were selected for QTA. QTA was applied to regions of interest in the primary tumor. Non-parametric Mann Whitney test assessed the ability of the QTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype. A recursive decision tree was developed to determine whether the differentiation of K-ras mutant from pan-wildtype tumors could be improved by sequential application of QTA parameters. Kaplan-Meier survival analysis assessed the ability of these markers to predict survival. RESULTS: QTA was applied to 48 cases identified, 27 had a K-ras mutation and 21 cases were pan-wildtype. Positive skewness and lower kurtosis were significantly associated with the presence of a K-ras mutation. A five node decision tree had sensitivity, specificity, and accuracy values (95% CI) of 96.3% (78.1-100), 81.0% (50.5-97.4), and 89.6% (72.9-97.0); respectively. Kurtosis was a significant predictor of OS and DFS, with a lower kurtosis value linked with poorer survival. CONCLUSIONS: Lower kurtosis and positive skewness are significantly associated with K-ras mutations. A QTA feature such as kurtosis is prognostic for OS and DFS. Non-invasive QTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival.

Epidemiology and Clinical Diagnosis of Parkinson Disease.

Parkinson disease (PD) is the second most common neurodegenerative disease, typically affecting elderly individuals and with a disproportionate male prevalence. Some genetic predispositions and environmental exposures are proposed risk factors for the development of PD. Cigarette smoking, caffeine intake, and increased serum uric acid have the strongest data supporting a reduced risk of PD. Mortality is slightly increased in most individuals with PD but certain clinical features and patient characteristics significantly increase mortality. Certain imaging modalities such as magnetic resonance imaging, transcranial ultrasound, and single-photon emission computed tomography can be useful in making diagnostic decisions in some cases of PD.

Sham surgery controls in Parkinson's disease clinical trials: views of participants.

BACKGROUND: Sham surgery controls are increasingly used in neurosurgical clinical trials in Parkinson's disease (PD) but remain controversial. We interviewed participants of such trials, specifically examining their understanding and attitudes regarding sham surgery. METHODS: We conducted semistructured qualitative interviews with participants of 3 sham surgery-controlled trials for PD, focusing on their understanding of sham design, their reactions to it, its impact on decision making, and their understanding of posttrial availability of the experimental intervention and its impact on decisions to participate. RESULTS: All subjects (n = 90) understood the 2-arm design; most (86%) described the procedural differences between the arms accurately. Ninety-two percent referred to scientific or regulatory reasons as rationales for the sham control, with 62% specifically referring to the placebo effect. Ninety-one percent said posttrial availability of the experimental intervention had a strong (48%) or some (43%) influence on their decision to participate, but only 68% understood the conditions for posttrial availability. CONCLUSIONS: Most subjects in sham surgery-controlled PD trials comprehend the sham surgery design and its rationale. Although there is room for improvement, most subjects of sham surgery trials appear to be adequately informed.

Comparison of enrollees and decliners of Parkinson disease sham surgery trials.

Concerns have been raised that persons with serious illnesses participating in high-risk research, such as PD patients in sham surgery trials, have unrealistic expectations and are vulnerable to exploitation. A comparison of enrollees and decliners of such research may provide insights about the adequacy of decision making by potential subjects. We compared 61 enrollees and 10 decliners of two phase II neurosurgical intervention (i.e., cellular and gene transfer) trials for PD regarding their demographic and clinical status, perceptions and attitudes regarding research risks, potential direct benefit, and societal benefit, and perspectives on the various potential reasons for and against participation. In addition to bivariate analyses, a logistic regression model examined variables regarding risks and benefits as predictors of participation status. Enrollees perceived lower risk of harm while tolerating higher risk of harm and were more action oriented, but did not have more advanced disease. Both groups rated hope for benefit as a strong reason to participate, whereas the fact that the study's purpose was not solely to benefit them was rated as "not a reason" against participation. Hope for benefit and altruism were rated higher than expectation of benefit as reasons in favor of participation for both groups. Enrollees and decliners are different in their views and attitudes toward risk. Although both are attracted to research because of hopes of personal benefit, this hope is clearly distinguishable from an expectation of benefit and does not imply a failure to understand the main purpose of research.

Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators.

BACKGROUND: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (Neurology 2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD. METHODS: Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale. RESULTS: Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysarthria [corrected] scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg). CONCLUSIONS: TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia. TRIAL REGISTRATION: Clinicaltrials.gov registration number (initial study): NCT00219804.

Ethics of sham surgery: perspective of patients.

Sham surgery is used as a control condition in neurosurgical clinical trials in Parkinson's disease (PD) but remains controversial. This study aimed to assess the perspective of patients with PD and the general public on the use of sham surgery controls. We surveyed consecutive patients from a university-based neurology outpatient clinic and a community-based general internal medicine practice. Background information was provided regarding PD and two possible methods of testing the efficacy of a novel gene transfer procedure, followed by questions that addressed participants' opinions related to the willingness to participate and permissibility of blinded and unblinded trial designs. Two hundred eighty-eight (57.6%) patients returned surveys. Patients with PD expressed less willingness to participate in the proposed gene transfer surgery trials. Unblinded studies received greater support, but a majority would still allow the use of sham surgery. Those in favor of sham surgery were more educated and more likely to use societal perspective rationales. Patients with PD are more cautious about surgical research participation than patients with non-PD. Their policy views were similar to others', with a majority supporting the use of sham controls. Future research needs to determine whether eliciting more considered judgments of laypersons would reveal different levels of support for sham surgery.

Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers.

BACKGROUND: Sham surgery is used in neurosurgical clinical trials in Parkinson disease (PD) but remains controversial. The controversy may be compounded when gene-transfer technologies are tested in sham surgical trials. OBJECTIVE: To determine the perspective of PD clinical researchers on the science and ethics of sham-surgery controls when used to test novel interventions such as gene transfer for PD. DESIGN: Internet survey eliciting both quantitative and qualitative responses. PARTICIPANTS: Investigator members of the Parkinson Study Group. RESULTS: Overall response rate was 103 (61.3%) of 168 researchers. A large majority (97%) of PD clinical researchers believe sham-surgery controls are better than unblinded controls for testing the efficacy of neurosurgical interventions such as gene transfer for PD. Half of the researchers believe an unblinded control efficacy trial would be unethical because it may lead to a falsely positive result. A minority (less than 22%) believe that an invasive sham condition that involves penetration of brain tissue is justified. CONCLUSION: It appears unlikely that the PD clinical research community will perceive future neurosurgical interventions for PD, such as gene-transfer therapies, as truly efficacious unless a sham-control condition is used to test it.

What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports.

Placebo, or sham surgery, as a control condition in surgical clinical trials in Parkinson disease (PD) remains controversial. The authors reviewed the adverse effects reported in double blind, placebo surgery controlled trials for PD. Placebo surgeries were generally safe and well tolerated but the number of subjects receiving the procedure was small. Harm occurred more frequently in subjects randomized to the experimental intervention.

Medical errors on an inpatient neurology service.

It has been proposed that "near misses" or "close calls" could serve as a focus for corrective action. Voluntary, anonymous error data were collected for 4 weeks and 235 events were reported: 168 were near misses and 67 resulted in adverse patient consequences. Of the 35 errors relating to diet, 17 (49%) resulted in adverse patient consequences, compared with only 5 of 43 (12%) of the errors related to medication.