The reproducibility issue and preclinical academic drug discovery: educational and institutional initiatives fostering translation success

ABSTRACT

Introduction: Drug discovery depends critically upon published results from the academy. The reproducibility of preclinical research findings reported by academia in the peer-reviewed literature has been called into question, seriously jeopardizing the value of academic science for inventing therapeutics.

Areas covered: The corrosive effects of the reproducibility issue on drug discovery are considered. Purported correctives imposed upon academia from the outside deal mainly with expunging fraudulent literature and imposing punitive sanctions on the responsible authors. The salutary influence of such post facto actions on the reproducibility of discovery-relevant preclinical research data from academia appears limited. Rather, intentional doctoral-scientist education focused on data replicability and translationally-meaningful science and active participation of university entities charged with research innovation and asset commercialization toward ensuring data quality are advocated as key academic initiatives for addressing the reproducibility issue.

Expert opinion: A mindset shift on the part of both senior university faculty and the academy to take responsibility for the data reproducibility crisis and commit proactively to positive educational, incentivization, and risk- and reward-sharing practices will be fundamental for improving the value of published preclinical academic research to drug discovery.     

Disability in Older Adults 1: Prevalence,Causes, and Consequences

The effects of disability on an aging population's health and welfare are an important issue in gerontological research. The rapid growth of the elderly population and increases in longevity have led to an ongoing debate about whether longer lives can be matched by longer active lives that are free from disability. After a detailed review of current disability literature, the authors discuss the impact of disability in the elderly, defining disability and reviewing three classes of disability—physical, mental, and social. Both subjective and objective disability measures are described, and disability trends and prevalence rates are reviewed and compared cross culturally, by gender, by age, and over time. The path from chronic disease to disability is described and the consequences of living with disability are discussed in terms of family burdens and the increased need for medical care.     

Testing a Brief Self-Directed Behavioral Weight Control Program

Clinical obesity treatments are of limited reach. Self-directed weight control attempts are common, but little attention has been given to providing guidance for such efforts in the population. The present research tests a brief intervention approach to weight control. Pilot data were collected from 66 University of Minnesota employees (72.7% women, 81.8% white) randomized to an assessment-only control condition or a single intervention session to teach empirically valid self-directed weight-control methods. Mean baseline weight was 87.1 kilograms (range 64.0–120.3 kilograms). Though statistically nonsignificant, intervention participants averaged greater weight loss by 6 months than controls (–.80 kilograms vs. –.19 kilograms), F(1, 44) = .47, p = .50, Cohen's d = .21. There was a significant group × time interaction for self-weighing frequency, F(2, 41) = 10.84, p < .001. With some enhancement and more attention to dissemination, a brief self-directed program has potential as a useful approach to population weight-gain prevention.     

Differences in awareness between persons with left and right hemispheric stroke

Abstract

Aim: The aim of this study was to investigate whether there are any differences in awareness of ability between persons with left and right hemispheric stroke. Methods: The sample consisted of data from the Assessment of Awareness of Ability (A³) database, primarily consisting of clients admitted to occupational therapy services. In total the study included 183 data records from clients, 78 with left and 105 with right hemispheric stroke. Awareness of ability was assessed using the Assessment of Awareness of Ability (A³). Differences in awareness were investigated using t-tests, CI, effect size, and differential item functioning. Results: No significant overall mean difference (t-test = 1.31, p = 0.19) in awareness between left and right hemispheric stroke was identified. However, significant differences (p < 0.05) were identified on three specific items included in the A³. In these cases, persons with right hemispheric stroke showed a more limited awareness. Conclusion: Persons with right hemispheric stroke have more pronounced problems with being aware of limitations in specific ADL performance skills compared with persons with left hemispheric stroke.     

On Functions,Abilities and Quality of Life After Subarachnoid Haemorrhage: Occupational Therapy Aspects

This investigation addresses functions/impairments, abilities/disabilities and quality of life (QoL) in a consequtive series of non-hospitalized long-term survivors [2, 5–12 years] of subarachnoid haemorrhage (SAH). The investigated parameters of functions/impairments were: motor, language, perceptual and memory functions. Abilities/disabilities studied were: activities of daily living (ADL) including both personal- and instrumental ADL, working and leisure capacities. Quality of life was assessed using a double visual analogue scale. Occurrence of depression was registered using a self-rating scale.

A questionnaire focusing motor and language impairments, personal ADL, work and leisure activities was initially mailed to 324 subjects. Most of them answered the questionnaire. Ten hospitalized subjects could not validly report their functions and abilities and for that reason were excluded.

In a follow-up investigation up to 247 long-term non-hospitalized subjects were investigated by a physician and an occupational therapist. A total of 82% had at least one impairment. The majority (73%) had memory impairment and among these subjects equal proportions (about 50%) had impairments of long-and short-term memory. Forty-five percent were perceptually impaired, while motor impairment occurred for 25% and aphasia in 10%. Only a small minority (9%) were, according to self-reports, regarded as being to some extent disabled in personal ADL. The corresponding numbers of disabled in instrumental ADL, leisure and working-capacity were 52%, 48% and 40% respectively. Depression was found in 22%—among whom the majority had minimal or mild depression. Overall QoL was judged to be unchanged or increased in 62% of cases and, therefore, decreased in 38%.

As expected, impairments to a significant degree caused disabilities. None of the five different categories of impairment were associated with mood (depressed/not depressed) and QoL (decreased/not decreased). Occurrence of depression was significantly associated with the different aspects of disabilities. In contrast, among a series of instrumental ADL-variables, leisure and working capacity, QoL was influenced negatively only by decreased ability to act sociably and, to a minor extent, by depressed mood.

Judging from the extent of decreased quality of life, it appears that nearly 40% of all non-hospitalized former victims of SAH have not coped successfully with the impact of the SAH. A follow-up programme aiming at optimizing the coping process of SAH victims is, therefore, outlined     

The anti-arthritic activity of total glycosides from Pterocephalus hookeri,a traditional Tibetan herbal medicine

Context: Pterocephalus hookeri (C. B. Clarke) Hock., a traditional Tibetan herbal medicine rich in glycosides, has been used to treat several diseases including rheumatoid arthritis.

Objective: To evaluate the anti-arthritic activity of total glycosides from P. hookeri, and its possible mechanisms of action.

Materials and methods: Anti-arthritic activity of total glycosides from P. hookeri (oral administration for 30 days at 14–56?mg/kg) was evaluated using paw swelling, arthritis scores and histopathological measurement in adjuvant-induced arthritis (AA) Sprague-Dawley rats. The NF-κB p65 expression in synovial tissues, and serum superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) levels was measured in AA rats, respectively. Further assessment of anti-inflammatory and analgesic activities of these glycosides were carried out using inflammation and hyperalgesia models induced by xylene, carrageenan, agar and acetic acid, respectively.

Results: Total glycosides (56?mg/kg) decreased the paw swelling (38.0%, p?p?p?p?p?p?p?Discussion and conclusion: Our findings confirmed the anti-arthritic property of the total glycosides from P. hookeri, which may be attributed to its inhibition on NF-κB signalling and oxidative stress.     

Participation in the Chronic Phase of Stroke

Abstract

Background: Participation is a multidimensional concept, consisting of an objective and a subjective dimension. Many studies have focused on determinants of only 1 dimension of participation post stroke. Objective: To describe participation (both objective and subjective) and to determine how physical and cognitive independence and subjective complaints (pain, fatigue, and mood) influence participation in community-dwelling stroke survivors in the Netherlands. Methods: The Utrecht Scale for Evaluation of Rehabilitation (USER) measures physical and cognitive independence and subjective complaints. USER-Participation measures 3 dimensions of participation: frequency (objective perspective), restrictions (subjective perspective), and satisfaction (subjective perspective). Spearman correlations and backward linear regression analyses were used to analyze associations between the 3 USER-Participation scores with demographics, stroke characteristics, physical and cognitive independence, and subjective complaints. Results: Of the 111 participants, 48.5% returned to work post stroke, but mostly for only 1 to 16 hours a week. Experienced participation restrictions were most prevalent in physical exercise, chores in/around the house, housekeeping, and outdoor activities. On average, participants were relatively satisfied with their participation, but dissatisfaction occurred in cognition, activities outdoors, and work/housekeeping. Regression analysis revealed that objective participation was determined by physical and cognitive independence, age, and education, whereas subjective participation was determined by physical and cognitive independence, fatigue, and mood. Conclusions: Most participants experienced participation problems, despite relatively good physical recovery. In addition to physical and cognitive factors, subjective complaints of persons with stroke should be addressed in the rehabilitation program.     

Medication Use in Alzheimer's Disease and Healthy Aging

Abstract

The purpose of this research was to determine if decreased utilization of specific medication in individuals with Alzheimer's disease (AD) reflects a global process of decreased medication usage. Participants were 1103 individuals (461 controls; 437 probable AD; 161 possible AD, and 44 Mixed Dementia), drawn from our Alzheimer's Disease Research Registry. Medication usage at entry into the registry did not differ between controls and probable AD cases. Possible AD and the mixed dementia cases took significantly more medications than controls or probable AD cases. Longitudinal analysis showed no significant changes in controls and mixed dementia cases up to 2 years, and use increased in possible and probable AD cases over time. Stratification of subjects by MMSE scores at entry showed no significant difference between groups. Medication use in probable AD patients does not differ from controls, and does not seem to be subject to systematic bias based on disease progression (as measured by MMSE scores). The presence of co-morbidity adds to medication utilization. Cognitive impairment does not appear to affect total medication use, suggesting that specific medication utilization patterns are unlikely to be the result of larger usage patterns.     

Adaptive Sliding Transfer for Toileting

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