Exercise intervention to prevent falls and enhance mobility in community dwellers after stroke: a protocol for a randomised controlled trial

Background: Stroke is the most common disabling neurological condition in adults. Falls and poor mobility are major contributors to stroke-related disability. Falls are more frequent and more likely to result in injury among stroke survivors than among the general older population. Currently there is good evidence that exercise can enhance mobility after stroke, yet ongoing exercise programs for general community-based stroke survivors are not routinely available. This randomised controlled trial will investigate whether exercise can reduce fall rates and increase mobility and physical activity levels in stroke survivors. Methods and design: Three hundred and fifty community dwelling stroke survivors will be recruited. Participants will have no medical contradictions to exercise and be cognitively and physically able to complete the assessments and exercise program. After the completion of the pre-test assessment, participants will be randomly allocated to one of two intervention groups. Both intervention groups will participate in weekly group-based exercises and a home program for twelve months. In the lower limb intervention group, individualised programs of weight-bearing balance and strengthening exercises will be prescribed. The upper limb/cognition group will receive exercises aimed at management and improvement of function of the affected upper limb and cognition carried out in the seated position. The primary outcome measures will be falls (measured with 12 month calendars) and mobility. Secondary outcome measures will be risk of falling, physical activity levels, community participation, quality of life, health service utilisation, upper limb function and cognition. Discussion: This study aims to establish and evaluate community-based sustainable exercise programs for stroke survivors. We will determine the effects of the exercise programs in preventing falls and enhancing mobility among people following stroke. This program, if found to be effective, has the potential to be implemented within existing community services. Trial registration: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000479505)

Amygdala Hypoactivity to Fearful Faces in Boys With Conduct Problems and Callous-Unemotional Traits

OBJECTIVE: Although early-onset conduct problems predict both psychiatric and health problems in adult life, little research has been done to index neural correlates of conduct problems. Emerging research suggests that a subgroup of children with conduct problems and elevated levels of callous-unemotional traits may be genetically vulnerable to manifesting disturbances in neural reactivity to emotional stimuli indexing distress. Using functional MRI, the authors evaluated differences in neural response to emotional stimuli between boys with conduct problems and elevated levels of callous-unemotional traits and comparison boys. METHOD: Seventeen boys with conduct problems and elevated levels of callous-unemotional traits and 13 comparison boys of equivalent age (mean=11 years) and IQ (mean=100) viewed blocked presentations of fearful and neutral faces. For each face, participants distinguished the sex of the face via manual response. RESULTS: Relative to the comparison group, boys with conduct problems and elevated levels of callous-unemotional traits manifested lesser right amygdala activity to fearful faces. CONCLUSIONS: This finding is in line with data from studies of adults with antisocial behavior and callous-unemotional traits (i.e., psychopaths), as well as from a recent study of adolescents with callous-unemotional traits, and suggests that the neural substrates of emotional impairment associated with callous-unemotional antisocial behavior are already present in childhood

Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients

Background Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. Objectives To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. Methods Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). Results Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5–36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18–28) and non-carriers (median score 22, IQR 16–28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). Conclusions Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls

Effectiveness of physiotherapy exercise following hip arthroplasty for osteoarthritis: a systematic review of clinical trials

Background: Physiotherapy has long been a routine component of patient rehabilitation following hip joint replacement. The purpose of this systematic review was to evaluate the effectiveness of physiotherapy exercise after discharge from hospital on function, walking, range of motion, quality of life and muscle strength, for osteoarthritic patients following elective primary total hip arthroplasty. Methods: Design: Systematic review, using the Cochrane Collaboration Handbook for Systematic Reviews of Interventions and the Quorom Statement. Database searches: AMED, CINAHL, EMBASE, KingsFund, MEDLINE, Cochrane library (Cochrane reviews, Cochrane Central Register of Controlled Trials, DARE), PEDro, The Department of Health National Research Register. Handsearches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings. No language restrictions were applied. Selection: Trials comparing physiotherapy exercise versus usual/standard care, or comparing two types of relevant exercise physiotherapy, following discharge from hospital after elective primary total hip replacement for osteoarthritis were reviewed. Outcomes: Functional activities of daily living, walking, quality of life, muscle strength and range of hip joint motion. Trial quality was extensively evaluated. Narrative synthesis plus meta-analytic summaries were performed to summarise the data. Results: 8 trials were identified. Trial quality was mixed. Generally poor trial quality, quantity and diversity prevented explanatory meta-analyses. The results were synthesised and meta-analytic summaries were used where possible to provide a formal summary of results. Results indicate that physiotherapy exercise after discharge following total hip replacement has the potential to benefit patients. Conclusion: Insufficient evidence exists to establish the effectiveness of physiotherapy exercise following primary hip replacement for osteoarthritis. Further well designed trials are required to determine the value of post discharge exercise following this increasingly common surgical procedure

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

Systems-Scale Analysis Reveals Pathways Involved in Cellular Response to Methamphetamine

Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/ contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions

Implementation fidelity of a nurse-led falls prevention program in acute hospitals during the 6-PACK trial

Background: When tested in a randomized controlled trial (RCT) of 31,411 patients, the nurse-led 6-PACK falls prevention program did not reduce falls. Poor implementation fidelity (i.e., program not implemented as intended) may explain this result. Despite repeated calls for the examination of implementation fidelity as an essential component of evaluating interventions designed to improve the delivery of care, it has been neglected in prior falls prevention studies. This study examined implementation fidelity of the 6-PACK program during a large multi-site RCT. Methods: Based on the 6-PACK implementation framework and intervention description, implementation fidelity was examined by quantifying adherence to program components and organizational support. Adherence indicators were: 1) falls-risk tool completion; and for patients classified as high-risk, provision of 2) a ‘Falls alert’ sign; and 3) at least one additional 6-PACK intervention. Organizational support indicators were: 1) provision of resources (executive sponsorship, site clinical leaders and equipment); 2) implementation activities (modification of patient care plans; training; implementation tailoring; audits, reminders and feedback; and provision of data); and 3) program acceptability. Data were collected from daily bedside observation, medical records, resource utilization diaries and nurse surveys. Results: All seven intervention components were delivered on the 12 intervention wards. Program adherence data were collected from 103,398 observations and medical record audits. The falls-risk tool was completed each day for 75% of patients. Of the 38% of patients classified as high-risk, 79% had a ‘Falls alert’ sign and 63% were provided with at least one additional 6-PACK intervention, as recommended. All hospitals provided the recommended resources and undertook the nine outlined program implementation activities. Most of the nurses surveyed considered program components important for falls prevention. Conclusions: While implementation fidelity was variable across wards, overall it was found to be acceptable during the RCT. Implementation failure is unlikely to be a key factor for the observed lack of program effectiveness in the 6-PACK trial. Trial registration: The 6-PACK cluster RCT is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000332921 (29 March 2011)

Tracking Parkinson's : Study Design and Baseline Patient Data

Peer reviewedPublisher PD

Resolving the ancestry of Austronesian-speaking populations

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion