Cognitive activity for the treatment of older adults with mild Alzheimer's Disease (AD) - PACE AD: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Participation in cognitive stimulation therapy (CST) may reduce the rate of cognitive decline in people with Alzheimer's disease (AD), however it is unclear if the training of carers to deliver activities is sufficient to improve the clinical outcome of patients. The Promoting Healthy Ageing with Cognitive Exercise for Alzheimer's Disease (PACE-AD) study has been designed to determine if change in cognitive function over a six month period can be achieved with participation in cognitive stimulating activities when the intervention is delivered to carers only as opposed to carers and patients.</p> <p>Methods/Design</p> <p>The study will aim to recruit 128 community-dwelling men and women with probable AD according to NINCDS-ADRDS criteria. Participants will be randomly allocated to one of two cognitive activity treatment groups: (1) Participants with mild AD and their companions together (2) Companions of participants with mild AD alone. The intervention will consist of a twelve-week program of cognitive stimulation. Seven weeks of the program will involve 90-minute group sessions delivered once per week while the remaining weeks of the program will involve structured home based activities with telephone support. The primary outcome measure of the study is the change from baseline in the total score on the Alzheimer Disease Assessment Scale-Cognitive (ADAS-COG). Secondary outcomes of interest include changes in health related quality of life, mood, memory, language, executive functions, independent living abilities and psychiatric symptoms for participants with mild AD. Changes in companion quality of life, mood, and general health will also be monitored. Primary endpoints will be collected 13 and 26 weeks after the baseline assessment.</p> <p>Discussion</p> <p>The proposed project will provide evidence as to whether CST for people with AD and their companions is more beneficial than when used for companions alone. Outcomes sought include a reduction of further cognitive decline and improved quality of life amongst older adults with mild AD. We anticipate that the results of this study will have implications for the development of cost-effective evidence-based best practice to treat people with mild AD.</p> <p>Trial registration</p> <p><a href="http://www.anzctr.org.au/ACTRN12610000653066.aspx">ACTRN12610000653066</a></p

GPML: an XML-based standard for the interchange of genetic programming trees

We propose a Genetic Programming Markup Language (GPML), an XML based standard for the interchange of genetic programming trees, and outline the benefits such a format would bring in allowing the deployment of trained genetic programming (GP) models in applications as well as the subsidiary benefit of allowing GP researchers to directly share trained trees. We present a formal definition of this standard and describe details of an implementation. In addition, we present a case study where GPML is used to implement a model predictive controller for the control of a building heating plant

CMV retinitis in China and SE Asia: the way forward

AIDS-related CMV retinitis is a common clinical problem in patients with advanced HIV/AIDS in China and Southeast Asia. The disease is causing blindness, and current clinical management, commonly characterized by delayed diagnosis and inadequate treatment, results in poor clinical outcomes: 21% - 36% of eyes with CMV retinitis are already blind at the time the diagnosis is first established by an ophthalmologist. CMV retinitis also identifies a group of patients at extraordinary risk of mortality, and the direct or indirect contribution of extra-ocular CMV disease to AIDS-related morbidity and mortality is currently unmeasured and clinically often overlooked. The obvious way to improve clinical management of CMV retinitis is to screen all patients with CD4 counts < 100 cells/μL with indirect ophthalmoscopy at the time they first present for care, and to provide systemic treatment with oral valganciclovir when active CMV retinitis is detected. Treatment of opportunistic infections is an integral part of HIV management, and, with appropriate training and support, CMV retinitis screening and treatment can be managed by the HIV clinicians, like all other opportunistic infections. Access to ophthalmologist has been problematic for HIV patients in China, and although non-ophthalmologists can perform screening, sophisticated ophthalmological skills are required for the management of retinal detachment and immune recovery uveitis, the major complications of CMV retinitis. CMV retinitis has been clinically ignored, in part, because of the perceived complexity and expense of treatment, and this obstacle can be removed by making valganciclovir affordable and widely available. Valganciclovir is an essential drug for developing successful programs for management of CMV retinitis in China and throughout SE Asia

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201

Optimal sampling of MRI slices for the assessment of knee cartilage volume for cross-sectional and longitudinal studies

BACKGROUND: MRI slices of 1.5 mm thickness have been used in both cross sectional and longitudinal studies of osteoarthritis, but is difficult to apply to large studies as most techniques used in measuring knee cartilage volumes require substantial post-image processing. The aim of this study was to determine the optimal sampling of 1.5 mm thick slices of MRI scans to estimate knee cartilage volume in males and females for cross-sectional and longitudinal studies. METHODS: A total of 150 subjects had a sagittal T1-weighted fat-suppressed MRI scan of the right knee at a partition thickness of 1.5 mm to determine their cartilage volume. Fifty subjects had both baseline and 2-year follow up MRI scans. Lateral, medial tibial and patellar cartilage volumes were calculated with different samples from 1.5 mm thick slices by extracting one in two, one in three, and one in four to compare to cartilage volume and its rate of change. Agreement was assessed by means of intraclass correlation coefficient (ICC) and Bland & Altman plots. RESULTS: Compared to the whole sample of 1.5 mm thick slices, measuring every second to fourth slice led to very little under or over estimation in cartilage volume and its annual change. At all sites and subgroups, measuring every second slice had less than 1% mean difference in cartilage volume and its annual rate of change with all ICCs ≥ 0.98. CONCLUSION: Sampling alternate 1.5 mm thick MRI slices is sufficient for knee cartilage volume measurement in cross-sectional and longitudinal epidemiological studies with little increase in measurement error. This approach will lead to a substantial decrease in post-scan processing time

The impact of individual Cognitive Stimulation Therapy (iCST) on cognition, quality of life, caregiver health, and family relationships in dementia: a randomized controlled trial

Background: Cognitive Stimulation Therapy (CST) is a well-established group psychosocial intervention for people with dementia. There is evidence that homebased programmes of cognitive stimulation delivered by family caregivers may benefit both the person and the caregiver. However, no previous studies have evaluated caregiver-delivered CST. This study aimed to evaluate the effectiveness of a home-based, caregiver-led individual Cognitive Stimulation Therapy (iCST) program in (i) improving cognition and quality of life (QoL) for the person with dementia and (ii) mental and physical health (wellbeing) for the caregiver. Methods and Findings: A single-blind, pragmatic randomized trial (RCT) at eight study sites across the UK. The intervention and blinded assessment of outcomes were conducted in participants’ homes. 356 people with mild to moderate dementia and their caregivers recruited from memory services, and community mental health teams. Participants were randomly assigned to iCST (75, 30 minute sessions) or treatment as usual (TAU) control over 25 weeks. iCST sessions consisted of themed activities designed to be mentally stimulating and enjoyable. Caregivers delivering iCST received training and support from an unblind researcher. Primary outcomes were cognition (Alzheimer’s Disease Assessment Scale cognitive [ADAS-Cog]) and self-reported quality of life (QoL) (Quality of Life Alzheimer’s Disease [QoL-AD]) for the person with dementia, and general health status (Short Form-12 [SF-12]) for the caregiver. Secondary outcomes included: quality of the caregiving relationship from the perspectives of the person and of the caregiver (Quality of the Carer Patient Relationships Scale), and health-related QoL (EQ5D) for the caregiver. Intention to treat (ITT) analyses were conducted. At the post-test (26 weeks), there were no differences between the iCST and TAU groups in the outcomes of cognition (MD = -0·55, 95% CI -2·00 to 0·90; p=0·45), and self-reported quality of life (QoL) (MD = -0·02, 95% CI -1·22 to 0·82; p= 0·97) for people with dementia, or caregivers’ general health status (MD=0·13, 95% CI -1·65 to 1·91; p=0·89). However, people with dementia receiving iCST rated the relationship with their caregiver more positively (MD = 1·77, 95% CI 0·26 to 3·28; p=0·02) and iCST improved QoL for caregivers (EQ-5D, MD = 0·06, 95% CI 0·02 to 0·10; p=0·01). Forty percent (72/180) of dyads allocated to iCST completed at least two sessions per week, with 22% (39/180) completing no sessions at all. Study limitations include low adherence to the intervention. Conclusions: There was no evidence that iCST has an effect on cognition or QoL for people with dementia. However, participating in iCST appeared to enhance the quality of the caregiving relationship and caregivers’ QoL

Relationship between radiographic changes and symptoms or physical examination findings in subjects with symptomatic medial knee osteoarthritis: a three-year prospective study

<p>Abstract</p> <p>Background</p> <p>Although osteoarthritis (OA) of the knee joints is the most common and debilitating joint disease in developed countries, the factors that determine the severity of symptoms are not yet understood well. Subjects with symptomatic medial knee OA were followed up prospectively to explore the relationship between radiographic changes and symptoms or physical examination findings.</p> <p>Methods</p> <p>One-hundred six OA knees in 68 subjects (mean age 71.1 years; 85% women) were followed up at 6-month intervals over 36 months. At each visit, knee radiographs were obtained, symptoms were assessed by a validated questionnaire, and the result of physical examination was recorded systematically using a specific chart. Correlations between the change of radiographs and clinical data were investigated in a longitudinal manner.</p> <p>Results</p> <p>During the study period, the narrowing of joint space width (JSW) was observed in 34 joints (32%). Although those knees were clinically or radiographically indistinguishable at baseline from those without JSW narrowing, differences became apparent at later visits during the follow-up. The subjects with knees that underwent JSW narrowing had severer symptoms, and the symptoms tended to be worse for those with higher rates of narrowing. A significant correlation was not found between the severity of symptoms and the growth of osteophytes. For the knees that did not undergo radiographic progression, the range of motion improved during the follow-up period, possibly due to the reduction of knee pain. Such improvement was not observed with the knees that underwent JSW narrowing or osteophyte growth.</p> <p>Conclusion</p> <p>The result of this study indicates that the symptoms of knee OA patients tend to be worse when JSW narrowing is underway. This finding may explain, at least partly, a known dissociation between the radiographic stage of OA and the severity of symptoms.</p

ENU Mutagenesis Identifies Mice with Morbid Obesity and Severe Hyperinsulinemia Caused by a Novel Mutation in Leptin

BACKGROUND: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. METHODOLOGY/PRINCIPAL FINDINGS: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. CONCLUSIONS/SIGNIFICANCE: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome