Evidence of cancer-linked rodent zoonoses from biophysical genomic variations.

As a mechanism to explore the role of environmental adaptation in establishing the optimal distribution of single nucleotide polymophisms (SNPs) within resident homeostatic populations, relationships between quantified environmental parameters and the frequencies of the variants are being explored. We have performed sequential double-blind scans on more than 30% of chromosome 3 in an attempt to discover possible relationships using simple mathematical functions that are indicative of "adaptive forces" on the variants due to specific quantified environmental agents. We have found an association of rs13071758 with rodent zoonotic diseases. This variant is within the FHIT gene, which spans the most fragile of the common fragile sites in human lymphoblasts. FHIT, which is highly sensitive to environmental carcinogens, is partially lost in most human cancers. This finding is consistent with other studies postulating an association between rodent zoonoses and cancer. We quantify the adaptive force on the T allele as 0.28 GEUs per unit of zoonotic rodent host richness.

Quantification of adaptive forces on SNP rs1010211 due to viral zoonotic pathogens.

Widespread genotyping of human populations in environmental homeostasis has created opportunities to quantify how environmental parameters affect the genomic distribution of variants in healthy populations. This represents an ongoing natural experiment upon the human species that can only be understood through developing models of adaptation. By examining the information dynamics of optimal SNP distributions within such populations, "adaptive forces" on genomic variants can be quantified through comparisons between different populations. To this end, we are performing double-blind scans of SNPs in order to ascertain any potential smooth functional relationships between the frequencies of the variants and changes in quantified environmental parameters. At present, we have sequentially examined more than twenty thousand SNPs (on chromosome 3) of nine homeostatic native populations for potential adaptive flagging of the variants as functions of 15 environmental parameters. Our first significant flag has related rs1010211 to viral pathogens in mammalian hosts. Such pathogens present a significant risk for the emergence of new infectious diseases in humans. This genomic variant is within the gene TNIK, which is a germinal center kinase (GCK). GCKs are participants in both adaptive and innate immune regulation. However, the function of TNIK is not fully understood. We quantify the adaptive force on the C allele due to the pathogens as 0.04 GEU's/viral species.

Predictive Factors for Conversion to Dementia in Individuals with Early-Onset Mild Cognitive Impairment.

INTRODUCTION: There is little research on factors predicting conversion to dementia in early-onset mild cognitive impairment (eoMCI), a transitional stage between healthy ageing and dementia in individuals below the age of 65. We aimed to examine whether sociodemographic and clinical factors at initial presentation predicted dementia progression in a cohort of eoMCI patients attending a memory service, at a university teaching hospital in the UK. METHODS: This is a retrospective case note study of individuals diagnosed with eoMCI between 2000 and 2013 at the Younger Person's Memory Service (YPMS) in Leicestershire, England. Data collected at assessment included social factors, demographic characteristics, and medical and psychiatric history, as well as standardized cognitive assessment scores. Variables were analysed using χ2 or independent sample t tests to identify associations. A Cox regression survival analysis was done to identify predictive factors for dementia conversion. An ROC analysis for total CAMCOG was used to investigate sensitivity and specificity for dementia converters versus non-converters. RESULTS: Out of 531 subjects who attended YPMS, 65 patients were given a diagnosis of eoMCI (47.7% female; mean age 56.4 ± 7.54 years). Of these, 21 (32.3%) converted to dementia during their course within the service. Comparison between subgroups revealed a significant association between dementia conversion and higher years of education and lower MMSE and CAMCOG (total and subscale) scores at baseline. Smoking history, alcohol use, or medical history such as diabetes or heart disease were not associated with conversion. Cox regression survival analysis showed higher education in years and lower total CAMCOG scores were significant predictors for conversion. Lower scores on the recent memory, remote memory, learning memory, and executive function subscales of the CAMCOG were also significant predictors for conversion. ROC curve analysis for total CAMCOG demonstrated that the best detection of dementia converters can be achieved with a cutoff score of 90.5/107 (sensitivity of 76.2% and specificity of 68.2%). Area under the curve was 0.808 (95% CI: 0.697-0.920). CONCLUSION: More years in education and lower cognitive scores on CAMCOG at initial assessment are associated with progression to dementia from eoMCI. Further research is required to explore these predictive factors more.

Predictors of Disease Progression in Early-Onset Alzheimer's Dementia: A Retrospective Cohort Study.

OBJECTIVES: Early-onset Alzheimer's disease (EOAD), defined as onset of AD before the age of 65 years, is less common than the late-onset type, and little is known about the factors affecting disease progression. The aim of the study was to investigate factors influencing disease progression in people with EOAD. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: People with EOAD who were assessed and attended the specialist memory service at a university teaching hospital in a European setting, between 2000 and 2010. MEASURES: Sociodemographic details and clinical and cognitive assessments at initial assessment were used as potential predictors of change in clinical status and outcome at final follow-up within the memory service. RESULTS: Of the 101 people diagnosed with EOAD during this period, 96 patients were followed up (53 women; aged 59 ± 4.9 years; mean follow-up 36.3 ± 29.12 months). Patients were classified as Stable (n = 25) if continued within the memory service or discharged to primary care, and those transferred to other specialist services (n = 66) for further inputs, institutional care (n = 4), or died (n = 1) were classified as Worseners (n = 71). Lower education (P = .008), lower Cambridge Cognition Examination scores (P = .049), and presence of family history of dementia [P = .012, χ2 (1) = 8.84] was associated with worse change in clinical status. Furthermore, cognitive deficits such as lower scores on comprehension, recent memory, and executive functions were found to predict a worse clinical outcome. CONCLUSIONS AND IMPLICATIONS: Identification of predictors of faster disease progression has significant clinical benefit, allowing clinicians to estimate prognosis and plan patient care accordingly.

Driving Cessation in Patients Attending a Young-Onset Dementia Clinic: A Retrospective Cohort Study.

BACKGROUND: Although driving by persons with dementia is an important public health concern, little is known about driving cessation in younger people with dementia. We aimed to determine the prevalence and factors affecting driving cessation in individuals with and without dementia aged under 65 years attending a memory clinic in a European setting. METHODS: Subjects were consecutive patients assessed at a specialist memory service at a university teaching hospital between 2000 and 2010. The data collected included demographic, clinical, standardized cognitive assessments as well as information on driving. Dementia diagnosis was made using ICD-10 criteria. RESULTS: Of the 225 people who were or had been drivers, 32/79 (41%) with young-onset dementia (YOD) stopped driving compared to 25/146 (17%) patients who had cognitive impairment due to other causes. Women were more likely to cease driving and voluntarily than men (p < 0.001). Diagnosis of YOD was associated with driving cessation (1.193, 95% CI 0.570-1.815, p ≤ 0.001), and was mediated by impairment in praxis with the highest indirect mediation effect (0.754, 95% CI 0.183-1.401, p = 0.009). CONCLUSIONS: YOD diagnosis, female gender, and impairment in praxis have a higher probability for driving cessation in those under 65 years of age with cognitive impairment.

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

Screening for depression in older people on acute medical wards: the validity of the Edinburgh Depression Scale.

BACKGROUND: depression is common in people with poor physical health, particularly within the acute medical in-patient setting. Co-morbid depression contributes to poor outcomes, and screening for depression in acute medical in-patients has been advocated. The Edinburgh Depression Scale (EDS) has been validated in a variety of general hospital patient groups, but not previously in older acute medical in-patients. METHODS: one hundred and eighteen patients aged 65 and older on acute medical wards were assessed using a standardised diagnostic interview (Present State Examination-Schedules for Clinical Assessment in Neuropsychiatry) to identify depression according to ICD-10 criteria. They subsequently completed the EDS. The performance characteristics at a range of thresholds were compared, and receiver operating characteristic curve analysis was performed. RESULTS: the optimal EDS cut-off for identifying ICD-10 depressive episode was 7/8, with a sensitivity of 88%, specificity of 77%, positive predictive value of 52% and negative predictive value of 96%. The area under the receiver operating characteristic curve was 0.91. CONCLUSION: the EDS was shown to be a useful instrument for detecting clinical depression in older people on acute medical wards in this study. Its performance was equivalent to other validated screening instruments in this population. Our findings add further weight to using the EDS as a screening instrument for depression in multiple general hospital settings.

Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.

BACKGROUND: Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. METHODS: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS: Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]). INTERPRETATION: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING: Medical Research Council and UK Alzheimer's Society.

Screening for depression in older adults on an acute medical ward: the validity of NICE guidance in using two questions.

BACKGROUND: depression is common in older people in general hospital settings and associated with poor outcomes. This study aimed to evaluate the validity of two screening questions recommended by the UK National Institute for Health and Clinical Excellence (NICE). METHODS: one hundred and eighteen patients aged over 65 years, admitted to acute medical wards at a teaching hospital, were interviewed in a standardised manner using relevant sections of the Present State Examination-Schedules for Clinical Assessment in Neuropsychiatry to identify depression according to ICD-10 criteria. Subsequently, participants completed the two depression screening questions and the 15-item version of the Geriatric Depression Scale (GDS-15). RESULTS: a threshold of one or more positive responses to the two NICE depression screening questions gave a sensitivity of 100%, specificity of 71%, positive predictive value (PPV) of 49% and negative predictive value (NPV) of 100%. The GDS-15 optimal cut-off was 6/7 with a sensitivity of 80%, specificity of 86%, PPV of 62% and NPV of 94%. A two-stage screening process utilising the NICE two questions followed by the GDS-15 with these cut-offs gave a sensitivity of 80%, specificity of 91%, PPV of 71% and NPV of 94%. CONCLUSION: the two depression questions perform well as an initial screening process for non-cognitively impaired older people in the acute medical setting. A positive response to either question would indicate that further assessment is required by a clinician competent in diagnosing depression in this population, or the possible use of a more detailed instrument such as the GDS-15 to reduce the number of false-positive cases.

Review of brief cognitive tests for patients with suspected dementia.

BACKGROUND: As the population ages, it is increasingly important to use effective short cognitive tests for suspected dementia. We aimed to review systematically brief cognitive tests for suspected dementia and report on their validation in different settings, to help clinicians choose rapid and appropriate tests. METHODS: Electronic search for face-to-face sensitive and specific cognitive tests for people with suspected dementia, taking ≤ 20 minutes, providing quantitative psychometric data. RESULTS: 22 tests fitted criteria. Mini-Mental State Examination (MMSE) and Hopkins Verbal Learning Test (HVLT) had good psychometric properties in primary care. In the secondary care settings, MMSE has considerable data but lacks sensitivity. 6-Item Cognitive Impairment Test (6CIT), Brief Alzheimer's Screen, HVLT, and 7 Minute Screen have good properties for detecting dementia but need further validation. Addenbrooke's Cognitive Examination (ACE) and Montreal Cognitive Assessment are effective to detect dementia with Parkinson's disease and Addenbrooke's Cognitive Examination-Revised (ACE-R) is useful for all dementias when shorter tests are inconclusive. Rowland Universal Dementia Assessment scale (RUDAS) is useful when literacy is low. Tests such as Test for Early Detection of Dementia, Test Your Memory, Cognitive Assessment Screening Test (CAST) and the recently developed ACE-III show promise but need validation in different settings, populations, and dementia subtypes. Validation of tests such as 6CIT, Abbreviated Mental Test is also needed for dementia screening in acute hospital settings. CONCLUSIONS: Practitioners should use tests as appropriate to the setting and individual patient. More validation of available tests is needed rather than development of new ones.

The utility of the Edinburgh Depression Scale as a screening tool for depression in Parkinson's disease.

OBJECTIVE: This study aimed to evaluate the Edinburgh Depression Scale (EDS) as a screening tool for use in a Parkinson's disease (PD) population. Many commonly used depression scales include items relating to somatic symptoms that also occur in PD, which could potentially result in inaccurate reporting of depressive symptoms. The EDS is a scale that incorporates no somatic items. METHOD: One hundred twenty patients attending specialist PD clinics were assessed using a standardised diagnostic interview (Present State Examination--Schedules for Clinical Assessment in Neuropsychiatry) to establish a diagnosis of DSM-IV depression. They later completed the EDS with another researcher who was blind to the results of diagnostic interview. A receiver operating characteristic curve analysis was carried out to identify the optimal threshold score on the EDS and the Brief EDS to identify any depressive disorder or major depression. The performance characteristics at a range of thresholds were compared. RESULTS: A cut-off score of 10/11 gave maximal discriminant validity, with 74% sensitivity, 92% specificity and 64% positive predictive value for the identification of any depression according to DSM-IV criteria. CONCLUSIONS: This study suggests that the EDS is both a valid and potentially useful instrument that can be used as a quick self-completion questionnaire for screening for depression in people who have PD.

Screening for depression in Parkinson's disease: the performance of two screening questions.

BACKGROUND: the study objective was to evaluate the validity of the two questions recommended by the UK. National Institute for Health and Clinical Excellence for depression screening in Parkinson's disease (PD). METHODS: one hundred and twenty patients attending a PD out-patient clinic were interviewed in a standardised manner using relevant sections of the Present State Examination- Schedules for Clinical Assessment in Neuropsychiatry to identify depression according to Diagnostic and Statistical Manual (4th edition) criteria. Participants then completed the two depression screening questions and the 15-item Geriatric Depression Scale (GDS-15). RESULTS: sensitivity, specificity, positive and negative predictive values of the two questions and GDS-15 for major and minor depression combined were calculated for different cut-off scores and a receiver operating characteristics (ROC) analysis was conducted. A threshold of one or more positive responses to the two screening questions gave a sensitivity of 100% and specificity of 84% (positive predictive value 54%, negative predictive value 100%). The area under the ROC curve was 0.95. The optimal cut-off for the GDS-15 was 5/6, which gave a sensitivity of 84% and specificity of 89% (positive predictive value 59%, negative predictive value 97%), and the area under the curve was 0.92. CONCLUSION: this study shows that the two depression screening questions can be used as an initial screen for depression in patients with PD who have no significant cognitive impairment. A positive response to either of the questions would indicate that further diagnostic assessment may be warranted.

Information Dynamics of Whole Genome Adaptation.

The human genome is a complex, dynamic information system that encodes principles of life and living systems. These principles are incorporated in the structure of human genome sequence variation and are foundational for the continuity of life and human survival. Using first principles of thermodynamics and statistical physics, we have developed analogous "genodynamic tools" for population genomic studies. Characterizing genomic information through the lens of physics has allowed us to develop energy measures for modeling genome-environment interactions. In developing biophysical parameters for genome-environment homeostasis, we found that stable genomic free energy trades off low genomic energy (genomic conservation and increased order) and high genomic entropy (genomic variation) with an environmental potential that drives the variation. In our approach, we assert that common variants are dynamic sites in the genome of a population and that the stability of whole genome adaptation is reflected in the frequencies of maintained diversity in common variants for the population in its environment. In this paper, we address the relativity of whole genome adaptation towards homeostasis. By this we mean that adaptive forces are directly reflected in the frequency distribution of alleles and/or haplotypes of the population relative to its environment, with adaptive forces driving the genome towards homeostasis. The use of genomic energy units as a biophysical metric in DNA sequence variation analyses provides new insights into the foundations of population biology and diversity. Using our biophysical tools, population differences directly reflect the adaptive influences of the environment on populations.

Single Nucleotide Polymorphisms: A Window into the Informatics of the Living Genome.

Nested in the environment of the nucleus of the cell, the 23 sets of chromosomes that comprise the human genome function as one integrated whole system, orchestrating the expression of thousands of genes underlying the biological characteristics of the cell, individual and the species. The extraction of meaningful information from this complex data set depends crucially upon the lens through which the data are examined. We present a biophysical perspective on genomic information encoded in single nucleotide polymorphisms (SNPs), and introduce metrics for modeling information encoded in the genome. Information, like energy, is considered to be a conserved physical property of the universe. The information structured in SNPs describes the adaptation of a human population to a given environment. The maintained order measured by the information content is associated with entropies, energies, and other state variables for a dynamic system in homeostasis. "Genodynamics" characterizes the state variables for genomic populations that are stable under stochastic environmental stresses. The determination of allelic energies allows the parameterization of specific environmental influences upon individual alleles across populations. The environment drives population-based genome variation. From this vantage point, the genome is modeled as a complex, dynamic information system defined by patterns of SNP alleles and SNP haplotypes.

Development of genodynamic metrics for exploring the biophysics of DNA polymorphisms.

Single nucleotide polymorphisms (SNPs) represent an important type of dynamic sites within the human genome. These common variants often locally correlate within more complex multi-SNP haploblocks that are maintained throughout generations in a stable population. Information encoded in the structure of SNPs and SNP haploblock variation can be characterized through a normalized information content metric. Genodynamics is being developed as the analogous "thermodynamics" characterizing the state variables for genomic populations that are stable under stochastic environmental stresses. Since living systems have not been found to develop in the absence of environmental influences, this paper describes the analogous genomic free energy metrics in a given environment. SNP haploblocks were constructed by Haploview v4.2 for five chromosomes from phase III HapMap data, and the genomic state variables for each chromosome were calculated. An in silico analysis was performed on SNP haploblocks with the lowest genomic energy measures. Highly favorable genomic energy measures were found to correlate with highly conserved SNP haploblocks. Moreover, the most conserved haploblocks were associated with an evolutionarily conserved regulatory element and domain.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial.

BACKGROUND: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS: To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD: A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS: In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

Donepezil and memantine for moderate-to-severe Alzheimer's disease.

BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Increased prevalence of insomnia and changes in hypnotics use in England over 15 years: analysis of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys.

STUDY OBJECTIVES: To investigate changes over 15 years in the prevalence of insomnia and its association with demographic characteristics and hypnotic medication use. DESIGN: Analysis of 3 cross-sectional national mental health surveys carried out in 1993, 2000, and 2007, which used comparable sampling methods and identical insomnia assessments. SETTING: Adults living in private households in England. PATIENTS OR PARTICIPANTS: 20,503 people aged 16-64 years. MEASUREMENTS AND RESULTS: Insomnia was defined according to 4 different criteria, using relevant questions from the revised Clinical Interview Schedule. Modest increases in insomnia prevalence were found over the survey periods (any symptoms increasing from 35.0% in 1993 to 38.6% in 2007; insomnia diagnosis from 3.1% to 5.8%, respectively). In all 3 surveys, similar strengths of association in relation to all criteria were found, with female gender, increased age, lower educational attainment, depression, unemployment, economic inactivity, and widowed, divorced, or separated status. Prevalence of hypnotic use was double in 2000 (0.8%) compared to 1993 (0.4%); from limited information on selected medications, there was no such increase between 2000 and 2007. The reasons reported for any sleep disturbance over the last month were generally similar across surveys, the most marked change being illness/discomfort increasing as an explanation from 14.3% to 17.4% to 19.0%. CONCLUSIONS: In the English general population, insomnia (by any definition) showed a modest but steady increase in prevalence over a 15-year period. Strengths of associations with demographic factors and self-reported reasons for sleep disturbance remained reasonably stable over this period.

A new biophysical metric for interrogating the information content in human genome sequence variation: Proof of concept.

The 21st century emergence of genomic medicine is shifting the paradigm in biomedical science from the population phenotype to the individual genotype. In characterizing the biology of disease and health disparities in population genetics, human populations are often defined by the most common alleles in the group. This definition poses difficulties when categorizing individuals in the population who do not have the most common allele(s). Various epidemiological studies have shown an association between common genomic variation, such as single nucleotide polymorphisms (SNPs), and common diseases. We hypothesize that information encoded in the structure of SNP haploblock variation in the human leukocyte antigen-disease related (HLA-DR) region of the genome illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. In this paper we describe the development and application of the normalized information content (NIC) as a novel metric based on SNP haploblock variation. The NIC facilitates translation of biochemical DNA sequence variation into a biophysical quantity derived from Boltzmann's canonical ensemble in statistical physics and used widely in information theory. Our normalization of this information metric allows for comparisons of unlike, or even unrelated, regions of the genome. We report here NIC values calculated for HLA-DR SNP haploblocks constructed by Haploview, a product of the International Haplotype Map Project. These haploblocks were scanned for potential regulatory elements using ConSite and miRBase, publicly available bioinformatics tools. We found that all of the haploblocks with statistically low NIC values contained putative transcription factor binding sites and microRNA motifs, suggesting correlation with genomic regulation. Thus, we were able to relate a mathematical measure of information content in HLA-DR SNP haploblocks to biologically relevant functional knowledge embedded in the structure of DNA sequence variation. We submit that NIC may be useful in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens and in decoding the functional significance of common variation in the human genome.

The meaning of reporting forgetfulness: a cross-sectional study of adults in the English 2007 Adult Psychiatric Morbidity Survey.

OBJECTIVES: we measured subjective memory impairment (SMI) across the whole adult age range in a representative, national survey. Age is the strongest risk factor for dementia and SMI may be a precursor of objective cognitive impairment. We therefore hypothesised that SMI prevalence would rise with age in a non-demented population. METHOD: we analysed data from the English 2007 Adult Psychiatric Morbidity Survey, representative of people in private households. Participants were asked whether they had noticed problems with forgetting in the last month, or forgotten anything important in the last week; and completed the modified Telephone Interview for Cognitive Status. RESULTS: of those contacted, 7,461 (57%) participated. After excluding participants screening positive for dementia, 2,168 (31.7%) reported forgetfulness in the last month, while 449 (6.4%) had forgotten something important in the last week. Reporting forgetfulness was not associated with age. In a multivariate analysis including cognition and age, the only significant associates of reporting forgetfulness were anxiety, depressive and somatic symptoms. CONCLUSIONS: our hypothesis that subjective forgetfulness prevalence would rise with age in a non-demented population was not supported. Although subjective forgetfulness can be an early symptom of future or mild dementia, it is common and non-specific and-at population level-is more likely to be related to mood than to be an early symptom of dementia. Asking those presenting with subjective forgetfulness additional questions about memory and functional decline and objective forgetfulness is likely to help clinicians to detect those at risk of dementia.