Association of measured physical performance and demographic and health characteristics with self-reported physical function: implications for the interpretation of self-reported limitations

<p>Abstract</p> <p>Background</p> <p>Self-reported limitations in physical function often have only weak associations with measured performance on physical tests, suggesting that factors other than performance commonly influence self-reports. We tested if personal or health characteristics influenced self-reported limitations in three tasks, controlling for measured performance on these tasks.</p> <p>Methods</p> <p>We used cross-sectional data on adults aged ≥ 60 years (<it>N </it>= 5396) from the Third National Health and Nutrition Examination Survey to examine the association between the repeated chair rise test and self-reported difficulty rising from a chair. We then tested if personal characteristics, health indicators, body composition, and performance on unrelated tasks were associated with self-reported limitations in this task. We used the same approach to examine associations between personal and health characteristics and self-reported difficulty walking between rooms, controlling for timed 8-foot walk, and self-reported difficulty getting out of bed, controlling for repeated chair rise test results.</p> <p>Results</p> <p>In multivariate analyses, participants who performed worse on the repeated chair rise test were more likely to report difficulty with chair rise. However, older age, lower education level, lower serum albumin, comorbidities, knee pain, and being underweight were also significantly associated with self-reported limitations with chair rise. Results were similar for difficulty walking between rooms and getting out of bed.</p> <p>Conclusions</p> <p>Self-reports of limitations in physical function are influenced by personal and health characteristics that reflect frailty, and should not be interpreted solely as measured difficulty performing the task.</p

Sentinel surveillance of HIV-1 transmitted drug resistance, acute infection and recent infection.

BackgroundHIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT) services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.Methodology/principal findingsA consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI) clinic from 2004 to 2006 (N = 9,868) were evaluated by standard enzyme-linked immunoassays (EIA). HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) was the most common pattern detected, present in 28 cases of resistance (59.6%). Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p&lt;0.001), unprotected anal intercourse (AOR = 2.27; p&lt;0.001), sex with a known HIV-infected partner (AOR = 1.64; p = 0.02), and history of gonorrhea (AOR = 1.62; p = 0.03).ConclusionsNew HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment

Comparative Study of Human and Mouse Postsynaptic Proteomes Finds High Compositional Conservation and Abundance Differences for Key Synaptic Proteins

Direct comparison of protein components from human and mouse excitatory synapses is important for determining the suitability of mice as models of human brain disease and to understand the evolution of the mammalian brain. The postsynaptic density is a highly complex set of proteins organized into molecular networks that play a central role in behavior and disease. We report the first direct comparison of the proteome of triplicate isolates of mouse and human cortical postsynaptic densities. The mouse postsynaptic density comprised 1556 proteins and the human one 1461. A large compositional overlap was observed; more than 70% of human postsynaptic density proteins were also observed in the mouse postsynaptic density. Quantitative analysis of postsynaptic density components in both species indicates a broadly similar profile of abundance but also shows that there is higher abundance variation between species than within species. Well known components of this synaptic structure are generally more abundant in the mouse postsynaptic density. Significant inter-species abundance differences exist in some families of key postsynaptic density proteins including glutamatergic neurotransmitter receptors and adaptor proteins. Furthermore, we have identified a closely interacting set of molecules enriched in the human postsynaptic density that could be involved in dendrite and spine structural plasticity. Understanding synapse proteome diversity within and between species will be important to further our understanding of brain complexity and disease

Arthritis, Occupational Class, and the Aging US Workforce

Objectives. The working poor sometimes delay retirement to survive. However, their higher risk of disease and disability threatens both their financial survival and their ability to work through the retirement years. We used the burden of disease attributable to arthritis by occupational class to illustrate the challenges faced by the older poor. Methods. We merged data from the National Health Interview Survey, Medical Expenditure Panel Survey, and the National Death Index into a single database. We then calculated and compared age- and occupational class–specific quality-adjusted life years (QALYs) between workers with and without arthritis by using unabridged life tables. Results. White-collar workers have a higher overall health-related quality of life than do other workers, and suffer fewer QALYs lost to arthritis at all ages. For instance, whereas 65-year-old white-collar workers without arthritis look forward to 17 QALYs of future life, blue-collar workers with arthritis experience only 11, and are much less likely to remain in the workforce than are those in service, farming, or white-collar jobs. Conclusions. To meet the needs of the aging workforce, more extensive health and disability insurance will be needed

Characterization of the proteome, diseases and evolution of the human postsynaptic density

We isolated the postsynaptic density from human neocortex (hPSD) and identified 1,461 proteins. hPSD mutations cause 133 neurological and psychiatric diseases and were enriched in cognitive, affective and motor phenotypes underpinned by sets of genes. Strong protein sequence conservation in mammalian lineages, particularly in hub proteins, indicates conserved function and organization in primate and rodent models. The hPSD is an important structure for nervous system disease and behavior

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband–parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams–Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10−6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10−8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia

Performance of Risk-Based Criteria for Targeting Acute HIV Screening in San Francisco

Federal guidelines now recommend supplemental HIV RNA testing for persons at high risk for acute HIV infection. However, many rapid HIV testing sites do not include HIV RNA or p24 antigen testing due to concerns about cost, the need for results follow-up, and the impact of expanded venipuncture on clinic flow. We developed criteria to identify patients in a municipal STD clinic in San Francisco who are asymptomatic but may still be likely to have acute infection.Data were from patients tested with serial HIV antibody and HIV RNA tests to identify acute HIV infection. BED-CEIA results were used to classify non-acute cases as recent or longstanding. Demographics and self-reported risk behaviors were collected at time of testing. Multivariate models were developed and preliminarily evaluated using predictors associated with recent infection in bivariate analyses as a proxy for acute HIV infection. Multivariate models demonstrating ≥70% sensitivity for recent infection while testing ≤60% of patients in this development dataset were then validated by determining their performance in identifying acute infections.From 2004-2007, 137 of 12,622 testers had recent and 36 had acute infections. A model limiting acute HIV screening to MSM plus any one of a series of other predictors resulted in a sensitivity of 83.3% and only 47.6% of patients requiring testing. A single-factor model testing only patients reporting any receptive anal intercourse resulted in 88.9% sensitivity with only 55.2% of patients requiring testing.In similar high risk HIV testing sites, acute screening using "supplemental" HIV p24 antigen or RNA tests can be rationally targeted to testers who report particular HIV risk behaviors. By improving the efficiency of acute HIV testing, such criteria could facilitate expanded acute case identification

Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder

Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic ‘hub’ genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2\u27s role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness

Synaptopathies: Dysfunction of Synaptic Function Confirmed rare copy number variants implicate novel genes in schizophrenia

Abstract Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets of genes underlying human mental disorders is a path towards this objective. Schizophrenia is a common disease with cognitive symptoms, high heritability and complex genetics. We have identified genes involved with schizophrenia by measuring differences in DNA copy number across the entire genome in 91 schizophrenia cases and 92 controls in the Scottish population. Our data reproduce rare and common variants observed in public domain data from &gt;3000 schizophrenia cases, confirming known disease loci as well as identifying novel loci. We found copy number variants in PDE10A (phosphodiesterase 10A), CYFIP1 [cytoplasmic FMR1 (Fragile X mental retardation 1)-interacting protein 1], K + channel genes KCNE1 and KCNE2, the Down&apos;s syndrome critical region 1 gene RCAN1 (regulator of calcineurin 1), cell-recognition protein CHL1 (cell adhesion molecule with homology with L1CAM), the transcription factor SP4 (specificity protein 4) and histone deacetylase HDAC9, among others (see http://www.genes2cognition.org/SCZ-CNV). Integrating the function of these many genes into a coherent model of schizophrenia and cognition is a major unanswered challenge