Showing papers by "Northwestern University published in 2011"

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

Abstract: Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.

Classification of primary progressive aphasia and its variants

Abstract: This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA—nonfluent/agrammatic, semantic, and logopenic—were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as “imaging-supported” if the expected pattern of atrophy is found and “with definite pathology” if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Universality in Oxygen Evolution Electrocatalysis on Oxide Surfaces

Abstract: Trends in electrocatalytic activity of the oxygen evolution reaction (OER) are investigated on the basis of a large database of HO* and HOO* adsorption energies on oxide surfaces. The theoretical overpotential was calculated by applying standard density functional theory in combination with the computational standard hydrogen electrode (SHE) model. We showed that by the discovery of a universal scaling relation between the adsorption energies of HOO* vs HO*, it is possible to analyze the reaction free energy diagrams of all the oxides in a general way. This gave rise to an activity volcano that was the same for a wide variety of oxide catalyst materials and a universal descriptor for the oxygen evolution activity, which suggests a fundamental limitation on the maximum oxygen evolution activity of planar oxide catalysts.

2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum

Abstract: Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...

International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases

Abstract: A Panel of International Experts was convened by the Infectious Diseases Society of America (IDSA) in collaboration with the European Society for Microbiology and Infectious Diseases (ESCMID) to update the 1999 Uncomplicated Urinary Tract Infection Guidelines by the IDSA. Co-sponsoring organizations include the American Congress of Obstetricians and Gynecologists, American Urological Association, Association of Medical Microbiology and Infectious Diseases-Canada, and the Society for Academic Emergency Medicine. The focus of this work is treatment of women with acute uncomplicated cystitis and pyelonephritis, diagnoses limited in these guidelines to premenopausal, non-pregnant women with no known urological abnormalities or co-morbidities. The issues of in vitro resistance prevalence and the ecological adverse effects of antimicrobial therapy (collateral damage) were considered as important factors in making optimal treatment choices and thus are reflected in the rankings of recommendations.

π-Conjugated Polymers for Organic Electronics and Photovoltaic Cell Applications†

Abstract: The optoelectronic properties of polymeric semiconductor materials can be utilized for the fabrication of organic electronic and photonic devices. When key structural requirements are met, these materials exhibit unique properties such as solution processability, large charge transporting capabilities, and/or broad optical absorption. In this review recent developments in the area of π-conjugated polymeric semiconductors for organic thin-film (or field-effect) transistors (OTFTs or OFETs) and bulk-heterojunction photovoltaic (or solar) cell (BHJ-OPV or OSC) applications are summarized and analyzed.

Mediation Analysis in Social Psychology: Current Practices and New Recommendations

Abstract: A key aim of social psychology is to understand the psychological processes through which independent variables affect dependent variables in the social domain. This objective has given rise to statistical methods for mediation analysis. In mediation analysis, the significance of the relationship between the independent and dependent variables has been integral in theory testing, being used as a basis to determine (1) whether to proceed with analyses of mediation and (2) whether one or several proposed mediator(s) fully or partially accounts for an effect. Synthesizing past research and offering new arguments, we suggest that the collective evidence raises considerable concern that the focus on the significance between the independent and dependent variables, both before and after mediation tests, is unjustified and can impair theory development and testing. To expand theory involving social psychological processes, we argue that attention in mediation analysis should be shifted towards assessing the magnitude and significance of indirect effects.

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth

Abstract: Intra-abdominal tumors, such as ovarian cancer, have a clear predilection for metastasis to the omentum, an organ primarily composed of adipocytes. Currently, it is unclear why tumor cells preferentially home to and proliferate in the omentum, yet omental metastases typically represent the largest tumor in the abdominal cavities of women with ovarian cancer. We show here that primary human omental adipocytes promote homing, migration and invasion of ovarian cancer cells, and that adipokines including interleukin-8 (IL-8) mediate these activities. Adipocyte-ovarian cancer cell coculture led to the direct transfer of lipids from adipocytes to ovarian cancer cells and promoted in vitro and in vivo tumor growth. Furthermore, coculture induced lipolysis in adipocytes and β-oxidation in cancer cells, suggesting adipocytes act as an energy source for the cancer cells. A protein array identified upregulation of fatty acid-binding protein 4 (FABP4, also known as aP2) in omental metastases as compared to primary ovarian tumors, and FABP4 expression was detected in ovarian cancer cells at the adipocyte-tumor cell interface. FABP4 deficiency substantially impaired metastatic tumor growth in mice, indicating that FABP4 has a key role in ovarian cancer metastasis. These data indicate adipocytes provide fatty acids for rapid tumor growth, identifying lipid metabolism and transport as new targets for the treatment of cancers where adipocytes are a major component of the microenvironment.

Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease

Abstract: Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.

The aligned rank transform for nonparametric factorial analyses using only anova procedures

Abstract: Nonparametric data from multi-factor experiments arise often in human-computer interaction (HCI). Examples may include error counts, Likert responses, and preference tallies. But because multiple factors are involved, common nonparametric tests (e.g., Friedman) are inadequate, as they are unable to examine interaction effects. While some statistical techniques exist to handle such data, these techniques are not widely available and are complex. To address these concerns, we present the Aligned Rank Transform (ART) for nonparametric factorial data analysis in HCI. The ART relies on a preprocessing step that "aligns" data before applying averaged ranks, after which point common ANOVA procedures can be used, making the ART accessible to anyone familiar with the F-test. Unlike most articles on the ART, which only address two factors, we generalize the ART to N factors. We also provide ARTool and ARTweb, desktop and Web-based programs for aligning and ranking data. Our re-examination of some published HCI results exhibits advantages of the ART.

Rylene and related diimides for organic electronics.

Abstract: Organic electron-transporting materials are essential for the fabrication of organic p-n junctions, photovoltaic cells, n-channel field-effect transistors, and complementary logic circuits. Rylene diimides are a robust, versatile class of polycyclic aromatic electron-transport materials with excellent thermal and oxidative stability, high electron affinities, and, in many cases, high electron mobilities; they are, therefore, promising candidates for a variety of organic electronics applications. In this review, recent developments in the area of high-electron-mobility diimides based on rylenes and related aromatic cores, particularly perylene- and naphthalene-diimide-based small molecules and polymers, for application in high-performance organic field-effect transistors and photovoltaic cells are summarized and analyzed.

Item banks for measuring emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS®): depression, anxiety, and anger.

Abstract: The authors report on the development and calibration of item banks for depression, anxiety, and anger as part of the Patient-Reported Outcomes Measurement Information System (PROMIS®). Comprehensive literature searches yielded an initial bank of 1,404 items from 305 instruments. After qualitative item analysis (including focus groups and cognitive interviewing), 168 items (56 for each construct) were written in a first person, past tense format with a 7-day time frame and five response options reflecting frequency. The calibration sample included nearly 15,000 respondents. Final banks of 28, 29, and 29 items were calibrated for depression, anxiety, and anger, respectively, using item response theory. Test information curves showed that the PROMIS item banks provided more information than conventional measures in a range of severity from approximately -1 to +3 standard deviations (with higher scores indicating greater distress). Short forms consisting of seven to eight items provided information comparable to legacy measures containing more items.

Does Simulation-Based Medical Education With Deliberate Practice Yield Better Results Than Traditional Clinical Education? A Meta-Analytic Comparative Review of the Evidence

Abstract: Purpose This article presents a comparison of the effectiveness of traditional clinical education toward skill acquisition goals versus simulation-based medical education (SBME) with deliberate practice (DP). Method This is a quantitative meta-analysis that spans 20 years, 1990 to 2010. A search strategy involving three literature databases, 12 search terms, and four inclusion criteria was used. Four authors independently retrieved and reviewed articles. Main outcome measures were extracted to calculate effect sizes.

Dendritic spine pathology in neuropsychiatric disorders

Abstract: Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.

Scanning tunnelling microscopy and spectroscopy of ultra-flat graphene on hexagonal boron nitride

Abstract: Using boron nitride as a substrate for graphene has been suggested as a promising way to reduce the disorder in graphene caused by space fluctuations. It is now shown by scanning tunnelling microscopy that graphene conforms perfectly to boron nitride and the charge fluctuations are minimal compared with the conventionally used substrate, silica. Boron nitride could really be the natural graphene substrate. Graphene has demonstrated great promise for future electronics technology as well as fundamental physics applications because of its linear energy–momentum dispersion relations which cross at the Dirac point1,2. However, accessing the physics of the low-density region at the Dirac point has been difficult because of disorder that leaves the graphene with local microscopic electron and hole puddles3,4,5. Efforts have been made to reduce the disorder by suspending graphene, leading to fabrication challenges and delicate devices which make local spectroscopic measurements difficult6,7. Recently, it has been shown that placing graphene on hexagonal boron nitride (hBN) yields improved device performance8. Here we use scanning tunnelling microscopy to show that graphene conforms to hBN, as evidenced by the presence of Moire patterns. However, contrary to predictions9,10, this conformation does not lead to a sizeable band gap because of the misalignment of the lattices. Moreover, local spectroscopy measurements demonstrate that the electron–hole charge fluctuations are reduced by two orders of magnitude as compared with those on silicon oxide. This leads to charge fluctuations that are as small as in suspended graphene6, opening up Dirac point physics to more diverse experiments.

Are leader stereotypes masculine? A meta-analysis of three research paradigms.

Abstract: This meta-analysis examined the extent to which stereotypes of leaders are culturally masculine. The primary studies fit into 1 of 3 paradigms: (a) In Schein's (1973) think manager-think male paradigm, 40 studies with 51 effect sizes compared the similarity of male and leader stereotypes and the similarity of female and leader stereotypes; (b) in Powell and Butterfield's (1979) agency-communion paradigm, 22 studies with 47 effect sizes compared stereotypes of leaders' agency and communion; and (c) in Shinar's (1975) masculinity-femininity paradigm, 7 studies with 101 effect sizes represented stereotypes of leadership-related occupations on a single masculinity-femininity dimension. Analyses implemented appropriate random and mixed effects models. All 3 paradigms demonstrated overall masculinity of leader stereotypes: (a) In the think manager-think male paradigm, intraclass correlation = .25 for the women-leaders similarity and intraclass correlation = .62 for the men-leaders similarity; (b) in the agency-communion paradigm, g = 1.55, indicating greater agency than communion; and (c) in the masculinity-femininity paradigm, g = 0.92, indicating greater masculinity than the androgynous scale midpoint. Subgroup and meta-regression analyses indicated that this masculine construal of leadership has decreased over time and was greater for male than female research participants. In addition, stereotypes portrayed leaders as less masculine in educational organizations than in other domains and in moderate- than in high-status leader roles. This article considers the relation of these findings to Eagly and Karau's (2002) role congruity theory, which proposed contextual influences on the incongruity between stereotypes of women and leaders. The implications for prejudice against women leaders are also considered.

The Network Origins of Aggregate Fluctuations

Abstract: This paper argues that in the presence of intersectoral input-output linkages, microeconomic idiosyncratic shocks may lead to aggregate fluctuations. In particular, it shows that, as the economy becomes more disaggregated, the rate at which aggregate volatility decays is determined by the structure of the network capturing such linkages. Our main results provide a characterization of this relationship in terms of the importance of different sectors as suppliers to their immediate customers as well as their role as indirect suppliers to chains of downstream sectors. Such higher-order interconnections capture the possibility of “cascade effects” whereby productivity shocks to a sector propagate not only to its immediate downstream customers, but also indirectly to the rest of the economy. Our results highlight that sizable aggregate volatility is obtained from sectoral idiosyncratic shocks only if there exists significant asymmetry in the roles that sectors play as suppliers to others, and that the “sparseness” of the input-output matrix is unrelated to the nature of aggregate fluctuations.

The Prevalence, Severity, and Distribution of Childhood Food Allergy in the United States

Abstract: OBJECTIVE: The goal of this study was to better estimate the prevalence and severity of childhood food allergy in the United States. METHODS: A randomized, cross-sectional survey was administered electronically to a representative sample of US households with children from June 2009 to February 2010. Eligible participants included adults (aged 18 years or older) able to complete the survey in Spanish or English who resided in a household with at least 1 child younger than 18 years. Data were adjusted using both base and poststratification weights to account for potential biases from sampling design and nonresponse. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy. Multiple logistic regression models were constructed to identify characteristics significantly associated with outcomes. RESULTS: Data were collected for 40 104 children; incomplete responses for 1624 children were excluded, which yielded a final sample of 38 480. Food allergy prevalence was 8.0% (95% confidence interval [CI]: 7.6–8.3). Among children with food allergy, 38.7% had a history of severe reactions, and 30.4% had multiple food allergies. Prevalence according to allergen among food-allergic children was highest for peanut (25.2% [95% CI: 23.3–27.1]), followed by milk (21.1% [95% CI: 19.4–22.8]) and shellfish (17.2% [95% CI: 15.6–18.9]). Odds of food allergy were significantly associated with race, age, income, and geographic region. Disparities in food allergy diagnosis according to race and income were observed. CONCLUSIONS: Findings suggest that the prevalence and severity of childhood food allergy is greater than previously reported. Data suggest that disparities exist in the clinical diagnosis of disease.

Finite sample properties of some alternative GMM estimators

Abstract: We investigate the small-sample properties of three alternative generalized method of moments (GMM) estimators of asset-pricing models. The estimators that we consider include ones in which the weighting matrix is iterated to convergence and ones in which the weighting matrix is changed with each choice of the parameters. Particular attention is devoted to assessing the performance of the asymptotic theory for making inferences based directly on the deterioration of GMM criterion functions.

The Effects of Quantitative Easing on Interest Rates: Channels and Implications for Policy

Abstract: We evaluate the effect of the Federal Reserve's purchase of long-term Treasuries and other long-term bonds (QE1 in 2008-09 and QE2 in 2010-11) on interest rates. Using an event-study methodology, we reach two main conclusions. First, it is inappropriate to focus only on Treasury rates as a policy target, because quantitative easing works through several channels that affect particular assets differently. We find evidence for a signaling channel, a unique demand for long-term safe assets, and an inflation channel for both QE1 and QE2, and a mortgage-backed securities (MBS) prepayment channel and a corporate bond default risk channel for QE1 only. Second, effects on particular assets depend critically on which assets are purchased. The event study suggests that MBS purchases in QE1 were crucial for lowering MBS yields as well as corporate credit risk and thus corporate yields for QE1, and Treasuries-only purchases in QE2 had a disproportionate effect on Treasuries and agency bonds relative to MBSs and corporate bonds, with yields on the latter falling primarily through the market's anticipation of lower future federal funds rates.

Low-temperature fabrication of high-performance metal oxide thin-film electronics via combustion processing

Abstract: Solution-deposited metal oxides show great potential for large-area electronics, but they generally require high annealing temperatures, which are incompatible with flexible polymeric substrates. Combustion processing is now reported as a new low-temperature route for the deposition of diverse metal oxide films, and high-performance transistors are demonstrated using this method.

Interventions to Reduce 30-Day Rehospitalization: A Systematic Review

Abstract: About 1 in 5 Medicare fee-for-service patients discharged from the hospital is rehospitalized within 30 days In this systematic review of 43 studies evaluating interventions to reduce readmission

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia

Abstract: ing cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motorneuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.

Children's Counting and Concepts of Number

Abstract: I Number Words.- 1 Introduction and Overview of Different Uses of Number Words.- 2 The Number-Word Sequence: An Overview of Its Acquisition and Elaboration.- II Correspondence Errors in Counting Objects.- 3 Correspondence Errors in Children's Counting.- 4 Effects of Object Arrangement on Counting Correspondence Errors and on the Indicating Act.- 5 Effects of Object Variables and Age of Counter on Correspondence Errors Made When Counting Objects in Rows.- 6 Correspondence Errors in Children's Counting: A Summary.- III Concepts of Cardinality.- 7 Children's Early Knowledge About Relationships Between Counting and Cardinality.- 8 Later Conceptual Relationships Between Counting and Cardinality: Addition and Subtraction of Cardinal Numbers.- 9 Uses of Counting and Matching in Cardinal Equivalence Situations: Equivalence and Order Relations on Cardinal Numbers.- IV Number Words, Counting, and Cardinality: The Increasing Integration of Sequence, Count, and Cardinal Meanings.- 10 Early Relationships Among Sequence Number Words, Counting Correspondence, and Cardinality.- 11 An Overview of Changes in Children's Number Word Concepts from Age 2 Through 8.- References.- Author Index.

Premature Age-Related Comorbidities Among HIV-Infected Persons Compared With the General Population

Abstract: Background Human immunodeficiency virus (HIV)‐infected patients may have a greater risk of noninfectious comorbidities (NICMs) compared with the general population We assessed the prevalence and risk factors for NICMs in a large cohort of HIV-infected adults and compared these findings with data from matched control subjects Methods We performed a case-control study involving antiretroviral therapy (ART)‐experienced HIVinfected patients treated at Modena University, Italy, from 2002 through 2009 These patients were compared with age-, sex-, and race-matched adults (control subjects) from the general population included in the CINECA ARNO database NICMs included cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure Polypathology (Pp) was defined as the concurrent presence of $2 NICMs Logistic regression models were constructed to evaluate associated predictors of NICMs and Pp Results There were 2854 patients and 8562 control subjects The mean age was 46 years, and 37% were women Individual NICM and Pp prevalences in each age stratum were higher among patients than among controls (all P ,001) Pp prevalence among patients aged 41‐50 years was similar to that among controls aged 51‐60 years (P value was not statistically significant); diabetes mellitus, cardiovascular disease, bone fractures, and renal failure were statistically independent after adjustment for sex, age, and hypertension Logistic regression models showed that independent predictors of Pp in the overall cohort were (all P , 001) age (odds ratio [OR], 111), male sex (OR, 177), nadir CD4 cell count ,200 cells/lL (OR, 446), and ART exposure (OR, 101) Conclusions Specific age-related NICMs and Pp were more common among HIV-infected patients than in the general population The prevalence of Pp in HIV-infected persons anticipated Pp prevalence observed in the general population among persons who were 10 years older, and HIV-specific cofactors (lower nadir CD4 cell count and more prolonged ART exposure) were identified as risk factors These data support the need for earlier screening for NICMs in HIV-infected patients

The national lung screening trial: Overview and study design

Abstract: The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5% It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest The NLST is such a trial The rationale for and design of the NLST are presented