Indiana University Indianapolis

Abstract This paper proposes and tests a model of IJV learning and performance that segments absorptive capacity into the three components originally proposed by Cohen and Levinthal (1990). First, trust between an IJV's parents and the IJV's relative absorptive capacity with its foreign parent are suggested to influence its ability to understand new knowledge held by foreign parents. Second, an IJV's learning structures and processes are proposed to influence its ability to assimilate new knowledge from those parents. Third, the IJV's strategy and training competence are suggested to shape its ability to apply the assimilated knowledge . Revisiting the Hungarian IJVs studied by Lyles and Salk (1996) 3 years later, we find support for the knowledge understanding and application predictions, and partial support for the knowledge assimilation prediction. Unexpectedly, our results suggest that trust and management support from foreign parents are associated with IJV performance but not learning. Our model and results offer a new perspective on IJV learning and performance as well as initial insights into how those relationships change over time. Copyright © 2001 John Wiley & Sons, Ltd.

Data on the number of U.S. women with low femoral bone mineral density (BMD) are currently available only from indirect estimates. We used dual-energy X-ray absorptiometry (DXA) measurements of femoral BMD from phase 1 of the third National Health and Nutrition Examination Survey (NHANES III, 1988-1991) to estimate prevalences of low femoral BMD in women ages 50 years and older using an approach proposed recently by an expert panel of the World Health Organization (WHO). Cutpoints for low BMD were derived from BMD data of 194 non-Hispanic white (NHW) women aged 20-29 years from the NHANES III dataset. The prevalence of older U.S. women with femoral osteopenia (BMD between 1 standard deviation [SD] and 2.5 SD below the mean of young NHW women) ranged from 34-50% in four different femur regions, which corresponds to approximately 12-17 million women. The prevalence with osteoporosis (BMD > 2.5 SD below the mean of young NHW women) ranged from 17-20%, or approximately 6-7 million women. Prevalences were 1.3-2.4 times higher in NHW women than non-Hispanic black women (NHB), and 0.8-1.2 times higher in NHW versus Mexican American (MA) women. The estimated numbers of NHW, NHB, and MA women with osteopenia were 10-15 million, 800,000-1.2 million, and 300,000-400,000, respectively; corresponding figures for osteoporosis were 5-6 million, 200,000-300,000, and 100,000 respectively. Thus, the first data on BMD from a nationally representative sample of older women show a substantial number with low femoral BMD.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years. DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group. SETTING: Six U.S. cities. PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently. INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training. MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function. RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93). CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

Research was conducted to develop valid and reliable scales to test the Health Belief Model (HBM). The dependent variable chosen for scale development was frequency of breast self-examination. Independent variables were constructs related to the HBM: susceptibility, seriousness, benefits, barriers, and health motivation. Analyses for construct validity and theory testing included factor analysis and multiple regression. Chronbach Alpha and Pearson r were used to compute reliabilities. Scales that were judged valid and reliable were susceptibility, seriousness, benefits, barriers, and health motivation.

Abstract Objective The Parkinson's Progression Markers Initiative ( PPMI ) is an observational, international study designed to establish biomarker‐defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease ( PD ) progression markers to accelerate disease‐modifying therapeutic trials. Methods A total of 423 untreated PD , 196 Healthy Control ( HC ) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter ( DAT ) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org . Results Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD . The total MDS ‐ UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD . On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios ( SBR ), respectively. Cerebrospinal fluid ( CSF ) was acquired from &gt;97% of all subjects. CSF (PD/HC/SWEDD pg/mL) α‐synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD ( P &lt; 0.03). Similarly, t ‐tau (45/53) and p ‐tau (16/18) were reduced in PD versus HC ( P &lt; 0.01), Interpretation PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.

Increased vascular permeability and excessive neovascularization are the hallmarks of endothelial dysfunction, which can lead to diabetic macular edema and proliferative diabetic retinopathy in the eye. Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular tissues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms alpha, betaII, and delta and >threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly by the beta-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC beta-isoform-selective inhibitor that did not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascular permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC beta-isoform-selective inhibitors may prove efficacious for the treatment of VEGF-associated ocular disorders such as diabetic retinopathy.

The Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has provided clinical, operational, and data management support to ADNI since its inception. This article reviews the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow-up of more than 800 subjects in the three original cohorts: healthy controls, amnestic mild cognitive impairment (now referred to as late MCI, or LMCI), and mild Alzheimer's disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal, clinical, and cognitive assessments. These data, when combined with genetic, neuroimaging, and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Furthermore, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI, with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow-up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.

A number of effective, low-cost strategies are available to identify and treat the person at risk for diabetic foot ulcers and lower-extremity amputation. These strategies must be more widely adopted by all diabetic care providers to maintain the integrity and function of the lower limb, and thus improve the quality of life for people with diabetes.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, rare lung disease resulting in chronic oto-sino-pulmonary disease in both children and adults. Many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials. This review article outlines consensus recommendations from PCD physicians in North America who have been engaged in a PCD centered research consortium for the last 10 years. These recommendations have been adopted by the governing board of the PCD Foundation to provide guidance for PCD clinical centers for diagnostic testing, monitoring, and appropriate short and long-term therapeutics in PCD patients.

BACKGROUND: Modern diagnostic strategies for venous thromboembolism (VTE) incorporate pretest probability (PTP; prevalence) assessment. The ability of diagnostic tests to correctly identify or exclude VTE is influenced by VTE prevalence and test accuracy characteristics. OBJECTIVE: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. METHODS: The American Society of Hematology (ASH) formed a multidisciplinary panel including patient representatives. The McMaster University GRADE Centre completed systematic reviews up to 1 October 2017. The panel prioritized questions and outcomes and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations. Test accuracy estimates and VTE population prevalence were used to model expected outcomes in diagnostic pathways. Where modeling was not feasible, management and accuracy studies were used to formulate recommendations. RESULTS: Ten recommendations are presented, by PTP for patients with suspected PE and lower extremity DVT, and for recurrent VTE and upper extremity DVT. CONCLUSIONS: For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is warranted. For PE diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas lower or upper extremity DVT diagnosis uses ultrasonography. Research is needed on new diagnostic modalities and to validate clinical decision rules for patients with suspected recurrent VTE.

INTRODUCTION: Recent studies suggested that muscle mass and muscle strength may independently or synergistically affect aging-related health outcomes in older adults; however, prospective data on mortality in the general population are sparse. METHODS: We aimed to prospectively examine individual and joint associations of low muscle mass and low muscle strength with all-cause mortality in a nationally representative sample. This study included 4449 participants age 50 yr and older from the National Health and Nutrition Examination Survey 1999 to 2002 with public use 2011 linked mortality files. Weighted multivariable logistic regression models were adjusted for age, sex, race, body mass index (BMI), smoking, alcohol use, education, leisure time physical activity, sedentary time, and comorbid diseases. RESULTS: Overall, the prevalence of low muscle mass was 23.1% defined by appendicular lean mass (ALM) and 17.0% defined by ALM/BMI, and the prevalence of low muscle strength was 19.4%. In the joint analyses, all-cause mortality was significantly higher among individuals with low muscle strength, whether they had low muscle mass (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.27-3.24 for ALM; OR, 2.53; 95% CI, 1.64-3.88 for ALM/BMI) or not (OR, 2.66; 95% CI, 1.53-4.62 for ALM; OR, 2.17; 95% CI, 1.29-3.64 for ALM/BMI). In addition, the significant associations between low muscle strength and all-cause mortality persisted across different levels of metabolic syndrome, sedentary time, and LTPA. CONCLUSIONS: Low muscle strength was independently associated with elevated risk of all-cause mortality, regardless of muscle mass, metabolic syndrome, sedentary time, or LTPA among US older adults, indicating the importance of muscle strength in predicting aging-related health outcomes in older adults.

BACKGROUND: Identifying hospitalized patients at risk for QT interval prolongation could lead to interventions to reduce the risk of torsades de pointes. Our objective was to develop and validate a risk score for QT prolongation in hospitalized patients. METHODS AND RESULTS: In this study, in a single tertiary care institution, consecutive patients (n=900) admitted to cardiac care units comprised the risk score development group. The score was then applied to 300 additional patients in a validation group. Corrected QT (QTc) interval prolongation (defined as QTc>500 ms or an increase of >60 ms from baseline) occurred in 274 (30.4%) and 90 (30.0%) patients in the development group and validation group, respectively. Independent predictors of QTc prolongation included the following: female (odds ratio, 1.5; 95% confidence interval, 1.1-2.0), diagnosis of myocardial infarction (2.4 [1.6-3.9]), septic shock (2.7 [1.5-4.8]), left ventricular dysfunction (2.7 [1.6-5.0]), administration of a QT-prolonging drug (2.8 [2.0-4.0]), ≥2 QT-prolonging drugs (2.6 [1.9-5.6]), or loop diuretic (1.4 [1.0-2.0]), age >68 years (1.3 [1.0-1.9]), serum K⁺ <3.5 mEq/L (2.1 [1.5-2.9]), and admitting QTc >450 ms (2.3; confidence interval [1.6-3.2]). Risk scores were developed by assigning points based on log odds ratios. Low-, moderate-, and high-risk ranges of 0 to 6, 7 to 10, and 11 to 21 points, respectively, best predicted QTc prolongation (C statistic=0.823). A high-risk score ≥11 was associated with sensitivity=0.74, specificity=0.77, positive predictive value=0.79, and negative predictive value=0.76. In the validation group, the incidences of QTc prolongation were 15% (low risk); 37% (moderate risk); and 73% (high risk). CONCLUSIONS: A risk score using easily obtainable clinical variables predicts patients at highest risk for QTc interval prolongation and may be useful in guiding monitoring and treatment decisions.

The clinical, histologic and laboratory findings in 466 cases of surgically proven polycystic ovaries collected from the literature were reviewed and compared with the findings in our series of 39 patients. The variability of the clinical features did not support the hypothesis of an associated syndrome. The histologic studies in the present series also failed to define a consistent entity. Wedge resection resulted in improvement of menstrual function in from 6 to 93 % of cases (in our series, 58%), and in pregnancy in 13 to 95% of cases (in our series, 33%). This further illustrates the lack of homogeneity in the clinical material. It was not possible to predict the results of surgery from clinical findings or urinary steroid studies. Evidence for the occasional coexistence of a hyperadrenal state was strong.

OBJECTIVES: To determine how well the interview-based, clinic-friendly International Academy of Nutrition and Aging (FRAIL) frailty scale predicts future disability and mortality in the African American Health (AAH) cohort compared with the clinic-friendly Study of Osteoporotic Fractures (SOF) frailty scale, the phenotype-based Cardiovascular Health Study (CHS) frailty scale, and the comprehensive Frailty Index (FI). DESIGN: Longitudinal cohort study. SETTING: Metropolitan St. Louis, Missouri. PARTICIPANTS: African American Health is a population-based panel study of African Americans (baseline age 49-65) from St. Louis, Missouri. Participants completed in-home assessments at baseline (N = 998) and 3- (n = 853) and 9- (n = 582) year follow-up. MEASUREMENTS: Outcomes included activity of daily living (ADL) and instrumental ADL difficulties at 3 and 9 years and 9-year mortality. Frailty measures included the FRAIL, SOF, and CHS scales and the FI. RESULTS: The FRAIL, SOF, CHS, and FI measures predicted new 3- and 9-year disability, and the FRAIL and FI scales predicted 9-year mortality. Receiver operating characteristic (ROC) contrasts showed that the FRAIL scale performed as well as (9-year disability and mortality) or better than (3-year disability) the CHS and SOF scales and the FI better than the FRAIL, CHS, and SOF scales for all outcomes except the FRAIL and CHS scales for 9-year ADL difficulties. The CHS and SOF scales were equivalent for all outcomes in ROC contrasts. CONCLUSION: Overall the FI and the FRAIL scale exhibited the strongest predictive validity for disability and mortality in AAH. The best prediction tool to identify frail individuals at risk of disability and mortality may be one that includes a comorbidity measure. The FRAIL scale includes a comorbidity item and is a brief interview-based measure that is easy to administer, score, and interpret. The FRAIL scale has demonstrated validity and may prove to be a valuable scale for use by clinicians.

Many open access journals have a reputation for being of low quality and being dishonest with regard to peer review and publishing costs. Such journals are labeled “predatory” journals. This study examines author profiles for some of these “predatory” journals as well as for groups of more well‐recognized open access journals. We collect and analyze the publication record, citation count, and geographic location of authors from the various groups of journals. Statistical analyses verify that each group of journals has a distinct author population. Those who publish in “predatory” journals are, for the most part, young and inexperienced researchers from developing countries. We believe that economic and sociocultural conditions in these developing countries have contributed to the differences found in authorship between “predatory” and “nonpredatory” journals.

BACKGROUND: Increased nut consumption has been associated with a reduced risk of major chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. However, the association between nut consumption and mortality remains unclear. METHODS: We examined the association between nut consumption and subsequent total and cause-specific mortality among 76,464 women in the Nurses' Health Study (1980-2010) and 42,498 men in the Health Professionals Follow-up Study (1986-2010). Participants with a history of cancer, heart disease, or stroke were excluded. Nut consumption was assessed at baseline and updated every 2 to 4 years. RESULTS: During 3,038,853 person-years of follow-up, 16,200 women and 11,229 men died. Nut consumption was inversely associated with total mortality among both women and men, after adjustment for other known or suspected risk factors. The pooled multivariate hazard ratios for death among participants who ate nuts, as compared with those who did not, were 0.93 (95% confidence interval [CI], 0.90 to 0.96) for the consumption of nuts less than once per week, 0.89 (95% CI, 0.86 to 0.93) for once per week, 0.87 (95% CI, 0.83 to 0.90) for two to four times per week, 0.85 (95% CI, 0.79 to 0.91) for five or six times per week, and 0.80 (95% CI, 0.73 to 0.86) for seven or more times per week (P<0.001 for trend). Significant inverse associations were also observed between nut consumption and deaths due to cancer, heart disease, and respiratory disease. CONCLUSIONS: In two large, independent cohorts of nurses and other health professionals, the frequency of nut consumption was inversely associated with total and cause-specific mortality, independently of other predictors of death. (Funded by the National Institutes of Health and the International Tree Nut Council Nutrition Research and Education Foundation.).

Grading of renal cell carcinoma (RCC) has been recognised as a prognostic factor for almost 100 years. Numerous grading systems have been proposed, initially focusing upon a constellation of cytological features and more recently on nuclear morphology. It has been recommended that grading of RCC should be based upon nucleolar prominence/eosinophilia for grades 1-3, while grade 4 requires nuclear anaplasia (including tumour giant cells, sarcomatoid differentiation and/or rhabdoid morphology). The grading system was adopted formally by the International Society of Urological Pathology (ISUP) and subsequently by the World Health Organisation (WHO), being designated the WHO/ISUP grading classification in the fourth edition of the WHO classification tumours of the urinary system and male genital organs (2016). This grading system has been validated for both clear cell and papillary RCC. Validation studies for chromophobe RCC failed to demonstrate a correlation between grade and outcome for both the superseded Fuhrman grading system and the WHO/ISUP grading classification, and it has been recommended that these tumours not be graded. The WHO/ISUP system has been incorporated into the structured reports of the International Cancer Collaboration on Cancer Reporting for both clear cell and papillary RCC. It is also noted that other types of RCC may be graded, but it must be emphasised in the report that this is for descriptive and diagnostic purposes, and not outcome prediction. More recent studies have shown the incorporation of the presence of tumour necrosis into RCC grading to improve outcome prediction, and this has been validated in several studies.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 10 -3 ) and candidate genes from knockout mice (P = 5.2 10 -3 ). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.