Reports of Beta’s Death Have Been Greatly Exaggerated

For decades the Capital Asset Pricing Model (CAPM) has been held as an article of faith among financial economists. The model, usually attributed to 1990 Nobel Laureate William Sharpe (1964), was also developed by Fischer Black (1972), John Lintner (1965), Jan Mossin (1966), and Jack Treyor (1965). CAPM attempted to quantify the relationship between risk and return. Both economists and financial practitioners have long believed that riskier assets must yield a higher expected rate of return to induce investors to hold them. The innovation of CAPM was to specify the particular risk measure that would be priced in the market.

Timeliness of routine childhood vaccination in low- and middle-income countries, 1978-2021: Protocol for a scoping review to map methodologic gaps and determinants.

The literature on the timeliness of childhood vaccination (i.e. vaccination at the earliest appropriate age) in low-and middle-income countries has important measurement and methodological issues that may limit their usefulness and cross comparison. We aim to conduct a comprehensive scoping review to map the existing literature with a key focus on how the literature on vaccination timeliness has evolved, how it has been defined or measured, and what determinants have been explored in the period spanning the last four decades. This scoping review protocol was developed based on the guidance for scoping reviews from the Joanna Briggs Institute. We will include English and French language peer-reviewed publications and grey literature on the timeliness of routine childhood vaccination in low-and middle-income countries published between January 1978 through to 2021. A three-step search strategy that involves an initial search of two databases to refine the keywords, a full search of all included electronic databases, and screening of references of previous studies for relevant articles missing from our full search will be employed. The search will be conducted in five electronic databases: MEDLINE, EMBASE, Global Health, CINAHL and Web of Science. Google search will also be conducted to identify relevant grey literature on vaccination timeliness. All retrieved titles from the search will be imported into Endnote X9.3.3 (Clarivate Analytics) and deduplicated. Two reviewers will screen the titles, abstracts and full texts of publications for eligibility using Rayyan-the web based application for screening articles for systematic reviews. Using a tailored data extraction template, we will extract relevant information from eligible studies. The study team will analyse the extracted data using descriptive statistical methods and thematic analysis. The results will be presented using tables, while charts and maps will be used to aid the visualisation of the key findings and themes. The proposed review will generate evidence on key methodological gaps in the literature on timeliness of childhood vaccination. Such evidence would shape the direction of future research, and assist immunisation programme managers and country-level stakeholders to address the needs of their national immunisation system

Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA)

Background: Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.<p></p> Objectives: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.<p></p> Methods Study design: international, cross-sectional. Patients: consecutive RA patients. Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).<p></p> Results: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)–erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.<p></p> Conclusions: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.<p></p&gt

Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste

Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood brain barrier. We evaluate the unique intra-cavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide pro-drug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytical methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized pre-clinically to develop Gliadel®. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in post-surgery 9L orthotopic gliosarcomas treated with intra-cavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histological confirmation of disease-free brain. Conclusions: The significant survival benefit of intra-cavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds

Towards an Intelligent Tutor for Mathematical Proofs

Computer-supported learning is an increasingly important form of study since it allows for independent learning and individualized instruction. In this paper, we discuss a novel approach to developing an intelligent tutoring system for teaching textbook-style mathematical proofs. We characterize the particularities of the domain and discuss common ITS design models. Our approach is motivated by phenomena found in a corpus of tutorial dialogs that were collected in a Wizard-of-Oz experiment. We show how an intelligent tutor for textbook-style mathematical proofs can be built on top of an adapted assertion-level proof assistant by reusing representations and proof search strategies originally developed for automated and interactive theorem proving. The resulting prototype was successfully evaluated on a corpus of tutorial dialogs and yields good results.Comment: In Proceedings THedu'11, arXiv:1202.453

The Inflammatory Response to Double Stranded DNA in Endothelial Cells Is Mediated by NFκB and TNFα

Endothelial cells represent an important barrier between the intravascular compartment and extravascular tissues, and therefore serve as key sensors, communicators, and amplifiers of danger signals in innate immunity and inflammation. Double stranded DNA (dsDNA) released from damaged host cells during injury or introduced by pathogens during infection, has emerged as a potent danger signal. While the dsDNA-mediated immune response has been extensively studied in immune cells, little is known about the direct and indirect effects of dsDNA on the vascular endothelium. In this study we show that direct dsDNA stimulation of endothelial cells induces a potent proinflammatory response as demonstrated by increased expression of ICAM1, E-selectin and VCAM1, and enhanced leukocyte adhesion. This response was dependent on the stress kinases JNK and p38 MAPK, required the activation of proinflammatory transcription factors NFκB and IRF3, and triggered the robust secretion of TNFα for sustained secondary activation of the endothelium. DNA-induced TNFα secretion proved to be essential in vivo, as mice deficient in the TNF receptor were unable to mount an acute inflammatory response to dsDNA. Our findings suggest that the endothelium plays an active role in mediating dsDNA-induced inflammatory responses, and implicate its importance in establishing an acute inflammatory response to sterile injury or systemic infection, where host or pathogen derived dsDNA may serve as a danger signal.United States. Dept. of Defense (CDMRP Predoctoral Training Award)National Institutes of Health (U.S.) (NIH BioMEMS Resource Center Grant P41 EB-002503)National Institutes of Health (U.S.) (NIH Grant RO1AI063795)Shriners Hospital for Childre

Multiple Chronic Conditions: Prevalence, Health Consequences, and Implications for Quality, Care Management, and Costs

Persons with multiple chronic conditions are a large and growing segment of the US population. However, little is known about how chronic conditions cluster, and the ramifications of having specific combinations of chronic conditions. Clinical guidelines and disease management programs focus on single conditions, and clinical research often excludes persons with multiple chronic conditions. Understanding how conditions in combination impact the burden of disease and the costs and quality of care received is critical to improving care for the 1 in 5 Americans with multiple chronic conditions. This Medline review of publications examining somatic chronic conditions co-occurring with 1 or more additional specific chronic illness between January 2000 and March 2007 summarizes the state of our understanding of the prevalence and health challenges of multiple chronic conditions and the implications for quality, care management, and costs

Cholesterol treatment with statins: Who is left out and who makes it to goal?

<p>Abstract</p> <p>Background</p> <p>Whether patient socio-demographic characteristics (age, sex, race/ethnicity, income, and education) are independently associated with failure to receive indicated statin therapy and/or to achieve low density lipoprotein cholesterol (LDL-C) therapy goals are not known. We examined socio-demographic factors associated with a) eligibility for statin therapy among those not on statins, and b) achievement of statin therapy goals.</p> <p>Methods</p> <p>Adults (21-79 years) participating in the United States (US) National Health and Nutrition Examination Surveys, 1999-2006 were studied. Statin eligibility and achievement of target LDL-C was assessed using the US Third Adult Treatment Panel (ATP III) on Treatment of High Cholesterol guidelines.</p> <p>Results</p> <p>Among 6,043 participants not taking statins, 10.4% were eligible. Adjusted predictors of statin eligibility among statin non-users were being older, male, poorer, and less educated. Hispanics were less likely to be eligible but not using statins, an effect that became non-significant with adjustment for language usually spoken at home. Among 537 persons taking statins, 81% were at LDL-C goal. Adjusted predictors of goal failure among statin users were being male and poorer. These risks were not attenuated by adjustment for healthcare access or utilization.</p> <p>Conclusion</p> <p>Among person's not taking statins, the socio-economically disadvantaged are more likely to be eligible and among those on statins, the socio-economically disadvantaged are less likely to achieve statin treatment goals. Further study is needed to identify specific amenable patient and/or physician factors that contribute to these disparities.</p