A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children.

AIMS/HYPOTHESIS: Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. METHODS: Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. RESULTS: We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). CONCLUSIONS/INTERPRETATION: The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children.

Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography.

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.

Volatile profiles of fungi--chemotyping of species and ecological functions.

Fungi emit a large spectrum of volatile organic compounds (VOCs). In the present study, we characterized and compared the odor profiles of ectomycorrhizal (EM), pathogenic and saprophytic fungal species with the aim to use these patterns as a chemotyping tool. Volatiles were collected from the headspace of eight fungal species including nine strains (four EM, three pathogens and two saprophytes) using the stir bar sorptive extraction method and analyzed by gas chromatography-mass spectrometry (GC-MS). After removal of VOCs released from the growth system, 54 VOCs were detected including 15 novel compounds not reported in fungi before. Principle component and cluster analyses revealed that fungal species differ in their odor profiles, particularly in the pattern of sesquiterpenes. The functional groups and species could be chemotyped by using their specific emission patterns. The different ecological groups could be predicted with probabilities of 90-99%, whereas for the individual species the probabilities varied between 55% and 83%. This study strongly supports the concept that the profiling of volatile compounds can be used for non-invasive identification of different functional fungal groups.

13-valent pneumococcal conjugate vaccine immune sera protects against pneumococcal serotype 1, 3, and 5 bacteremia in a neonatal rat challenge model.

PCV7 was first licensed in the United States in 2000 based on clinical efficacy studies. Since the introduction, PCV7 has demonstrated protective effectiveness for each of the vaccine serotypes. More recently, PCV13 has been licensed in more than 60 countries based on serological noninferiority to PCV7 for the shared serotypes and noninferiority to the least immunogenic serotypes of PCV7 for the additional 6 serotypes in PCV13. To evaluate whether the functional antibody responses to serotypes 1, 3, and 5 were sufficient to protect animals challenged with virulent strains of these serotypes, rhesus macaques were immunized with three clinical doses of PCV13. The macaques mounted robust anti-capsular polysaccharide IgG and opsonophagocytic killing (OPA) responses to each serotype contained in the vaccine. Pooled pre-immunization sera and post-immunization serum pools were tested in a neonatal rat bacteremia model. Passive transfer of pooled post-immunization sera, but not pre-immunization sera, protected neonatal rats from lethal IP challenge with serotype 1, 3, or 5 strains. The functional activity of PCV13 immune sera against a virulent type 3 strain was further evaluated using sera from human children immunized with 4 doses of PCV7 or PCV13. Pooled sera from children immunized with PCV13, but not pooled sera from children immunized with PCV7, which does not contain the serotype 3 polysaccharide conjugate, protected neonatal rats from lethal IP challenge with a highly encapsulated and virulent serotype 3 strain. These data suggest that PCV13 will provide protection against pneumococcal serotype 1, 3, and 5 disease in human populations, even at relatively low OPA titers.

Physician Opinions about American Board of Family Medicine Self-Assessment Modules (2006-2016).

INTRODUCTION: Maintenance of Certification (MOC) was implemented to help physicians remain current with evolving medical standards, but has been criticized for being irrelevant to practice. We assessed family physicians' (FPs') opinions about the content of American Board of Family Medicine (ABFM) self-assessment modules (SAMs). METHODS: We used ABFM administrative data from feedback surveys completed after each of the 16 SAMs from 2006 to 2016. FPs rated agreement with 2 statements-1) "Content is appropriate for my practice," and 2) "Content was presented at an appropriate level"-on a scale of 1 (strongly disagree) to 6 (strongly agree). We calculated mean ratings of each statement by year and stratified by Knowledge Assessment (KA) and Clinical Simulation (CS) portions of the SAM. We plotted mean ratings by FPs' age at their first SAM completion and the total number of SAMs completed. RESULTS: SAMs were completed (n = 633,198) from 2006 to 2016 with 448,408 (71%) feedback surveys completed. The annual mean ratings of both statements varied little (less than 0.5) and were above 4.5 for all SAMs. CS ratings were consistently lower than KA ratings. FPs of all ages at first SAM provided similar ratings and agreement with content appropriateness increased with repeated exposure to SAMs. CONCLUSION: Over 11 years, the content of ABFM SAMs was regarded by FPs as appropriate for practice and presented at an appropriate level. Continued monitoring of feedback is necessary to keep the content of MOC programs relevant for physicians' practice.

The Prevalence of Asymptomatic Cervical and Lumbar Facet Arthropathy: A Computed Tomography Study.

STUDY DESIGN: Case control study. PURPOSE: To determine the prevalence and degree of asymptomatic cervical and lumbar facet joint arthritis. We retrospectively reviewed 500 computed tomography (CT) scans of cervical facet joints obtained from 50 subjects. Moreover, 500 lumbar facet joints obtained from an additional 50 subjects were reviewed. OVERVIEW OF LITERATURE: Numerous reports in the literature indicate that joint arthritis is a major source of axial neck and low back pain. However, the diagnostic value of this condition, based on degenerative changes seen on radiological studies, remains controversial because significant imaging findings may not correlate with corresponding symptoms. The CT scan is a sensitive method for facet joint evaluation and may reveal degenerative abnormalities. Previous studies have described the prevalence of facet arthropathy in symptomatic patients, according to radiological findings; however, no study to date has assessed its prevalence in asymptomatic patients. METHODS: We retrospectively reviewed the neck and abdominal CT scans of patients had been examined for non-spinal pathologies (i.e., thyroid disease, rule out cancer, ascites). Electronic medical records were reviewed to exclude patients with histories of either neck or back pain. Arthritis severity was graded using a previously published four-point CT scale. RESULTS: The prevalence of asymptomatic cervical facet arthritis (grade 1-3) was 33% (grade 1, 19%; grade 2, 11%; and grade 3, 3%). Among asymptomatic patients, 37% had scalable lumbar facet join arthritis (grade 1, 24%; grade 2, 9%; and grade 3, 4%). There was a statistically significant difference (chi-square test, p<0.0001) in the number of older individuals with arthritic degeneration at the cervical and lumbar levels compared with that of younger individuals. The C6-C7 and L5-S1 levels were the most likely to show arthritic changes. CONCLUSIONS: Arthritic changes to the cervical and lumbar facet joints are prevalent among patients, and in some cases are asymptomatic. These findings were more common in older patients and at lower spinal levels.

Comparison of AR, ITS, CBT, and Didactic Training and Evaluation of Retinopathy-Based Diagnosis.

RESEARCH OBJECTIVE: To test the relative efficacy of adaptive and fixed simulator training vs. adaptive and fixed computer-based training (CBT) vs. traditional lecture. METHODS: Ninety-two board certified Family Physicians were given a pretest, followed by training under one of five randomly assigned training conditions: (i) adaptive CBT; (ii) non-adaptive CBT; (iii) adaptive simulator; (iv) non-adaptive simulator; and (v) lecture. Subjects were given a post-test immediately after training and again in 6 weeks. In the adaptive groups, the content presented to subjects was a function of the subjects' knowledge and performance, under control of a MOODLE LMS. In the lecture component, a physician projected images identical to the images in the CBT component of the study. RESULTS: No significant differences (p = 0.89 for ANOVA) in baseline knowledge between the five groups, based on pretest scores; In each of the five groups, our intervention resulted in immediate changes in knowledge (95% CI), based on analysis of pretest and PostTest1 scores; and, with the exception of subjects with non-adaptive, simulator intervention, all groups had significant decay in knowledge between the first and second post-tests (95% CI). CONCLUSION: Periodic simulator intervention could result in significant knowledge retention over extended periods of time.

TrkB agonists ameliorate obesity and associated metabolic conditions in mice.

Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity in rodents and/or humans. Here, we show that peripheral administration of neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and body weight in a dose-dependent manner in several murine models of obesity. NT4 treatment increased lipolysis, reduced body fat content and leptin, and elicited long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After treatment termination, body weight gradually recovered to control levels in obese mice with functional leptin receptor. A single intrahypothalamic application of minute amounts of NT4 or an agonist trkB antibody also reduced food intake and body weight in mice. Taken together with the genetic evidence, our findings support the concept that trkB signaling, which originates in the hypothalamus, directly modulates appetite, metabolism, and taste preference downstream of the leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and weight-reducing effects independent of stress induction, visceral discomfort, or pain sensitization and thus emerge as a potential therapeutic for metabolic disorders.

Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis.

BACKGROUND: In a phase 2a clinical trial of AN1792 (Study 201), a potential immunotherapeutic agent for use in Alzheimer's disease (AD), approximately 6% of the treated AD patients (18/300) developed meningoencephalitis (ME). OBJECTIVE: To elucidate potential immune mechanisms of treatment-induced ME. METHODS: Peripheral blood mononuclear cells obtained from patients who received AN1792 were stimulated in vitro either with beta-amyloid (Abeta) or various overlapping peptides of Abeta(1-42), followed by quantification of cytokine-secreting cells by enzyme-linked immunosorbent spot assay. RESULTS: A significant difference in the quality of the T-cell responses between patients in Study 201 and those in earlier studies of AN1792 was noted. T-cell responses specific to the carboxy terminus of Abeta elicited from patients' peripheral blood mononuclear cells in an earlier multiple dose study (Study 102) were Th2 biased, while those from Study 201 were biased toward a proinflammatory Th1 response. Antibody responses in both studies were quantitatively and qualitatively similar (as determined by epitope mapping). The addition of polysorbate 80 to the formulation used in Study 201 is the most likely explanation for the difference in the T-cell response. CONCLUSION: ME following injection of AN1792 may be related to immune response differences driven by a formulation change. To address this, a novel peptide-carrier protein conjugate using an amino-terminal fragment of Abeta (ACC-001) has been developed to avoid potentially harmful T-cell responses, while maintaining a similar antibody response to that of AN1792. Immunotherapeutic trials using this treatment approach in AD patients are in progress.

Physician Perceptions of Performance Feedback in a Quality Improvement Activity.

Physician performance and peer comparison feedback can affect physician care quality and patient outcomes. This study aimed to understand family physician perspectives of the value of performance feedback in quality improvement (QI) activities. This study analyzed American Board of Family Medicine open-ended survey data collected between 2004 and 2014 from physicians who completed a QI module that provided pre- and post-QI project individual performance data and peer comparisons. Physicians made 3480 comments in response to a question about this performance feedback, which were generally positive in nature (86%). Main themes that emerged were importance of accurate feedback data, enhanced detail in the content of feedback, and ability to customize peer comparison groups to compare performance to peers with similar patient populations or practice characteristics. Meaningful and tailored performance feedback may be an important tool for physicians to improve their care quality and should be considered an integral part of QI project design.

Current progress in beta-amyloid immunotherapy.

As neuroscientists, we are taught that the brain is immune privileged and thus unlikely to be affected by the peripheral immune system. Accordingly, initial results demonstrating the effectiveness of beta-amyloid (Abeta) immunotherapy in mouse models of Alzheimer's disease (AD) were viewed with considerable surprise and some skepticism. Many groups have since demonstrated efficacy with Abeta immunotherapy in models of AD, using Abeta-based immunogens and anti-Abeta antibodies. Clinical trials involving Abeta immunotherapy for AD are in progress and are providing a wealth of information around the amyloid hypothesis of AD. Abeta immunotherapy is also raising new opportunities and questions about the general role of the immune system in neurodegenerative diseases.

Physician Satisfaction With and Practice Changes Resulting From American Board of Family Medicine Maintenance of Certification Performance in Practice Modules.

INTRODUCTION: Physician payment in the United States will be increasingly tied to quality measurement and performance. Whether participation in quality improvement (QI) through Maintenance of Certification for Family Physicians Performance in Practice Modules (PPMs) is useful and results in practice change remains unknown. METHODS: All PPM feedback data from inception to April 2014 were analyzed using descriptive statistics by year, topic, and number of PPMs completed. Qualitative content analysis was applied to analyze responses to open-ended questions on practice changes. RESULTS: Of note, 29,755 diplomates completed 38,201 PPMs; median 1 interquartile range (1, 1). Nearly two-thirds (65.8%, n = 25,150) of PPMs had completed feedback surveys. Of note, 78.7% of respondents indicated that they would change patient care and 90.2% indicated that they would continue QI activities after completing the PPM. Respondents endorsed high relevance to practice (90.5%), high currency of clinical information (86.4%), and high usefulness of clinical information (80.5%). When feedback was analyzed by the number of PPMs completed, respondents were less likely to change care but reported increased usefulness to practice and stable intention to continue QI efforts with more PPMs completed. Of note, 86.0% of respondents who said that they would change care provided examples: these varied by PPM topic but "doing more," focusing on patients, and education were common. DISCUSSION: These findings suggest that QI completed through the PPMs may assist family physicians in improving the care they provide. Furthermore, ratings by the number of PPMs completed suggest that repeated exposure to QI efforts produce continued relevance and usefulness, even when changes in practice decline.

Methods for Performing Survival Curve Quality-of-Life Assessments.

BACKGROUND: Many medical decisions involve an implied choice between alternative survival curves, typically with differing quality of life. Common preference assessment methods neglect this structure, creating some risk of distortions. METHODS: Survival curve quality-of-life assessments (SQLA) were developed from Gompertz survival curves fitting the general population's survival. An algorithm was developed to generate relative discount rate-utility (DRU) functions from a standard survival curve and health state and an equally attractive alternative curve and state. A least means squared distance algorithm was developed to describe how nearly 3 or more DRU functions intersect. These techniques were implemented in a program called X-Trade and tested. RESULTS: SQLA scenarios can portray realistic treatment choices. A side effect scenario portrays one prototypical choice, to extend life while experiencing some loss, such as an amputation. A risky treatment scenario portrays procedures with an initial mortality risk. A time trade scenario mimics conventional time tradeoffs. Each SQLA scenario yields DRU functions with distinctive shapes, such as sigmoid curves or vertical lines. One SQLA can imply a discount rate or utility if the other value is known and both values are temporally stable. Two SQLA exercises imply a unique discount rate and utility if the inferred DRU functions intersect. Three or more SQLA results can quantify uncertainty or inconsistency in discount rate and utility estimates. Pilot studies suggested that many subjects could learn to interpret survival curves and do SQLA. LIMITATIONS: SQLA confuse some people. Compared with SQLA, standard gambles quantify very low utilities more easily, and time tradeoffs are simpler for high utilities. When discount rates approach zero, time tradeoffs are as informative and easier to do than SQLA. CONCLUSIONS: SQLA may complement conventional utility assessment methods.

Adding flexible temporal constraints to identify chronic comorbid conditions in ambulatory claims data.

Chronic comorbid conditions are important predictors of primary care outcomes, provide context for clinical decisions, and are potential complications of diseases and treatments. Comorbidity indices and multimorbidity categorization strategies based on administrative claims data enumerate diagnostic codes in easily modifiable lists, but usually have inflexible temporal requirements, such as requiring two claims greater than 30 days apart, or three claims in three quarters. Table structures and claims data search algorithms were developed to support flexible temporal constraints. Tables of disease categories allow subgroups with different numbers of events, different times between similar claims, variable periods of interest, and specified diagnostic code substitutability. The strategy was tested on five years of private insurance claims from 2.2 million working age adults. The contrast between rarely recorded, high prevalence diagnoses (smoking and obesity) and frequently recorded but not necessarily chronic diagnoses (musculoskeletal complaints) demonstrated the advantage of flexible temporal criteria.

Improving quality of care and guideline adherence for asthma through a group self-assessment module.

BACKGROUND: The quality of care for asthma remains suboptimal. Compliance with guidelines remains low, but improved adherence to guidelines may increase the quality of care. but. We conducted a trial to determine whether group Self-Assessment Module (SAM) activities led by a facilitator and conducted as part of Maintenance of Certification for Family Physicians (MC-FP) would increase knowledge of and adherence to asthma guidelines. METHODS: Participating physicians completed audits of the charts of patients with asthma before and 6 months after a group SAM. Surveys of physicians' knowledge of asthma guidelines were administered immediately before, immediately after, and 6 months after the group SAM. We tested for differences in knowledge of and adherence to guidelines before and after the SAM using χ(2) and t tests. RESULTS: Thirty-eight physicians in Virginia completed the SAM and had complete data. Participants completed more MC-FP activities than other physicians but were comparable in other characteristics. Except for prescribing controller medications for persistent asthma, all other quality measures significantly improved 6 months after the group SAM. Diagnosis by severity improved from 48.3% to 80.2%, and the use of action plans increased from 8.1% to 54.1%. Physicians' knowledge of guidelines improved immediately after the SAM and was sustained at 6 months. Increased knowledge translated into clinical skills: 30% of participants reported comfort with assessing control after the SAM, which increased to 97.5% 6 months after the SAM. CONCLUSIONS: Group SAMs may be an effective method to increase physicians' knowledge of and adherence to clinical guidelines.