Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis

OBJECTIVE: Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA). METHODS: The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying antirheumatic drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, \u3c 25, 25-30, \u3e 30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes. RESULTS: We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed \u3e /=7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI \u3e 30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI \u3c /=25. CONCLUSION: DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups

Identifying factors associated with concordance with the American College of Rheumatology rheumatoid arthritis treatment recommendations

BACKGROUND: Factors associated with care concordant with the American College of Rheumatology (ACR) recommendations for the use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) are unknown. METHODS: We identified a national cohort of biologic-naive patients with RA with visits between December 2008 and February 2013. Treatment acceleration (initiation or dose escalation of biologic and nonbiologic DMARDs) in response to moderate to high disease activity (using the Clinical Disease Activity Index) was assessed. The population was divided into two subcohorts: (1) methotrexate (MTX)-only users and (2) multiple nonbiologic DMARD users. In both subcohorts, we compared the characteristics of patients who received care consistent with the ACR recommendations (e.g., prescriptions for treatment acceleration) and their providers with the characteristics of those who did not at the conclusion of one visit and over two visits, using logistic regression and adjusting for clustering of patients by rheumatologist. RESULTS: Our study included 741 MTX monotherapy and 995 multiple nonbiologic DMARD users cared for by 139 providers. Only 36.2 % of MTX monotherapy users and 39.6 % of multiple nonbiologic DMARD users received care consistent with the recommendations after one visit, which increased over two visits to 78.3 % and 76.2 %, respectively (25-30 % achieved low disease activity by the second visit without DMARD acceleration). Increasing time since the ACR publication on RA treatment recommendations was not associated with improved adherence. CONCLUSIONS: Allowing two encounters for treatment acceleration was associated with an increase in care concordant with the recommendations; however, time since publication was not

Impact of animal strain on gene expression in a rat model of acute cardiac rejection

<p>Abstract</p> <p>Background</p> <p>The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway), microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC).</p> <p>Results</p> <p>In heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC ≥ 3). Only 13 genes were affected by both strain and rejection, which was < 1% (13/1368) of all probesets differentially expressed in ACR. However, for PBMC, strain alone affected 265 probesets (FDR 10% and FC ≥ 3) and the addition of ACR had little further effect. Pathway analysis of these differentially expressed strain effect genes connected them with immune response, cell motility and cell death, functional themes that overlap with those related to ACR. After accounting for animal strain, additional analysis identified 30 PBMC candidate genes potentially associated with ACR.</p> <p>Conclusion</p> <p>In ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes.</p

Continuing medical education challenges in chronic fatigue syndrome

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) affects at least 4 million people in the United States, yet only 16% of people with CFS have received a diagnosis or medical care for their illness. Educating health care professionals about the diagnosis and management of CFS may help to reduce population morbidity associated with CFS.</p> <p>Methods</p> <p>This report presents findings over a 5-year period from May 2000 to June 2006 during which we developed and implemented a health care professional educational program. The objective of the program was to distribute CFS continuing education materials to providers at professional conferences, offer online continuing education credits in different formats (e.g., print, video, and online), and evaluate the number of accreditation certificates awarded.</p> <p>Results</p> <p>We found that smaller conference size (OR = 80.17; 95% CI 8.80, 730.25), CFS illness related target audiences (OR = 36.0; 95% CI 2.94, 436.34), and conferences in which CFS research was highlighted (OR = 4.15; 95% CI 1.16, 14.83) significantly contributed to higher dissemination levels, as measured by visit rates to the education booth. While print and online courses were equally requested for continuing education credit opportunities, the online course resulted in 84% of the overall award certificates, compared to 14% for the print course. This remained consistent across all provider occupations: physicians, nurses, physician assistants, and allied health professionals.</p> <p>Conclusion</p> <p>These findings suggest that educational programs promoting materials at conferences may increase dissemination efforts by targeting audiences, examining conference characteristics, and promoting online continuing education forums.</p

Epstein-Barr Virus Coinfection in Cerebrospinal Fluid Is Associated With Increased Mortality in Malawian Adults With Bacterial Meningitis

Mortality from adult bacterial meningitis exceeds 50% in sub-Saharan Africa. We postulated that—particularly in individuals infected with human immunodeficiency virus (HIV)—herpes simplex virus, varicella zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in the cerebrospinal fluid (CSF) contribute to poor outcome. CSF from 149 Malawian adults with bacterial meningitis and 39 controls were analyzed using polymerase chain reaction. EBV was detected in 79 of 149 bacterial meningitis patients. Mortality (54%) was associated with higher CSF EBV load when adjusted for HIV (P = .01). CMV was detected in 11 of 115 HIV-infected patients, 8 of whom died. The mechanisms by which EBV and CMV contribute to poor outcome require further investigation

Diagnostics to Support Elimination of Lymphatic Filariasis-Development of Two Target Product Profiles

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: Product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools

A train-the-trainer education and promotion program: chronic fatigue syndrome – a diagnostic and management challenge

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) is a complicated illness for providers and patients. Fewer than 20% of persons with CFS have been diagnosed and treated. For providers, compounding the issue are the challenges in making a diagnosis due to the lack of a biomedical marker.</p> <p>Methods</p> <p>The objective of the CFS diagnosis and management curriculum was to instruct core trainers as to the evaluation, diagnosis, and management of CFS. Over a two year period, 79 primary care physicians, physician assistants, and nurse practitioners from diverse regions in the U.S. participated as core trainers in a two day Train-the-Trainer (TTT) workshop. As core trainers, the workshop participants were expected to show increases in knowledge, self-efficacy, and management skills with the primary goal of conducting secondary presentations.</p> <p>Results</p> <p>The optimal goal for each core trainer to present secondary training to 50 persons in the health care field was not reached. However, the combined core trainer group successfully reached 2064 primary care providers. Eighty-two percent of core trainers responded "Very good" or "Excellent" in a post-tessurvey of self-efficacy expectation and CFS diagnosis. Data from the Chicago workshops showed significant improvement on the Primary Care Opinion Survey (p < 0.01) and on the Relevance and Responsibility Factors of the CAT survey (p = 0.03 and p = 0.04, respectively). Dallas workshop data show a significant change from pre- to post-test scores on the CFS Knowledge test (p = 0.001). Qualitative and process evaluation data revealed that target audience and administrative barriers impacted secondary training feasibility.</p> <p>Conclusion</p> <p>Data show the workshop was successful in meeting the objectives of increasing CFS knowledge and raising perceived self-efficacy towards making a diagnosis. The CFS TTT program informed an educational provider project by shifting the format for physicians to grand rounds and continuing medical education design while retaining TTT aspects for nurse practitioners and physicians assistants. Evaluations also indicate that secondary trainings may be more readily employed and accepted if administrative barriers are addressed early in the planning phases.</p

The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study.

PURPOSE: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries. METHODS: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to "health district" size: populations of 100,000-250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1-9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1-9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes. RESULTS: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries. CONCLUSION: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015

Protecting Endangered Species: Do the Main Legislative Tools Work?

It is critical to assess the effectiveness of the tools used to protect endangered species. The main tools enabled under the U.S. Endangered Species Act (ESA) to promote species recovery are funding, recovery plan development and critical habitat designation. Earlier studies sometimes found that statistically significant effects of these tools could be detected, but they have not answered the question of whether the effects were large enough to be biologically meaningful. Here, we ask: how much does the recovery status of ESA-listed species improve with the application of these tools? We used species' staus reports to Congress from 1988 to 2006 to quantify two measures of recovery for 1179 species. We related these to the amount of federal funding, years with a recovery plan, years with critical habitat designation, the amount of peer-reviewed scientific information, and time listed. We found that change in recovery status of listed species was, at best, only very weakly related to any of these tools. Recovery was positively related to the number of years listed, years with a recovery plan, and funding, however, these tools combined explain <13% of the variation in recovery status among species. Earlier studies that reported significant effects of these tools did not focus on effect sizes; however, they are in fact similarly small. One must conclude either that these tools are not very effective in promoting species' recovery, or (as we suspect) that species recovery data are so poor that it is impossible to tell whether the tools are effective or not. It is critically important to assess the effectiveness of tools used to promote species recovery; it is therefore also critically important to obtain population status data that are adequate to that task

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation