Genomic Analysis Points to Multiple Genetic Mechanisms for Non-Transformable Campylobacter jejuni ST-50.

Campylobacter jejuni and Campylobacter coli are well known for their natural competence, i.e., their capacity for the uptake of naked DNA with subsequent transformation. This study identifies non-transformable C. jejuni and C. coli strains from domestic animals and employs genomic analysis to investigate the strain genotypes and their associated genetic mechanisms. The results reveal genetic associations leading to a non-transformable state, including functional DNase genes from bacteriophages and mutations within the cts-encoded DNA-uptake system, which impact the initial steps of the DNA uptake during natural transformation. Interestingly, all 38 tested C. jejuni ST-50 strains from the United States exhibit a high prevalence of non-transformability, and the strains harbor a variety of these genetic markers. This research emphasizes the role of these genetic markers in hindering the transfer of antimicrobial resistance (AMR) determinants, providing valuable insights into the genetic diversity of Campylobacter. As ST-50 is a major clone of C. jejuni globally, we additionally determined the prevalence of the genetic markers for non-transformability among C. jejuni ST-50 from different regions of the world, revealing distinct patterns of evolution and a strong selective pressure on the loss of competence in ST-50 strains, particularly in the agricultural environment in the United States. Our findings contribute to a comprehensive understanding of genetic exchange mechanisms within Campylobacter strains, and their implications for antimicrobial resistance dissemination and evolutionary pathways within specific lineages.

Differences in the Propensity of Different Antimicrobial Resistance Determinants to Be Disseminated via Transformation in Campylobacter jejuni and Campylobacter coli.

Campylobacter jejuni and Campylobacter coli are leading zoonotic foodborne pathogens, and the drugs of choice for human campylobacteriosis are macrolides (e.g., erythromycin) and fluoroquinolones. C. jejuni and C. coli are naturally competent for transformation via naked DNA uptake, but potential differences in transformation frequency (TF) for different antimicrobial resistance (AMR) markers remain poorly understood. We determined TFs for resistance to different antibiotics using as recipient a derivative of C. jejuni NCTC 11168 (strain SN:CM) with donor DNA from multidrug-resistant C. jejuni or C. coli. TF for nalidixic acid resistance ranked significantly highest (~1.4 × 10-3), followed by resistance to streptomycin and gentamicin. Tetracycline resistance via chromosomal tet(O) was less commonly transferred (~7.6 × 10-7), while transformation to erythromycin resistance was rare (≤4.7 × 10-8). We also determined TFs with the contemporary poultry-derived strains C. jejuni FSIS 11810577 and C. coli FSIS 1710488 as recipients. TFs to nalidixic acid and streptomycin resistance remained the highest (~7 × 10-4). However, TF for gentamicin resistance was remarkably low in certain recipient-donor combinations, while average TF for erythromycin resistance was noticeably higher (~3 × 10-6) than with SN:CM. Findings from this experimental model provide insights into factors that may impact transformation-mediated transfer of AMR leading to AMR dissemination in the agricultural ecosystem.

High-Throughput Detection of Autoantigen-Specific B Cells Among Distinct Functional Subsets in Autoimmune Donors.

Antigen-specific B cells (ASBCs) can drive autoimmune disease by presenting autoantigen to cognate T cells to drive their activation, proliferation, and effector cell differentiation and/or by differentiating into autoantibody-secreting cells. Autoantibodies are frequently used to predict risk and diagnose several autoimmune diseases. ASBCs can drive type 1 diabetes even when immune tolerance mechanisms block their differentiation into antibody-secreting cells. Furthermore, anti-histidyl tRNA synthetase syndrome patients have expanded IgM+ Jo-1-binding B cells, which clinically diagnostic IgG Jo-1 autoantibodies may not fully reflect. Given the potential disconnect between the pathologic function of ASBCs and autoantibody secretion, direct study of ASBCs is a necessary step towards developing better therapies for autoimmune diseases, which often have no available cure. We therefore developed a high-throughput screening pipeline to 1) phenotypically identify specific B cell subsets, 2) expand them in vitro, 3) drive them to secrete BCRs as antibody, and 4) identify wells enriched for ASBCs through ELISA detection of antibody. We tested the capacity of several B cell subset(s) to differentiate into antibody-secreting cells following this robust stimulation. IgM+ and/or IgD+, CD27- memory, memory, switched memory, and BND B cells secreted B cell receptor (BCR) as antibody following in vitro stimulation, whereas few plasmablasts responded. Bimodal responses were observed across autoimmune donors for IgM+ CD21lo and IgM- CD21lo B cells, consistent with documented heterogeneity within the CD21lo subset. Using this approach, we detected insulin-binding B cell bias towards CD27- memory and CD27+ memory subsets in pre-symptomatic type 1 diabetes donors. We took advantage of routine detection of Jo-1-binding B cells in Jo-1+ anti-histidyl tRNA synthetase syndrome patients to show that Jo-1-binding B cells and total B cells expanded 20-30-fold using this culture system. Overall, these studies highlight technology that is amenable to small numbers of cryopreserved peripheral blood mononuclear cells that enables interrogation of phenotypic and repertoire attributes of ASBCs derived from autoimmune patients.

Better Asthma Management with Advanced Technology: Creation of an Asthma Utilization Rx Analyzer (AURA) Tool.

With nearly 23 million people affected by asthma each year, optimizing care among patients with persistent disease is a constant challenge for health care providers. The Asthma Utilization Rx Analyzer (AURA) tool enables health plan managers to evaluate quality and resource utilization for its members with asthma by analyzing medical and pharmacy claims. Customizable quality measures allow users of the tool to generate results from specific plans in order to optimize asthma disease management.

Sino-Nasal 5 Questionnaire is Associated with Poor Asthma Control in Children with Asthma.

Up to 80% of asthmatic children may experience upper airway symptoms which are often perceived as coming from the lower airways. Currently, there are no validated questionnaires to assess upper airway contribution to pediatric asthma symptoms. The Sino-Nasal 5 (SN-5) questionnaire was previously validated for identifying radiographic confirmed sinus disease in children. In this study, we hypothesize that significant SN-5 scores (≥3.5) are associated with abnormal National Asthma Education and Prevention Program (NAEPP) based asthma impairment and control in asthmatic children. Retrospective data collected on children with asthma referred for pulmonary evaluation included age, gender, ethnicity, NAEPP asthma severity, asthma control (Test for Respiratory and Asthma Control in Kids (TRACK) < 5 years, Asthma Control Test (ACT) 5 years) and pulmonary function testing. Associations between SN-5 scores and asthma impairment and control were identified. Seventy-six children were evaluated; 38% were female with a mean age of 6.9 years. Significant SN-5 scores were associated with decreased control of daytime symptoms (odds ratio (OR): 0.16 (95% confidence interval (CI): 0.06-0.44)), night time awakenings (0.09 (0.03-0.29)), activity interference (0.2 (0.06-0.68)), NAEPP defined asthma control (0.32 (0.12-0.85)) and poor asthma control based on TRACK (p < 0.001) and ACT (p < 0.001). This suggests upper airways may play a larger role in perceived lower airway symptoms, and SN-5 may be beneficial in assessing the contribution of upper airway conditions on asthma control.

Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs.

BACKGROUND: Ferric citrate (FC) is a new phosphorus binder shown to increase serum iron stores while reducing intravenous iron and erythropoiesis-stimulating agent usage. Such reductions could lower hospitalization rates and associated costs. METHODS: Hospitalizations during a Phase III trial were compared between FC and active control (AC). Hospitalization costs were estimated using the 2013 US Renal Data System Annual Data Report. RESULTS: 34.6% of FC patients were hospitalized at least once versus 45.6% of the AC group (risk reduction 24.2%; p = 0.02). There were 181 unique hospitalizations in the FC group versus 239 in the AC group, for a difference of 58 hospitalizations. Total potential savings was US$ 867,622 in hospitalization costs in the FC group. If the hospitalization reduction in our study was applied to the general end-stage renal disease population, this could translate into a savings of US$ 3002/patient/year. CONCLUSIONS: Patients receiving FC experienced fewer hospitalizations with the potential for significant savings.

Assessment of drug therapy management and the prevalence of heart failure in a managed care population with hypertension.

OBJECTIVES: To (1) determine the prevalence of heart failure (HF) and cardiovascular risk factors within a hypertensive managed care population, (2) measure blood pressure goal attainment in patients with concurrent HF and hypertension (HTN), and (3) assess the use of drug therapy for diabetic and nondiabetic patients with concurrent HF and HTN, particularly regarding the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). METHODS: Eligible patients were identified through a review of medical and pharmacy claims data from 10 managed care organizations (MCOs) and 2 specialty medical groups (4.6 million total members) from June 1998 through July 2001. From approximately 850,000 members in the claims database identified as hypertensive, 7,226 were randomly selected for medical chart review. Of these, 6,935 medical charts had a confirmed diagnosis of HTN but not HF, and 291 (4%) had confirmed HTN and HF. The study population--291 patients with HTN and HF--provided information on demographic characteristics, prevalence of cardiovascular risk factors and relevant comorbidities, and systolic and diastolic blood pressure. Current antihypertensive therapy prescription fill rate was evaluated using pharmacy claims. RESULTS: Patients with diagnoses of HTN and HF confirmed in the medical chart (N=291) were included in the present analysis. HF prevalence among hypertensive patients was 4% (291 of 7,226). Mean age of the study patients was 68.3 years, and 52.9% of the patients were female. Key cardiovascular risk factors included gender (men and postmenopausal women) (89.3%), age > 60 years (73.5%), hyperlipidemia (47.4%), and diabetes (38.8%). Of the total sample, only 30.1% of the diabetic (34 of 113) and 26.4% of the nondiabetic (47 of 178) patients with HF had their blood pressure controlled to the goal level of < 130/85 mm Hg recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the national guideline in effect at the time. Overall, 64.7% of HF patients for whom we had pharmacy claims were receiving an ACE inhibitor or an ARB. CONCLUSIONS: The study results indicate a deficit in the treatment of HTN among HF patients with and without diabetes, including failure to achieve blood pressure goals (< 130/85 mm Hg at the time of this study period). More aggressive quality improvement programs are necessary to educate providers and patients on the importance of treating blood pressure to nationally accepted goal using antihypertensives proven beneficial for hypertensive patients with HF.

The hypertension management program: identifying opportunities for improvement.

To date, relatively few programs have been evaluated that were designed to affect the clinical practice patterns of primary care physicians who treat patients with hypertension. In particular, studies that have evaluated blood pressure control as a clinical outcome before and after an intervention are lacking. The Hypertension Management Program, developed by Applied Health Outcomes, is a quality improvement program designed to improve the medical management of hypertension in population-based health care settings. This program is in the process of continuing to collect baseline data from health maintenance organizations, conducting physician-focused interventions designed for improving clinical care, and collecting postintervention data between 6 and 12 months after the intervention is completed to determine its effect. The authors present the rationale for conducting large-scale hypertension management programs that measure outcomes, as well as preliminary baseline and postintervention data from the Hypertension Management Program, based on a current database of more than 1.9 million individuals enrolled in eight health care plans.

Determinants of uncontrolled hypertension in an African-American population.

OBJECTIVES: The purpose of this study was to assess blood pressure control and the determinants of uncontrolled blood pressure among African-American hypertensive patients. DESIGN: Baseline clinical data were collected as part of a nationwide hypertension quality improvement initiative. An analysis of determinants of uncontrolled blood pressure was conducted using logistic regression for the following variables: angina, congestive heart failure, coronary artery disease, diabetes, family history of cardiovascular disease or stroke, hyperlipidemia, left ventricular hypertrophy, and tobacco use. SETTING: 10 managed care/advanced physician organizations. PATIENTS: Pharmacy and medical claims covering 1,965,000 lives were reviewed and 292,996 members with a hypertension-related claim were identified between June 1, 1998 and July 1, 2001. A random sample (N = 5,935) was selected for chart review. The present analysis was conducted on the subset of African-American patients (N = 440) included in this sample. RESULTS: Approximately 66% of the African-American patients were female, the mean age was 60.4 years, 47.8% had dyslipidemia, and 31.4% had diabetes. Approximately 64% had uncontrolled hypertension. Patients with diabetes were 3 times more likely to have uncontrolled blood pressure as were patients without diabetes (OR = 2.92; P < .0001). CONCLUSIONS: Blood pressure control in the African-American population is lower than the Healthy People 2010 goal of 50%. African Americans with hypertension and diabetes are at an increased risk for uncontrolled blood pressure. Treating this high-risk population more aggressively may reduce long-term complications and decrease mortality.

Hematologic outcomes of myelodysplastic syndromes treatment with hypomethylating agents in community practice.

INTRODUCTION: Hypomethylating agents (HMAs) treat myelodysplastic syndromes (MDS) through suppression of abnormal clones that may cause low hemoglobin (Hgb), platelet (PLT) deficiencies, and reduced absolute neutrophil count (ANC). Our study examined hematologic outcomes in MDS among patients treated with HMAs in a large community hematology-oncology practice. MATERIALS AND METHODS: A retrospective study using electronic medical record data studied patients who received at least one cycle of a single HMA (decitabine [DAC] or azacitidine [AZA]) for MDS from June 1, 2006, to May 31, 2009, who had pretreatment and end-of-treatment Hgb, PLT counts, and ANC available. Multivariate logistic regression assessed predictors of end-of-treatment response (Hgb ≥ 11 g/dL without transfusion or erythrocyte stimulating agent; PLT ≥ 100,000 cells/µL without transfusion; ANC ≥ 1000 cells/mm(3) without colony stimulating factor) adjusting for baseline laboratory values, age, gender, and comorbidities. HMA choice was studied as a predictor of outcome. RESULTS: A total of 137 patients (mean age, 72.2 years; 57% male) met full inclusion criteria (DAC = 84, AZA = 53). Mean number of cycles was four (range, 1-16 cycles) for DAC and five (range, 1-23 cycles) for AZA. Total number of cycles significantly predicted Hgb, PLT, and ANC response (odds ratio [OR] 1.19, P = .029; OR 1.15, P = .031; OR 1.16, P = .047, respectively). Growth factor use at any point during HMA treatment was negatively associated with Hgb and ANC response (OR 0.85, P = .007; OR 0.96, P = .046). There was no difference between treatments in likelihood of PLT or ANC response. CONCLUSIONS: Patients treated with HMAs for MDS are more likely to achieve hematologic response when treated with a greater number of cycles.

Predicted coronary heart disease risk reduction and dual blood pressure/cholesterol goal attainment in patients with hypertension treated in real-world clinical practice.

Hypertension and dyslipidemia are highly co-prevalent, but often poorly controlled, coronary heart disease (CHD) risk factors. A retrospective cohort study was conducted between January 2004 and April 2008 to compare estimated 10-year CHD risk reduction and dual blood pressure and low-density lipoprotein cholesterol goal attainment (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III]) in patients with a first prescription for amlodipine monotherapy, co-prescribed amlodipine + statin, or single-pill amlodipine/atorvastatin. In total, 2739 patients were prescribed amlodipine monotherapy, 653 were co-prescribed amlodipine + statin, and 227 were prescribed single-pill amlodipine/atorvastatin. Baseline CHD risk was similar in all 3 cohorts (11.0%-12.5%). Relative CHD risk reduction was greater in those prescribed single-pill amlodipine/atorvastatin (24.5%) compared with amlodipine monotherapy (14.4%, P<.01), and co-prescribed amlodipine + statin (18.4%, P=.01). The findings were driven by greater dual goal attainment for patients prescribed single-pill amlodipine/atorvastatin (50.2%) compared with amlodipine monotherapy (31.7%, P<.05) and co-prescribed amlodipine + statin (37.5%, P<.05).

Provider organization performance assessment utilizing diabetes physician recognition program.

OBJECTIVE: To examine the level of care in a large provider organization with respect to the Diabetes Physician Recognition Program (DPRP) standards of care and describe treatment patterns, diabetes-related complications, and achievement of clinical goals among patients stratified by glycemic control levels. STUDY DESIGN: Observational, retrospective, chart review study assessing care among patients with diabetes. METHODS: Diabetic patients aged > or =5 years who were prescribed insulin or oral hypoglycemics/antihyperglycemics for at least 12 months by 1 of 14 DPRP-participating physicians from the provider organization were eligible. A sample of patient medical charts was collected. Descriptive statistics were generated to assess demographic and clinical variables, with subanalyses for patients in the 3 glycosylated hemoglobin (A1C) cohorts. Data were used to describe the demographics, disease prevalence, comorbidities, clinical outcomes, and treatment patterns of the study population. Results were assessed according to national treatment guidelines. RESULTS: Almost all DPRP recognition measures were met and/or exceeded. More than 90% of patients received appropriate assessments. The majority achieved the A1C, blood pressure, and low-density lipoprotein control levels recommended by national treatment guidelines. Patients with multiple comorbidities had worse levels of control, with only 14.3% of patients achieving all 3 treatment goals. Nearly 30% of patients had diabetes-related complications, most commonly kidney disease. CONCLUSIONS: Differences in control and treatment patterns exist in patients with varying levels of glycemic control. Opportunities exist to improve diabetes care through goal attainment. Further research is needed to determine whether specific measures of care correlate with levels of glycemic control.

Blood pressure control and pharmacotherapy patterns in the United States before and after the release of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.

OBJECTIVES: Despite recommendations from the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), only 36.8% of patients were at target blood pressure (BP) in 2003 and 2004. The objective of this study was to assess improvements in BP control and treatment patterns before and after the publication of JNC 7. METHODS: This was a retrospective, time series analysis of 27 provider groups and managed care organizations from 1998 through 2006. Patients with hypertension were identified from more than 4000 physicians. Medical charts were collected and clinical data were evaluated using prevailing JNC criteria during the time period before and after JNC 7. RESULTS: A total of 19,258 patients were identified with hypertension: 15,258 included in the before-JNC 7 cohort and 4,000 in the after-JNC 7 cohort. BP control in the before-JNC 7 cohort was 40.8% compared with 49.3% in the after-JNC 7 cohort (P < .0001). After controlling for demographic and clinical covariates, patients in the before-JNC 7 cohort were 45% less likely to achieve BP control compared with the after-JNC 7 cohort (odds ratio, 0.551; P < .0001). CONCLUSION: Although findings indicate BP control is improving, a significant need for further improvement remains.

Dosing patterns, drug costs, and hematologic outcome in anemic patients with chronic kidney disease switching from darbepoetin alfa to epoetin alfa.

OBJECTIVE: To compare real-world dosing patterns, drug costs, and hematologic outcome in anemic chronic kidney disease (CKD) patients, not receiving dialysis, who switched from darbepoetin alfa (DARB) to epoetin alfa (EPO) in a community practice setting. RESEARCH DESIGN AND METHODS: This retrospective observational chart review from a US nephrology clinic included 153 anemic CKD patients > or = 18 years of age who did not receive dialysis during the study period, switched from DARB to EPO between 8/2003 and 8/2005, and received > or = 2 doses of both agents. Paired t-test and McNemar's chi-square were performed comparing pre-switch and post-switch outcomes. RESULTS: Mean interval between doses increased from 24.3 +/- 11.1 days with DARB to 28.8 +/- 19.8 days with EPO (p = 0.001). Weighted mean pre-switch weekly dose for DARB was 25 mug, while weighted mean post-switch weekly dose for EPO was 7090 Units, resulting in a dose ratio (Units EPO:microg DARB) of 287:1. These doses resulted in mean weekly costs of $110 (DARB) and $86 (EPO). Mean hemoglobin (Hb) levels increased over time from 10.8 g/dL at 6 months pre-switch to 11.1 g/dL 6 months after EPO initiation (p = 0.0132). Mean Hb levels were > 11 g/dL, but below 12 g/dL, while patients received EPO. CONCLUSIONS: Patients switching from DARB to EPO had a greater mean interval between doses, lower drug costs, and consistently maintained recommended Hb levels over time. LIMITATIONS: The reverse direction (EPO to DARB) was not investigated. Although treatment outcomes were not assessed in a randomized, controlled setting, the study's observational nature provided actual evidence in a real-world setting.