Expression, Purification, and Biological Evaluation of XTEN-GCSF in a Neutropenic Rat Model.

Granulocyte colony-stimulating factor (GCSF) stimulates the proliferation of neutrophils but it has low serum half-life. Therefore, the present study was done to investigate the effect of XTENylation on biological activity, pharmacokinetics, and pharmacodynamics of GCSF in a neutropenic rat model. XTEN tag was genetically fused to the N-terminal region of GCSF-encoding gene fragment and subcloned into pET28a expression vector. The cytoplasmic expressed recombinant protein was characterized through intrinsic fluorescence spectroscopy (IFS), dynamic light scattering (DLS), and size exclusion chromatography (SEC). In vitro biological activity of the XTEN-GCSF protein was evaluated on NFS60 cell line. Hematopoietic properties and pharmacokinetics were also investigated in a neutropenic rat model. An approximately 140 kDa recombinant protein was detected on SDS-PAGE. Dynamic light scattering and size exclusion chromatography confirmed the increase in hydrodynamic diameter of GCSF molecule after XTENylation. GCSF derivatives showed efficacy in proliferation of NFS60 cell line among which the XTEN-GCSF represented the lowest EC50 value (100.6 pg/ml). Pharmacokinetic studies on neutropenic rats revealed that XTEN polymer could significantly increase protein serum half-life in comparison with the commercially available GCSF molecules. PEGylated and XTENylated GCSF proteins were more effective in stimulation of neutrophils compared to the GCSF molecule alone. XTENylation of GCSF represented promising results in in vitro and in vivo studies. This approach can be a potential alternative to PEGylation strategies for increasing serum half-life of protein.

How successful was the use of a community of practice for the implementation of evidence-based practices for heart failure within the United States Department of Veterans Affairs: Insights from a formative evaluation.

BACKGROUND: Communities of Practice (CoPs) are a promising approach to facilitate the implementation of evidence-based practices (EBPs) to improve care for chronic conditions like heart failure (HF). CoPs involve a complex process of acquiring and converting both explicit and tacit knowledge into clinical activities. This study describes the conceptualization, creation, capacity-building and dissemination of a CoP sustained over 9 years, and evaluates its value and impact on EBP. METHODS: In July 2006, a CoP called the Heart Failure Provider Network (HF Network) was established within the United States Department of Veterans Affairs (VA) with the overarching goal of improving the quality of care for HF patients. We assessed (formative) the HF Network in terms of its various activities (inputs) and proximal impacts (mediators) at the individual level, and its distal impacts (outcomes) at the site level including implementation of new/improved EBPs at the systemwide level. RESULTS: The HF Network membership grew steadily over the 9 years. The CoP has involved a total of 1341 multidisciplinary and multilevel members at all 144 VA Health Care Systems (sites). Most members were practising clinicians (n = 891, 66.4%), followed by administrators (n = 342, 25.5%), researchers (n = 70, 5.2%) and others (n = 38, 2.8%). Participation was assessed to be "active" for 70.6% versus "passive" for 29.4% of members. The distribution of active members (clinicians 64.7%, administrators 21.6%) was similar to the distribution of overall membership. CONCLUSIONS: Survey respondents perceived the HF Network as useful in terms of its varied activities and resources relevant for patient care. Strong evidence shows that these members, particularly those who considered themselves influential in improving quality of care, noted multiple benefits of membership, which included confirmation of their own clinical practices, evidence-based changes to their practice and help in understanding facilitators and barriers in setting up or running HF clinics and other programmes. Such CoPs have strong impacts on the quality of care being delivered for both mandated and non-mandated initiatives.

Interventions to Increase Leukocyte Testing during Treatment with Dimethyl Fumarate.

Dimethyl fumarate (DMF), a treatment for multiple sclerosis, may cause leukopenia and infection. Accordingly, periodic white blood cell (WBC) monitoring is recommended. We sought to evaluate the US Department of Veteran Affairs' safety program which provides facilities with a list of patients prescribed DMF therapy without a documented white blood cell count (WBC). We identified 118 sites with patients treated with DMF from 1 January 2016 through 30 September 2016. Each site was asked if any of seven interventions were used to improve WBC monitoring (academic detailing, provider education without academic detailing, electronic clinical reminders, request for provider action plan, draft orders for WBC monitoring, patient mailings, and patient calls). The survey response rate was 78%. For the 92 responding sites (78%) included sites (1115 patients) the mean rate of WBC monitoring was 54%. In multivariate analysis, academic detailing increased the rate by 17% (95% CI 4 to 30%, p = 0.011) and provider education increased the rate by 9% (95% CI 0.6 to 18%, p = 0.037). The WBC monitoring rate increased by 3.8% for each additional intervention used (95% CI 1.2-6.4%, p = 0.005). Interventions focused on the physician, including academic detailing, were associated with improved WBC monitoring for patients at risk for leukopenia from DMF treatment.

Impact of the Hospital to Home Initiative on Readmissions in the VA Health Care System.

BACKGROUND: Hospital to Home (H2H) is a national quality improvement initiative sponsored by the Institute for Healthcare Improvement and the American College of Cardiology, with the goal of reducing readmission for patients hospitalized with heart disease. We sought to determine the impact of H2H within the Veterans Affairs (VA) health care system. METHODS: Using a controlled interrupted time series, we determined the association of VA hospital enrollment in H2H with the primary outcome of 30-day all-cause readmission following a heart failure hospitalization. VA heart failure providers were surveyed to determine quality improvement projects initiated in response to H2H. Secondary outcomes included initiation of recommended H2H projects, follow-up within 7 days, and total hospital days at 30 days and 1 year. RESULTS: Sixty-five of 104 VA hospitals (66%) enrolled in the national H2H initiative. Hospital characteristic associated with H2H enrollment included provision of tertiary care, academic affiliation, and greater use of home monitoring. There was no significant difference in mean 30-day readmission rates (20.0% ± 5.0% for H2H vs 19.3% ± 5.9% for non-H2H hospitals; P = .48) The mean fraction of patients with a cardiology visit within 7 days was slightly higher for H2H hospitals (3.0% ± 2.4% for H2H vs 2.0% ± 1.9% for non-H2H hospitals; P = .05). Patients discharged from H2H hospitals had fewer mean hospitals days during the following year (7.6% ± 2.6% for H2H vs 9.2% ± 3.0 for non-H2H; P = .01) early after launch of H2H, but the effect did not persist. CONCLUSIONS: VA hospitals enrolling in H2H had slightly more early follow-up in cardiology clinic but no difference in 30-day readmission rates compared with hospitals not enrolling in H2H.

Lack of Left Ventricular Ejection Fraction Measurement Following a High B-type Natriuretic Peptide Value.

BACKGROUND: The objective of this study was to determine how often providers did not obtain a recommended measure of left ventricular ejection fraction (LVEF) following a high B-type natriuretic peptide (BNP) value when the LVEF was not known to be low (<40%). Such patients may benefit from life-prolonging treatment. METHODS: We identified consecutive patients (inpatient or outpatient) with a BNP value of at least 200 pg/mL within a single VA health care system (3 inpatient facilities and 8 community clinics) during a 10-month period (September 2008-June 2009). We performed chart review to determine results of any imaging study performed (inside or outside the health system) prior to or after the high BNP value. RESULTS: Of the 296 patients with a high BNP, 212 were not known to have a low LVEF. Of these, 99 (47%) did not have the guideline recommended follow-up LVEF study. Among those that survived at least 6 months following BNP and a follow-up echocardiogram was indicated (no prior LVEF or prior LVEF was > 40%), mortality was 20% if an echocardiogram was performed within 6 months of the BNP and 27% if it was not performed within 6 months of BNP testing (P = 0.21). CONCLUSION: Approximately half of patients with a high BNP and an LVEF not known to be low did not have a follow-up guideline recommended LVEF study and may have unrecognized heart failure. Our findings suggest that a trial is warranted of a clinical pathway where those patients with a high BNP and without appropriate follow-up are randomized to have their physician receive a notification of the high BNP value.

Facilitation of a Multihospital Community of Practice to Increase Enrollment in the Hospital to Home National Quality Improvement Initiative.

BACKGROUND: Hospital to Home (H2H) is a national quality improvement (QI) initiative composed of three recommended hospital interventions to improve the transition of care for hospitalized patients with heart disease. A study was conducted to determine if enrollment of Department of Veterans Affairs (VA) hospitals in H2H and adoption of the recommended interventions would both increase following facilitation of an existing Heart Failure (HF) provider-based community of practice (COP) within the VA health care system. The VA HF COP includes more than 800 VA providers and other VA staff from VA inpatient medical centers. METHODS: In 2010, 122 VA hospitals were randomized to facilitation using the VA HF COP (intervention) or no facilitation (control). COP members from intervention hospitals were invited to periodic teleconferences promoting H2H and received multiple e-mails asking members to report interest and then progress in H2H implementation. RESULTS: Among the 61 hospitals randomized to HF COP facilitation, 33 (54%) enrolled in H2H, compared with 6 (10%) of 61 control hospitals (p<.001) at five months after randomization. Of 38 intervention hospitals responding to the follow-up survey, 13 stated they had initiated 22 QI projects as a result of the H2H campaign. Another 7 hospitals had planned H2H projects. Of 20 control hospitals that responded, 5 had initiated 9 projects as a result of H2H, and no additional hospitals had plans to do so. CONCLUSIONS: Facilitation using the VA HF COP was successful in increasing enrollment in the H2H initiative and providing implementation support for recommended QI projects. Multihospital provider groups are a potentially valuable tool for implementation of national QI campaigns.

Clinical reminders to providers of patients with reduced left ventricular ejection fraction increase defibrillator referral: a randomized trial.

BACKGROUND: Many patients who are candidates for implantable cardioverter defibrillators (ICDs) are not referred for potential implantation. We sought to determine if a simple provider reminder would increase referrals. METHODS AND RESULTS: We identified consecutive patients from January 2007 through July 2010 in the VA Palo Alto Health Care System with a left ventricular ejection fraction<35% on echocardiography. Patients were excluded using available administrative data only (no chart review) if they were known to have an ICD, if they were ≥80 years old, or if they did not have a current primary care or cardiology provider within the system. We randomized patients to no intervention or a clinical note to the provider in the medical record. The outcomes were referral for consideration of defibrillator implantation (primary) and documented discussion (secondary). Of 330 patients with left ventricular ejection fraction≤35%, 128 were known to have an ICD, 85 were no longer followed in the healthcare system, and 28 were ≥80 years old, leaving 89 patients to be randomized. Forty-six patients were randomized to intervention and 43 to control. Eleven of 46 (24%) intervention patients were referred for consideration of ICD implantation during the following 6 months versus 1 of 43 (2%) control patients (P=0.004). Overall, 31 of 46 (67%) intervention patients versus 19 of 43 (44%) control patients had documentation discussing potential candidacy for defibrillators (P=0.05). CONCLUSIONS: In patients with low left ventricular ejection fraction, a simple electronic medical record-based intervention directed to their providers improved the rates of referral for ICD implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01217827.

Clinical reminders attached to echocardiography reports of patients with reduced left ventricular ejection fraction increase use of beta-blockers: a randomized trial.

BACKGROUND: Although beta-blockers are known to prolong survival for patients with reduced left ventricular ejection fraction, they are often underused. We hypothesized that a reminder attached to the echocardiography report would increase the use of beta-blockers for patients with reduced left ventricular ejection fraction. METHODS AND RESULTS: We randomized 1546 consecutive patients with a left ventricular ejection fraction <45% found on echocardiography at 1 of 3 laboratories to a reminder for use of beta-blockers or no reminder. Patients were excluded from analysis if they died within 30 days of randomization (n=89), did not receive medications through the Veterans Affairs system after 30 days (n=180), or underwent echocardiography at >1 laboratory (n=6). The primary outcome was a prescription for an oral beta-blocker between 1 and 9 months after randomization. The mean age of the 1271 included patients was 69 years; 60% had a history of heart failure, and 51% were receiving treatment with beta-blockers at the time of echocardiography. More patients randomized to the reminder had a subsequent beta-blocker prescription (74%, 458 of 621) compared with those randomized to no reminder (66%, 428 of 650; P=0.002). The effect of the reminder was not significantly different for subgroups based on patient location (inpatient versus outpatient) or prior use of beta-blockers. CONCLUSIONS: A reminder attached to the echocardiography report increased the use of beta-blockers in patients with depressed left ventricular systolic function.

Translating research into practice: organizational issues in implementing automated decision support for hypertension in three medical centers.

Information technology can support the implementation of clinical research findings in practice settings. Technology can address the quality gap in health care by providing automated decision support to clinicians that integrates guideline knowledge with electronic patient data to present real-time, patient-specific recommendations. However, technical success in implementing decision support systems may not translate directly into system use by clinicians. Successful technology integration into clinical work settings requires explicit attention to the organizational context. We describe the application of a "sociotechnical" approach to integration of ATHENA DSS, a decision support system for the treatment of hypertension, into geographically dispersed primary care clinics. We applied an iterative technical design in response to organizational input and obtained ongoing endorsements of the project by the organization's administrative and clinical leadership. Conscious attention to organizational context at the time of development, deployment, and maintenance of the system was associated with extensive clinician use of the system.

Accuracy of computerized outpatient diagnoses in a Veterans Affairs general medicine clinic.

BACKGROUND: Electronically available data, both administrative, such as outpatient encounter diagnostic data, and clinical, such as problem lists, are being used increasingly for outcome and quality assessment, risk adjustment, and clinical reminder systems. OBJECTIVE: To determine the accuracy of outpatient primary care diagnostic information recorded in administrative and clinical files in a Veterans Affairs VISTA (Veterans Health Information Systems and Technology Architecture) database compared with medical chart notes. STUDY DESIGN: Cross-sectional medical chart review of 148 patients attending a general medicine clinic at a university-affiliated Veterans Affairs hospital for 9 diagnoses relevant to the choice of drug therapy for hypertension. PATIENTS AND METHODS: An administrative file of encounter diagnoses, for a 2-year period, and a clinical file of the problem list maintained by the clinician were the sources of electronic diagnoses. We compared these sources with diagnoses abstracted by medical chart review. We estimated the sensitivity and specificity of each electronic data source for detecting medical chart note diagnoses. RESULTS: The sensitivity for 8 of the 9 study diagnoses was greater than 80% in the administrative file and 49% in the clinical problem list. The specificity was good for the administrative file (91% to 100%) and even better for the clinical file (98% to 100%). CONCLUSIONS: Outpatient encounter diagnoses relevant to hypertension recorded as electronic data had high specificity, and some codes had high sensitivity when collected over multiple visits. The administrative file was more sensitive but less specific than the clinical file. Administrative vs clinical files can be selected to minimize either the false-negative or the false-positive designations, respectively, as dictated by the needs of the quality assessment review.