A Formative Evaluation of Diabetes Self-Management Education and Support Within the Virtual Medical Center.

The Diabetes Self-Management Education and Support (DSMES) program provides education and medical monitoring of diabetes to Veterans through the Virtual Medical Center (VMC). Qualitative interviews were conducted with 15 key stakeholders (4-DSMES VMC trainers, 5-clinical faculty, and 6-Veterans) from across Ohio urban and rural populations for up to 1h about their experiences using the program and suggestions for improvement. All the Veterans interviewed were able to access care within the DSMES VMC and reported a positive experience using the program, and improved diabetes self-management. Other stakeholders suggested more administrative and technical support for the DSMES VMC to increase awareness for VA staff and Veterans of the program to improve recruitment, and to shift to a web-based platform that is more easily accessible by clicking a link to reduce technical issues with downloading the program. These findings can inform future implementation efforts using technology to increase access to care allowing better health education for Veterans.

A mixed-methods evaluation of the national implementation of the Hospital-Acquired Pneumonia Prevention by Engaging Nurses (HAPPEN) initiative.

OBJECTIVE: To describe healthcare provider, veteran, and organizational barriers to, challenges to, and facilitators of implementation of the oral care Hospital-Acquired Pneumonia Prevention by Engaging Nurses (HAPPEN) initiative to prevent non-ventilator-associated hospital-acquired pneumonia (NV-HAP). DESIGN: Concurrent mixed methods. Qualitative interviews of staff and patients were conducted in addition to a larger survey of VA employees regarding implementation. SETTING: Medical surgical or extended care units in 6 high-complexity (01a-c) VA hospitals. PARTICIPANTS: Between January 2020 and February 2021, we interviewed 7 staff and 7 veterans, and we received survey responses from 91 staff. INTERVENTION: Provide education, support, and oral care supplies to prevent NV-HAP. RESULTS: Barriers to HAPPEN implementation and tracking at the pilot sites included maintaining oral care supplies and completion of oral care documentation. Facilitators for HAPPEN implementation included development of supportive formal and informal nurse leaders, staff engagement, and shared beliefs in the importance of care quality and infection prevention. Nurses worked together as a team to provide consistent oral care. Oral care was viewed as an essential infection control practice (not just "a task") and was considered part of the "culture" and "mission" in caring for veterans. CONCLUSIONS: Nurse leaders and direct-care staff were engaged throughout HAPPEN implementation, and most reported feeling supported and well prepared as they walked through the steps. Veterans reported positive experiences and increased knowledge about prevention of pneumonia. Lessons learned included building a community of practice and sharing expertise, which led to the successful replication of the HAPPEN initiative nationwide, improving patient safety and care quality and influencing health policy.

Refining the Implementation of a Hub-and-Spoke Model for TelePain Through Qualitative Inquiry.

The hub-and-spoke telehealth model leverages centrally located providers who utilize telehealth technology to bring specialized care to medically underserved areas. This model has the potential to promote equitable access to healthcare. However, few studies address how to facilitate the adoption and implementation of hub-and-spoke telehealth. We examined spoke site providers' experiences with TelePain, a national hub-and-spoke model of interdisciplinary chronic pain care, with a focus on improving future implementation. We conducted semi-structured individual interviews (20-45 min) with 27 VA spoke site providers via teleconferencing between August 2020 and February 2021. Interview transcripts were coded in Atlas.ti 8.0 using deductive (identified a priori and used to build the interview guide) and inductive (emerging) codes. Our analysis identified the following themes stressed by the spoke sites: (1) spoke sites needed to envision how TelePain services would work at their site before deciding to adopt; (2) TelePain implementation needed to fit into local existing care processes; (3) hub sites needed to understand spoke sites' context (e.g., via needs assessment) to tailor the services accordingly, and (4) hub-and-spoke sites needed to establish bidirectional communication. Our findings provide a practical guide to improve future rollout of hub-and-spoke telehealth models. Recommendations focus on the role of the hub site in promoting program adoption by (1) developing a clear and detailed marketing plan and (2) considering how the program can be adapted to fit the local spoke site context. To improve implementation, hub-and-spoke sites must establish ongoing and consistent bidirectional communication; this is particularly critical in the everchanging post-peak pandemic healthcare system. An important next step is the development of recommendations and guidelines for implementing hub-and-spoke telehealth, as well as examining pain outcomes for patients touched by this program.

Workforce Development to Improve Access to Pain Care for Veterans: A Qualitative Analysis of VA-ECHO Participant Experiences.

Background/Objective: The prevalence of chronic pain and its links to the opioid epidemic have given way to widespread aims to improve pain management care and reduce opioid use, especially in rural areas. Pain Management Specialty Care Access Network-Extension for Community Health Outcomes (VA-ECHO) promotes increased pain care access to rural Veterans through knowledge sharing from specialists to primary care providers (PCPs). We explored PCP participants' experiences in VA-ECHO and pain management care. Methods: This qualitative study is based on a descriptive secondary analysis of semi-structured interviews (n = 10) and 3 focus groups with PCPs participating in VA-ECHO from 2017-2019. A rapid matrix analysis approach was used to analyze participants' responses. Results: VA-ECHO was an effective workforce development strategy for meeting PCPs' training needs by providing pain management knowledge and skills training (eg alternative care approaches and communicating treatment options). Having protected time to participate in VA-ECHO was a challenge for many PCPs, mitigated by leadership and administrative support. Participants who volunteer to participate had more positive experiences than those required to attend. Conclusions: VA-ECHO could be used for meeting the workforce development needs of PCPs. Respondents were satisfied with the program citing improvement in their practice and increased confidence in providing pain management care to Veterans despite some challenges to participation. These findings offer insight into using VA-ECHO to meet the VHA's workforce development to improve Veterans' access to pain management care. The ECHO model presents opportunities for workforce development in large complex healthcare systems and garnering ongoing support for this training model is necessary for promoting workforce development for PCPs.

Development of a Highly Sensitive Neurofilament Light Chain Assay on an Automated Immunoassay Platform.

Background: Neurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in the cerebrospinal fluid (CSF) and blood. Numerous studies on MS have demonstrated that NfL is correlated with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, and widely accessible assay is needed. Our objective was to develop a novel NfL assay on an automated, globally available immunoassay platform and validate its performance. Methods: A prototype NfL assay was first developed and evaluated on the ADVIA Centaur® XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), within-lab precision, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types on the Atellica® IM system and transferred to Siemens' CLIA laboratory where it was analytically validated as a laboratory-developed test (LDT). Results: In this study, an LLoQ of 1.85 pg/mL, within-lab precision <6%, and an assay range of up to 646 pg/mL were demonstrated with the serum prototype assay. Cross-reactivity of <0.7% with the neurofilament medium and heavy chains was observed. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively. The optimized version of the NfL assay demonstrated specimen equivalence with additional plasma tube types and was analytically validated as an LDT. Conclusion: The analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we suggest that the assay is acceptable for use in both research and clinical practice settings to determine elevated NfL levels in patients.

"I was Unsure at First": A Qualitative Evaluation of Patient Perceptions of VA Clinical Video Telehealth Visits in the V-IMPACT Program.

Virtual Integrated Multi-Site Patient Aligned Care Team (V-IMPACT) was a Veterans Health Administration (VHA) initiative created to increase access to primary care for Veterans through Clinical Video Telehealth (CVT) appointments. Between January and August 2019, we conducted 48 semi-structured qualitative interviews with Veterans who had a V-IMPACT appointment. Many participants shared feelings of skepticism before their first appointments but for some, their opinions changed. Veterans talked about how their opinion of video care changed for the better when it made care more convenient or timelier or met their health care needs. For some Veterans, their opinion about video care stayed the same or worsened because they had a poor relationship or rapport with their provider, did not feel like they received needed care, or did not feel like video care was useful. These findings offer an opportunity for telecare providers to better understand and support patients and to deliver effective care in the context of rapidly growing telehealth modalities.

Healthcare providers experiences with shared medical appointments for heart failure.

Shared medical appointments (SMAs) offer a means for providing knowledge and skills needed for chronic disease management to patients. However, SMAs require a time and attention investment from health care providers, who must understand the goals and potential benefits of SMAs from the perspective of patients and providers. To better understand how to gain provider engagement and inform future SMA implementation, qualitative inquiry of provider experience based on a knowledge-attitude-practice model was explored. Semi-structured interviews were conducted with 24 health care providers leading SMAs for heart failure at three Veterans Administration Medical Centers. Rapid matrix analysis process techniques including team-based qualitative inquiry followed by stakeholder validation was employed. The interview guide followed a knowledge-attitude-practice model with a priori domains of knowledge of SMA structure and content (understanding of how SMAs were structured), SMA attitude/beliefs (general expectations about SMA use), attitudes regarding how leading SMAs affected patients, and providers. Data regarding the patient referral process (organizational processes for referring patients to SMAs) and suggested improvements were collected to further inform the development of SMA implementation best practices. Providers from all three sites reported similar knowledge, attitude and beliefs of SMAs. In general, providers reported that the multi-disciplinary structure of SMAs was an effective strategy towards improving clinical outcomes for patients. Emergent themes regarding experiences with SMAs included improved self-efficacy gained from real-time collaboration with providers from multiple disciplines, perceived decrease in patient re-hospitalizations, and promotion of self-management skills for patients with HF. Most providers reported that the SMA-setting facilitated patient learning by providing opportunities for the sharing of experiences and knowledge. This was associated with the perception of increased comradery and support among patients. Future research is needed to test suggested improvements and to develop best practices for training additional sites to implement HF SMA.

Update to the European Bioanalysis Forum recommendation on biomarkers assays; bringing context of use into practice.

In 2012, the European Bioanalysis Forum published a recommendation on biomarker method development and the bioanalysis of biomarkers in support of drug development. Since then, there has been significant discussion on how to bring the topic of context of use of biomarker assays to the forefront so that the purpose of the assay, the use of the data and the decisions being made with the data are well defined and clearly understood, not just by the bioanalytical scientist, but across all stakeholders. Therefore, it is imperative that discussions between the bioanalytical laboratory and the end users of the data happen early (and regularly) in the drug development process to enable the right assays to be developed and appropriately validated to generate the correct data and allow suitable decisions to be made. This updated refinement to the previous European Bioanalysis Forum recommendation will highlight the items to consider when discussing context of use for biomarker assay development and validation, thus enabling the correct conversations to occur and the move away from the misapplication of PK assay validation criteria to biomarker assays.

Comparison of Molecular Subtyping and Antimicrobial Resistance Detection Methods Used in a Large Multistate Outbreak of Extensively Drug-Resistant Campylobacter jejuni Infections Linked to Pet Store Puppies.

Campylobacter jejuni is a leading cause of enteric bacterial illness in the United States. Traditional molecular subtyping methods, such as pulsed-field gel electrophoresis (PFGE) and 7-gene multilocus sequence typing (MLST), provided limited resolution to adequately identify C. jejuni outbreaks and separate out sporadic isolates during outbreak investigations. Whole-genome sequencing (WGS) has emerged as a powerful tool for C. jejuni outbreak detection. In this investigation, 45 human and 11 puppy isolates obtained during a 2016-2018 outbreak linked to pet store puppies were sequenced. Core genome multilocus sequence typing (cgMLST) and high-quality single nucleotide polymorphism (hqSNP) analysis of the sequence data separated the isolates into the same two clades containing minor within-clade differences; however, cgMLST analysis does not require selection of an appropriate reference genome, making the method preferable to hqSNP analysis for Campylobacter surveillance and cluster detection. The isolates were classified as sequence type 2109 (ST2109)-a rarely seen MLST sequence type. PFGE was performed on 38 human and 10 puppy isolates; PFGE patterns did not reliably predict clustering by cgMLST analysis. Genetic detection of antimicrobial resistance determinants predicted that all outbreak-associated isolates would be resistant to six drug classes. Traditional antimicrobial susceptibility testing (AST) confirmed a high correlation between genotypic and phenotypic antimicrobial resistance determinations. WGS analysis linked C. jejuni isolates in humans and pet store puppies even when canine exposure information was unknown, aiding the epidemiological investigation during the outbreak. WGS data were also used to quickly identify the highly drug-resistant profile of these outbreak-associated C. jejuni isolates.

A Qualitative Evaluation of the Pain Management VA-ECHO Program Using the RE-AIM Framework: The Participant's Perspective.

Introduction: Veterans frequently seek chronic pain care from their primary care providers (PCPs) who may not be adequately trained to provide pain management. To address this issue the Veterans Health Administration (VHA) Office of Specialty Care adopted the Specialty Care Access Network Extension for Community Healthcare Outcomes (VA-ECHO née SCAN-ECHO). The VA-ECHO program offered training and mentoring by specialists to PCPs and their staff. VA-ECHO included virtual sessions where expertise was shared in two formats: (1) didactics on common pain conditions, relevant psychological disorders, and treatment options and (2) real-time consultation on patient cases. Materials and methods: VA-ECHO participants' perspectives were obtained using a semi-structured interview guide designed to elicit responses based on the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. A convenience sampling was used to recruit PCPs and non-physician support staff participants. Non-physicians from rural VHA sites were purposively sampled to gain diverse perspectives. Findings: This qualitative study yielded data on each RE-AIM domain except reach. Program reach was not measured as it is outside the scope of this study. Respondents reported program effectiveness as gains in knowledge and skills to improve pain care delivery. Effective incorporation of learning into practice was reflected in respondents' perceptions of improvements in: patient engagement, evidenced-based approaches, appropriate referrals, and opioid use. Program adoption included how participating health care systems selected trainees from a range of sites and roles to achieve a wide reach of pain expertise. Participation was limited by time to attend and facilitated by institutional support. Differences and similarities were noted in implementation between hub sites. Maintenance was revealed when respondents noted the importance of the lasting relationships formed between fellow participants. Discussion: This study highlights VA-ECHO program attributes and unintended consequences. These findings are expected to inform future use of VA-ECHO as a means to establish a supportive consultation network between primary and specialty care providers to promote the delivery evidence-based pain management practices.

A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus.

A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multiple dosing of intravenous and subcutaneous BIIB059. BDCA2 internalization (PD marker) was measured for all subjects by monitoring reduction of BDCA2 on pDC cell surface and used for development of the popPD model. A two-compartment popPK model with linear plus non-linear elimination was found to best describe BIIB059 PK. BDCA2 levels were best captured using an indirect response model with stimulation of the elimination of BDCA2. Clearance in SLE subjects was 25% higher compared to HV (6.87 vs 5.52 mL/h). Bodyweight was identified as only other covariate on clearance and central volume. The estimates of EC50 and Emax were 0.35 µg/mL and 8.92, respectively. No difference in EC50 and Emax was observed between SLE and HV. The popPK/PD model described the data accurately, as evaluated by pcVPCs and bootstrap. The presented popPK/PD model for BIIB059 provides valuable insight into the dynamics and dose-response relationship of BIIB059 for the treatment of SLE and CLE and was used to guide dose selection for the Phase 2 clinical study (NCT02847598).

2019 White Paper On Recent Issues in Bioanalysis: FDA BMV Guidance, ICH M10 BMV Guideline and Regulatory Inputs (Part 2 - Recommendations on 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and Regulatory Agencies' Input on Bioanalysis, Biomarkers and Immunogenicity).

The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis, issues 22 and 24 (2019), respectively.

Well-developed ligand-binding assays demonstrate robust performance using singlet analysis.

Aim: Replicate sample testing has long been regarded as a necessity for bioanalytical laboratory testing, especially in the realm of ligand-binding assays (LBAs). In an era in which results were derived from crude test tube-based assays, the replication of results was warranted. Those assays were often imprecise and required multiple replicates to arrive at results that approached accuracy. However, given technological advancements and excellent accuracy and precision of many modern LBAs, the practice of replicate testing should be re-evaluated. Although most regulatory guidelines allow for singlet testing when sufficient robustness and precision are demonstrated during validation, duplicate testing is still common practice. Recently however, several articles have been published that support singlet analysis for LBAs performed on a platform with automated liquid handling. Results: Data from five pharmacokinetic assay validations and five clinical and preclinical studies originally run in duplicate were re-evaluated in singlet and found to be nearly identical to the original duplicate results. Conclusion: We confirm that well-developed LBAs produce comparable data whether evaluated in singlet or duplicate. Additionally, automation is not requisite for singlet testing.

Onsite investigation at a mail-order hatchery following a multistate Salmonella illness outbreak linked to live poultry-United States, 2018.

Centers for Disease Control and Prevention (CDC), health departments, and other state and federal partners have linked contact with live poultry to 70 human Salmonella outbreaks in the United States from 2000 to 2017, which resulted in a total of 4,794 illnesses, 894 hospitalizations, and 7 deaths. During human salmonellosis outbreaks environmental sampling is rarely conducted as part of the outbreak investigation. CDC was contacted by state health officials on June 12, 2018, to provide support during an investigation of risk factors for Salmonella infections linked to live poultry originating at a mail-order hatchery. From January 1, 2018, to June 15, 2018, 13 human Salmonella infections in multiple states were attributed to exposure to live poultry from a single hatchery. Two serotypes of Salmonella were associated with these infections, Salmonella Enteritidis and Salmonella Litchfield. Molecular subtyping of the S. Enteritidis clinical isolates revealed they were closely related genetically (within 0 to 9 alleles) by core genome multi-locus sequence typing (cgMLST) to isolates obtained from environmental samples taken from hatchery shipping containers received at retail outlets. Environmental sampling and onsite investigation of practices was conducted at the mail-order hatchery during an investigation on June 19, 2018. A total of 45 environmental samples were collected, and 4 (9%) grew Salmonella. A chick box liner from a box in the pre-shipping area yielded an isolate closely related to the S. Enteritidis outbreak strain (within 1 to 9 alleles by cgMLST). The onsite investigation revealed lapses in biosecurity, sanitation, quality assurance, and education of consumers. Review of Salmonella serotype testing performed by the hatchery revealed that the number of samples and type of samples collected monthly varied. Also, S. Enteritidis was identified at the hatchery every year since testing began in 2016. Recommendations to the hatchery for biosecurity, testing, and sanitation measures were made to help reduce burden of Salmonella in the hatchery and breeding flocks, thereby reducing the occurrence of human illness.

Perspectives on gender parity in bioanalysis: an interview with Lauren Stevenson.

Biography Lauren is Senior Director, Development Biomarkers & Bioanalytical Sciences at Biogen, Cambridge, MA, USA where she leads a team of talented scientists, setting bioanalytical and biomarker strategies and developing pharmacokinetics (PK), immunogenicity and biomarker assays in support of programs at all stages of development, from discovery to post-marketing. Lauren's team currently supports over 40 therapeutic programs, delivering PK and immunogenicity strategy and execution for Biogen's large molecule, antisense oligonucleotide (ASO0 and gene therapy portfolio as well as developing biomarkers in support of multiple sclerosis, immunology, fibrosis, rare and neurodegenerative disease indications. Externally, Lauren engages the broader industry and regulatory agencies as an invited speaker and course instructor at multiple conferences and workshops each year. In concert with her scientific role, Lauren is passionate about people development, has received certification as a Strengths coach and is active in mentorship and career development programs.

Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus.

BACKGROUND: Plasmacytoid DCs (pDC) produce large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis. BIIB059 is a humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. A first-in-human study was conducted to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects of single BIIB059 doses in healthy volunteers (HV) and patients with SLE with active cutaneous disease as well as proof of biological activity and preliminary clinical response in the SLE cohort. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted in HV (n = 54) and patients with SLE (n = 12). All subjects were monitored for adverse events. Serum BIIB059 concentrations, BDCA2 levels on pDCs, and IFN-responsive biomarkers in whole blood and skin biopsies were measured. Skin disease activity was determined using the Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A). RESULTS: Single doses of BIIB059 were associated with favorable safety and PK profiles. BIIB059 administration led to BDCA2 internalization on pDCs, which correlated with circulating BIIB059 levels. BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score. CONCLUSIONS: Single doses of BIIB059 were associated with favorable safety and PK/PD profiles and robust target engagement and biological activity, supporting further development of BIIB059 in SLE. The data suggest that targeting pDCs may be beneficial for patients with SLE, especially those with cutaneous manifestations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02106897. FUNDING: Biogen Inc.