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 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).

Multidrug-Resistant Campylobacter jejuni Outbreak Linked to Puppy Exposure - United States, 2016-2018.

Campylobacter causes an estimated 1.3 million diarrheal illnesses in the United States annually (1). In August 2017, the Florida Department of Health notified CDC of six Campylobacter jejuni infections linked to company A, a national pet store chain based in Ohio. CDC examined whole-genome sequencing (WGS) data and identified six isolates from company A puppies in Florida that were highly related to an isolate from a company A customer in Ohio. This information prompted a multistate investigation by local and state health and agriculture departments and CDC to identify the outbreak source and prevent additional illness. Health officials from six states visited pet stores to collect puppy fecal samples, antibiotic records, and traceback information. Nationally, 118 persons, including 29 pet store employees, in 18 states were identified with illness onset during January 5, 2016-February 4, 2018. In total, six pet store companies were linked to the outbreak. Outbreak isolates were resistant by antibiotic susceptibility testing to all antibiotics commonly used to treat Campylobacter infections, including macrolides and quinolones. Store record reviews revealed that among 149 investigated puppies, 142 (95%) received one or more courses of antibiotics, raising concern that antibiotic use might have led to development of resistance. Public health authorities issued infection prevention recommendations to affected pet stores and recommendations for testing puppies to veterinarians. This outbreak demonstrates that puppies can be a source of multidrug-resistant Campylobacter infections in humans, warranting a closer look at antimicrobial use in the commercial dog industry.

Adaptation of Lean Six Sigma Methodologies for the Evaluation of Veterans Choice Program at 3 Urban Veterans Affairs Medical Centers.

OBJECTIVE: The Veterans Health Administration (VHA) is adapting to meet the changing needs of our Veterans. VHA leaders are promoting quality improvement strategies including Lean Six Sigma (LSS). This study used LSS tools to evaluate the Veterans Choice Program (VCP), a program that aims to improve access to health care services for eligible Veterans by expanding health care options to non-VHA providers. RESEARCH DESIGN: LSS was utilized to assess the current process and efficiency patterns of the VCP at 3 VHA Medical Centers. LSS techniques were used to assess data obtained through semistructured interviews with Veterans, staff, and providers to describe and evaluate the VCP process by identifying wastes and defects. RESULTS: The LSS methodology facilitated the process of targeting priorities for improvement and constructing suggestions to close identified gaps and inefficiencies. Identified key process wastes included inefficient exchange of clinical information between stakeholders in and outside of the VHA; poor dissemination of VCP programmatic information; shortages of VCP-participating providers; duplication of appointments; declines in care coordination; and lack of program adaptability to local processes. Recommendations for improvement were formulated using LSS. CONCLUSIONS: This evaluation illustrates how LSS can be utilized to assess a nationally mandated health care program. By focusing on stakeholder, staff, and Veteran perspectives, process defects in the VCP were identified and improvement recommendations were made. However, the current LSS language used is not intuitive in health care and similar applications of LSS may consider using new language and goals adapted specifically for health care.

State Laws Requiring Hand Sanitation Stations at Animal Contact Exhibits-United States, March-April 2016.

In the United States, animal contact exhibits, such as petting zoos and agricultural fairs, have been sources of zoonotic infections, including infections with Escherichia coli, Salmonella, and Cryptosporidium (1-4). The National Association of State Public Health Veterinarians recommends handwashing after contact with animals as an effective prevention measure to disease transmission at these exhibits (4). This report provides a list of states that have used law, specifically statutes and regulations, as public health interventions to increase hand sanitation at animal contact exhibits. The report is based on an assessment conducted by CDC's Public Health Law Program, in collaboration with the Division of Foodborne, Waterborne, and Environmental Diseases in CDC's National Center for Emerging and Zoonotic Infectious Diseases. The assessment found that seven states have used statutes or regulations to require hand sanitation stations at these exhibits (5). Jurisdictions seeking to improve rates of hand sanitation at animal contact exhibits can use this report as a resource in developing their own legal interventions.

A realist review of shared medical appointments: How, for whom, and under what circumstances do they work?

BACKGROUND: Shared medical appointments (SMAs) are doctor-patient visits in which groups of patients are seen by one or more health care providers in a concurrent session. There is a growing interest in understanding the potential benefits of SMAs in various contexts to improve clinical outcomes and reduce healthcare costs. This study builds upon the existing evidence base that suggests SMAs are indeed effective. In this study, we explored how they are effective in terms of the underlying mechanisms of action and under what circumstances. METHODS: Realist review methodology was used to synthesize the literature on SMAs, which included a broad search of 800+ published articles. 71 high quality primary research articles were retained to build a conceptual model of SMAs and 20 of those were selected for an in depth analysis using realist methodology (i.e.,middle-range theories and and context-mechanism-outcome configurations). RESULTS: Nine main mechanisms that serve to explain how SMAs work were theorized from the data immersion process and configured in a series of context-mechanism-outcome configurations (CMOs). These are: (1) Group exposure in SMAs combats isolation, which in turn helps to remove doubts about one's ability to manage illness; (2) Patients learn about disease self-management vicariously by witnessing others' illness experiences; (3) Patients feel inspired by seeing others who are coping well; (4) Group dynamics lead patients and providers to developing more equitable relationships; (5) Providers feel increased appreciation and rapport toward colleagues leading to increased efficiency; (6) Providers learn from the patients how better to meet their patients' needs; (7) Adequate time allotment of the SMA leads patients to feel supported; (8) Patients receive professional expertise from the provider in combination with first-hand information from peers, resulting in more robust health knowledge; and (9) Patients have the opportunity to see how the physicians interact with fellow patients, which allows them to get to know the physician and better determine their level of trust. CONCLUSIONS: Nine overarching mechanisms were configured in CMO configurations and discussed as a set of complementary middle-range programme theories to explain how SMAs work. It is anticipated that this innovative work in theorizing SMAs using realist review methodology will provide policy makers and SMA program planners adequate conceptual grounding to design contextually sensitive SMA programs in a wide variety of settings and advance an SMA research agenda for varied contexts.

Notes from the Field: Four Multistate Outbreaks of Human Salmonella Infections Linked to Small Turtle Exposure - United States, 2015.

In August 2015, the Food and Drug Administration (FDA) notified CDC of a consumer complaint involving Salmonella Sandiego infection in a child (the index patient), who had acquired a small turtle (shell length <4 inches [<10 cm]) at an Alabama flea market. The subsequent investigation, which included examining data from PulseNet, the national molecular subtyping network for foodborne disease surveillance, identified four multistate Salmonella outbreaks: two involving Salmonella Sandiego and two involving Salmonella Poona. These serotypes have been linked to small turtles in previous outbreaks (1,2). Although selling small turtles as pets in the United States has been banned since 1975 (3), illegal sales still occur at discount stores and flea markets and by street vendors. CDC investigated to determine the extent of the outbreaks and prevent additional infections.

Utility of the clostridial site-specific recombinase TnpX to clone toxic-product-encoding genes and selectively remove genomic DNA fragments.

TnpX is a site-specific recombinase responsible for the excision and insertion of the transposons Tn4451 and Tn4453 in Clostridium perfringens and Clostridium difficile, respectively. Here, we exploit phenotypic features of TnpX to facilitate genetic mutagenesis and complementation studies. Genetic manipulation of bacteria often relies on the use of antibiotic resistance genes; however, a limited number are available for use in the clostridia. The ability of TnpX to recognize and excise specific DNA fragments was exploited here as the basis of an antibiotic resistance marker recycling system, specifically to remove antibiotic resistance genes from plasmids in Escherichia coli and from marked chromosomal C. perfringens mutants. This methodology enabled the construction of a C. perfringens plc virR double mutant by allowing the removal and subsequent reuse of the same resistance gene to construct a second mutation. Genetic complementation can be challenging when the gene of interest encodes a product toxic to E. coli. We show that TnpX represses expression from its own promoter, PattCI, which can be exploited to facilitate the cloning of recalcitrant genes in E. coli for subsequent expression in the heterologous host C. perfringens. Importantly, this technology expands the repertoire of tools available for the genetic manipulation of the clostridia.

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.

Re-thinking the current paradigm for clinical immunogenicity assessment: an update from the discussion in the European Bioanalysis Forum.

Immunogenicity regulatory guidance and industry recommendations have evolved over the last two decades since unexpected immune reactions were first reported with erythropoietin. Since then, the guidelines and practices for immunogenicity have stemmed from a reaction to a high-risk molecule causing significant clinical impact. Similar thinking is often applied to all biotherapeutic drugs, even when a well-defined risk assessment suggests otherwise. In recent years, the current testing paradigm for immunogenicity has been challenged with more informative approaches being proposed. In a Focus Workshop held by the European Bioanalysis Forum in September 2023, the current immunogenicity testing paradigm was challenged based on the experience and learning of 20+ years of immunogenicity strategies. The workshop recommendations proposed a new paradigm, challenging the value of multiple tiers depending on the immunogenicity risk assessment based on context of use and moving toward treating immunogenicity as a pharmacodynamic biomarker for the drug. Such rethinking ultimately results in the appropriate and efficient focusing of resources on immunogenicity testing strategies that benefit patients most, moving to a new paradigm where implementation of appropriate and truly informative immunogenicity testing strategies, depending on the context-of-use, become the norm .

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Work and social adjustment in patients with anorexia nervosa.

OBJECTIVE AND METHODS: The Work and Social Adjustment Scale (WSAS) assesses patients' perceptions of impairment in everyday functioning and has been reported as a simple and reliable self-report measure in different psychiatric disorders. This study compared WSAS data from an anorexia nervosa (AN) patient group with that from healthy controls (HCs) and published data from other patient groups. A total of 160 female participants (AN, 77; HC, 83) completed the WSAS as well as measures of eating disorder symptom severity and brief assessments of anxiety and depression. RESULTS: Work and Social Adjustment Scale scores for the AN group were found to be in the severely impaired range, whereas the scores for those within the HC group indicated very little, or no impairment. Total WSAS scores in the AN group were significantly correlated with severity of clinical symptoms, and eating disorder-specific symptoms were the best predictor of social and occupational functional impairment. The greatest impairment in the AN group was reported in the realm of social leisure. CONCLUSIONS: Consistent with reports in other clinical populations, it is suggested that the WSAS could be an extremely useful and meaningful measure to assess social and occupational functioning in people with eating disorders, in addition to eating disorder-specific assessments.

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.

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.

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.

"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.

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.