Bridging clinical informatics and implementation science to improve cancer symptom management in ambulatory oncology practices: experiences from the IMPACT consortium.

Objectives: To report lessons from integrating the methods and perspectives of clinical informatics (CI) and implementation science (IS) in the context of Improving the Management of symPtoms during and following Cancer Treatment (IMPACT) Consortium pragmatic trials. Materials and Methods: IMPACT informaticists, trialists, and implementation scientists met to identify challenges and solutions by examining robust case examples from 3 Research Centers that are deploying systematic symptom assessment and management interventions via electronic health records (EHRs). Investigators discussed data collection and CI challenges, implementation strategies, and lessons learned. Results: CI implementation strategies and EHRs systems were utilized to collect and act upon symptoms and impairments in functioning via electronic patient-reported outcomes (ePRO) captured in ambulatory oncology settings. Limited EHR functionality and data collection capabilities constrained the ability to address IS questions. Collecting ePRO data required significant planning and organizational champions adept at navigating ambiguity. Discussion: Bringing together CI and IS perspectives offers critical opportunities for monitoring and managing cancer symptoms via ePROs. Discussions between CI and IS researchers identified and addressed gaps between applied informatics implementation and theory-based IS trial and evaluation methods. The use of common terminology may foster shared mental models between CI and IS communities to enhance EHR design to more effectively facilitate ePRO implementation and clinical responses. Conclusion: Implementation of ePROs in ambulatory oncology clinics benefits from common understanding of the concepts, lexicon, and incentives between CI implementers and IS researchers to facilitate and measure the results of implementation efforts.

Japanese Encephalitis Virus Surveillance in U.S. Army Installations in the Republic of Korea from 2021 to 2023.

Japanese encephalitis is a disease caused by the Japanese encephalitis virus (JEV) and is a concern for U.S. military personnel stationed in the Republic of Korea (ROK). The recent literature reports a potential shift from GI to GV as the dominant genotype circulating in east Asia. In the ROK, GV has been reported in a few Culex spp., but not in the main JEV vector, Cx. tritaeniorhynchus. The goal of this surveillance was to shed light on the current knowledge of the epidemiology of JEV in the ROK by analyzing mosquito collection data from three consecutive years, 2021-2023, and molecularly detecting and genotyping JEV in all Culex spp. collected in several military locations across the ROK. In this study, we detected only JEV GI in Cx. tritaeniorhynchus in 2021 samples. In contrast, all 2022 and 2023 positive samples were GV and detected in Cx. bitaeniorhynchus, Cx. orientalis, and Cx. pipiens. Results support a shift in JEV genotype in the ROK and suggest that for GV, Culex spp. other than Cx. tritaeniorhynchus may be playing an important role.

Free Energy Analysis of Peptide-Induced Pore Formation in Lipid Membranes by Bridging Atomistic and Coarse-Grained Simulations.

Antimicrobial peptides (AMPs) are attractive materials for combating the antimicrobial resistance crisis because they can kill target microbes by directly disrupting cell membranes. Although thousands of AMPs have been discovered, their molecular mechanisms of action are still poorly understood. One broad mechanism for membrane disruption is the formation of membrane-spanning hydrophilic pores which can be stabilized by AMPs. In this study, we use molecular dynamics simulations to investigate the thermodynamics of pore formation in model single-component lipid membranes in the presence of one of three AMPs: aurein 1.2, melittin and magainin 2. To overcome the general challenge of modeling long time scale membrane-related behaviors, including AMP binding, clustering, and pore formation, we develop a generalizable methodology for sampling AMP-induced pore formation. This approach involves the long equilibration of peptides around a pore created with a nucleation collective variable by performing coarse-grained simulations, then backmapping equilibrated AMP-membrane configurations to all-atom resolution. We then perform all-atom simulations to resolve free energy profiles for pore formation while accurately modeling the interplay of lipid-peptide-solvent interactions that dictate pore formation free energies. Using this approach, we quantify free energy barriers for pore formation without direct biases on peptides or whole lipids, allowing us to investigate mechanisms of pore formation for these 3 AMPs that are a consequence of unbiased peptide diffusion and clustering. Further analysis of simulation trajectories then relates variations in pore lining by AMPs, AMP-induced lipid disruptions, and salt bridges between AMPs to the observed pore formation free energies and corresponding mechanisms. This methodology and mechanistic analysis have the potential to generalize beyond the AMPs in this study to improve our understanding of pore formation by AMPs and related antimicrobial materials.

Health Information Technology Documentation and Referrals for Intimate Partner Violence and Sexual Assault.

BACKGROUND: Hospital settings provide a unique opportunity to screen for intimate partner violence (IPV) and sexual assault (SA) yet often lack health information technology (IT) solutions for generating reliable and valid medicolegal documentation via forensic reports. OBJECTIVES: The objective of the project was to evaluate a pilot, technology "tool" for documenting cases of IPV and SA that could support forensic nurse examiners and related stakeholders in generating high-quality documentation and coordinating victim support services. METHODS: The tool was a digital health intervention implemented for use among forensic nurse examiners, law enforcement, victim support organizations, and more within four counties of California. We conducted a mixed-methods pilot study that captured data around the adoption, use, and impact of having access to the newly implemented tool. RESULTS: The tool successfully went live in all four pilot counties at different time points with different proportions of use by county and form type: exams, referrals, addenda, risk assessments, and other. Participants were motivated to use the tool out of a perceived need for data handling functionalities that went beyond traditional manual (paper) means. Key functionalities included body mapping, data quality controls within validated forms, attaching addenda to already existing case reports, and the means to distribute data to external recipients. Further study and development are needed on functions to incorporate into body maps and forms and understanding the information needs of law enforcement and victim support organizations. CONCLUSION: Our evaluation demonstrated the feasibility and acceptability of a health IT tool to support forensic nurse documentation of IPV and SA and direct information to multiple legal and support-related stakeholders. Areas of future development include integrating IPV- and SA-related data standards for digitized forms, enhancements to the body mapping feature, and understanding the needs of those who receive digital data from forensic nurse examiners within the tool.

Public comfort with the use of ChatGPT and expectations for healthcare.

OBJECTIVES: To examine whether comfort with the use of ChatGPT in society differs from comfort with other uses of AI in society and to identify whether this comfort and other patient characteristics such as trust, privacy concerns, respect, and tech-savviness are associated with expected benefit of the use of ChatGPT for improving health. MATERIALS AND METHODS: We analyzed an original survey of U.S. adults using the NORC AmeriSpeak Panel (n = 1787). We conducted paired t-tests to assess differences in comfort with AI applications. We conducted weighted univariable regression and 2 weighted logistic regression models to identify predictors of expected benefit with and without accounting for trust in the health system. RESULTS: Comfort with the use of ChatGPT in society is relatively low and different from other, common uses of AI. Comfort was highly associated with expecting benefit. Other statistically significant factors in multivariable analysis (not including system trust) included feeling respected and low privacy concerns. Females, younger adults, and those with higher levels of education were less likely to expect benefits in models with and without system trust, which was positively associated with expecting benefits (P = 1.6 × 10-11). Tech-savviness was not associated with the outcome. DISCUSSION: Understanding the impact of large language models (LLMs) from the patient perspective is critical to ensuring that expectations align with performance as a form of calibrated trust that acknowledges the dynamic nature of trust. CONCLUSION: Including measures of system trust in evaluating LLMs could capture a range of issues critical for ensuring patient acceptance of this technological innovation.

Making Science Computable Using Evidence-Based Medicine on Fast Healthcare Interoperability Resources: Standards Development Project.

BACKGROUND: Evidence-based medicine (EBM) has the potential to improve health outcomes, but EBM has not been widely integrated into the systems used for research or clinical decision-making. There has not been a scalable and reusable computer-readable standard for distributing research results and synthesized evidence among creators, implementers, and the ultimate users of that evidence. Evidence that is more rapidly updated, synthesized, disseminated, and implemented would improve both the delivery of EBM and evidence-based health care policy. OBJECTIVE: This study aimed to introduce the EBM on Fast Healthcare Interoperability Resources (FHIR) project (EBMonFHIR), which is extending the methods and infrastructure of Health Level Seven (HL7) FHIR to provide an interoperability standard for the electronic exchange of health-related scientific knowledge. METHODS: As an ongoing process, the project creates and refines FHIR resources to represent evidence from clinical studies and syntheses of those studies and develops tools to assist with the creation and visualization of FHIR resources. RESULTS: The EBMonFHIR project created FHIR resources (ie, ArtifactAssessment, Citation, Evidence, EvidenceReport, and EvidenceVariable) for representing evidence. The COVID-19 Knowledge Accelerator (COKA) project, now Health Evidence Knowledge Accelerator (HEvKA), took this work further and created FHIR resources that express EvidenceReport, Citation, and ArtifactAssessment concepts. The group is (1) continually refining FHIR resources to support the representation of EBM; (2) developing controlled terminology related to EBM (ie, study design, statistic type, statistical model, and risk of bias); and (3) developing tools to facilitate the visualization and data entry of EBM information into FHIR resources, including human-readable interfaces and JSON viewers. CONCLUSIONS: EBMonFHIR resources in conjunction with other FHIR resources can support relaying EBM components in a manner that is interoperable and consumable by downstream tools and health information technology systems to support the users of evidence.

Perspectives on the role of industry in informatics research and authorship.

OBJECTIVES: Advances in informatics research come from academic, nonprofit, and for-profit industry organizations, and from academic-industry partnerships. While scientific studies of commercial products may offer critical lessons for the field, manuscripts authored by industry scientists are sometimes categorically rejected. We review historical context, community perceptions, and guidelines on informatics authorship. PROCESS: We convened an expert panel at the American Medical Informatics Association 2022 Annual Symposium to explore the role of industry in informatics research and authorship with community input. The panel summarized session themes and prepared recommendations. CONCLUSIONS: Authorship for informatics research, regardless of affiliation, should be determined by International Committee of Medical Journal Editors uniform requirements for authorship. All authors meeting criteria should be included, and categorical rejection based on author affiliation is unethical. Informatics research should be evaluated based on its scientific rigor; all sources of bias and conflicts of interest should be addressed through disclosure and, when possible, methodological mitigation.

Mutation of wbtJ, a N-formyltransferase involved in O-antigen synthesis, results in biofilm formation, phase variation and attenuation in Francisella tularensis.

Two clinically important subspecies, Francisella tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (type B) are responsible for most tularaemia cases, but these isolates typically form a weak biofilm under in vitro conditions. Phase variation of the F. tularensis lipopolysaccharide (LPS) has been reported in these subspecies, but the role of variation is unclear as LPS is crucial for virulence. We previously demonstrated that a subpopulation of LPS variants can constitutively form a robust biofilm in vitro, but it is unclear whether virulence was affected. In this study, we show that biofilm-forming variants of both fully virulent F. tularensis subspecies were highly attenuated in the murine tularaemia model by multiple challenge routes. Genomic sequencing was performed on these strains, which revealed that all biofilm-forming variants contained a lesion within the wbtJ gene, a formyltransferase involved in O-antigen synthesis. A ΔwbtJ deletion mutant recapitulated the biofilm, O-antigen and virulence phenotypes observed in natural variants and could be rescued through complementation with a functional wbtJ gene. Since the spontaneously derived biofilm-forming isolates in this study were a subpopulation of natural variants, reversion events to the wbtJ gene were detected that eliminated the phenotypes associated with biofilm variants and restored virulence. These results demonstrate a role for WbtJ in biofilm formation, LPS variation and virulence of F. tularensis.

The Longitudinal Implementation Strategy Tracking System (LISTS): feasibility, usability, and pilot testing of a novel method.

BACKGROUND: Systematic approaches are needed to accurately characterize the dynamic use of implementation strategies and how they change over time. We describe the development and preliminary evaluation of the Longitudinal Implementation Strategy Tracking System (LISTS), a novel methodology to document and characterize implementation strategies use over time. METHODS: The development and initial evaluation of the LISTS method was conducted within the Improving the Management of SymPtoms during And following Cancer Treatment (IMPACT) Research Consortium (supported by funding provided through the NCI Cancer MoonshotSM). The IMPACT Consortium includes a coordinating center and three hybrid effectiveness-implementation studies testing routine symptom surveillance and integration of symptom management interventions in ambulatory oncology care settings. LISTS was created to increase the precision and reliability of dynamic changes in implementation strategy use over time. It includes three components: (1) a strategy assessment, (2) a data capture platform, and (3) a User's Guide. An iterative process between implementation researchers and practitioners was used to develop, pilot test, and refine the LISTS method prior to evaluating its use in three stepped-wedge trials within the IMPACT Consortium. The LISTS method was used with research and practice teams for approximately 12 months and subsequently we evaluated its feasibility, acceptability, and usability using established instruments and novel questions developed specifically for this study. RESULTS: Initial evaluation of LISTS indicates that it is a feasible and acceptable method, with content validity, for characterizing and tracking the use of implementation strategies over time. Users of LISTS highlighted several opportunities for improving the method for use in future and more diverse implementation studies. CONCLUSIONS: The LISTS method was developed collaboratively between researchers and practitioners to fill a research gap in systematically tracking implementation strategy use and modifications in research studies and other implementation efforts. Preliminary feedback from LISTS users indicate it is feasible and usable. Potential future developments include additional features, fewer data elements, and interoperability with alternative data entry platforms. LISTS offers a systematic method that encourages the use of common data elements to support data analysis across sites and synthesis across studies. Future research is needed to further adapt, refine, and evaluate the LISTS method in studies with employ diverse study designs and address varying delivery settings, health conditions, and intervention types.

Playing in the clinical decision support sandbox: tools and training for all.

Objectives: Introduce the CDS-Sandbox, a cloud-based virtual machine created to facilitate Clinical Decision Support (CDS) developers and implementers in the use of FHIR- and CQL-based open-source tools and technologies for building and testing CDS artifacts. Materials and Methods: The CDS-Sandbox includes components that enable workflows for authoring and testing CDS artifacts. Two workshops at the 2020 and 2021 AMIA Annual Symposia were conducted to demonstrate the use of the open-source CDS tools. Results: The CDS-Sandbox successfully integrated the use of open-source CDS tools. Both workshops were well attended. Participants demonstrated use and understanding of the workshop materials and provided positive feedback after the workshops. Discussion: The CDS-Sandbox and publicly available tutorial materials facilitated an understanding of the leading-edge open-source CDS infrastructure components. Conclusion: The CDS-Sandbox supports integrated use of the key CDS open-source tools that may be used to introduce CDS concepts and practice to the clinical informatics community.

Patient-Facing Clinical Decision Support for High Blood Pressure Control: Patient Survey.

BACKGROUND: High blood pressure (HBP) affects nearly half of adults in the United States and is a major factor in heart attacks, strokes, kidney disease, and other morbidities. To reduce risk, guidelines for HBP contain more than 70 recommendations, including many related to patient behaviors, such as home monitoring and lifestyle changes. Thus, the patient's role in controlling HBP is crucial. Patient-facing clinical decision support (CDS) tools may help patients adhere to evidence-based care, but customization is required. OBJECTIVE: Our objective was to understand how to adapt CDS to best engage patients in controlling HBP. METHODS: We conducted a mixed methods study with two phases: (1) survey-guided interviews with a limited cohort and (2) a nationwide web-based survey. Participation in each phase was limited to adults aged between 18 and 85 years who had been diagnosed with hypertension. The survey included general questions that assessed goal setting, treatment priorities, medication load, comorbid conditions, satisfaction with blood pressure (BP) management, and attitudes toward CDS, and also a series of questions regarding A/B preferences using paired information displays to assess perceived trustworthiness of potential CDS user interface options. RESULTS: We conducted 17 survey-guided interviews to gather patient needs from CDS, then analyzed results and created a second survey of 519 adults with clinically diagnosed HBP. A large majority of participants reported that BP control was a high priority (83%), had monitored BP at home (82%), and felt comfortable using technology (88%). Survey respondents found displays with more detailed recommendations more trustworthy (56%-77% of them preferred simpler displays), especially when incorporating social trust and priorities from providers and patients like them, but had no differences in action taken. CONCLUSIONS: Respondents to the survey felt that CDS capabilities could help them with HBP control. The more detailed design options for BP display and recommendations messaging were considered the most trustworthy yet did not differentiate perceived actions.

A survey of computable biomedical knowledge repositories.

Introduction: While data repositories are well-established in clinical and research enterprises, knowledge repositories with shareable computable biomedical knowledge (CBK) are relatively new entities to the digital health ecosystem. Trustworthy knowledge repositories are necessary for learning health systems, but the policies, standards, and practices to promote trustworthy CBK artifacts and methods to share, and safely and effectively use them are not well studied. Methods: We conducted an online survey of 24 organizations in the United States known to be involved in the development or deployment of CBK. The aim of the survey was to assess the current policies and practices governing these repositories and to identify best practices. Descriptive statistics methods were applied to data from 13 responding organizations, to identify common practices and policies instantiating the TRUST principles of Transparency, Responsibility, User Focus, Sustainability, and Technology. Results: All 13 respondents indicated to different degrees adherence to policies that convey TRUST. Transparency is conveyed by having policies pertaining to provenance, credentialed contributors, and provision of metadata. Repositories provide knowledge in machine-readable formats, include implementation guidelines, and adhere to standards to convey Responsibility. Repositories report having Technology functions that enable end-users to verify, search, and filter for knowledge products. Less common TRUST practices are User Focused procedures that enable consumers to know about user licensing requirements or query the use of knowledge artifacts. Related to Sustainability, less than a majority post describe their sustainability plans. Few organizations publicly describe whether patients play any role in their decision-making. Conclusion: It is essential that knowledge repositories identify and apply a baseline set of criteria to lay a robust foundation for their trustworthiness leading to optimum uptake, and safe, reliable, and effective use to promote sharing of CBK. Identifying current practices suggests a set of desiderata for the CBK ecosystem in its continued evolution.

Provider Perspectives on Patient- and Provider-Facing High Blood Pressure Clinical Decision Support.

BACKGROUND: Hypertension, persistent high blood pressures (HBP) leading to chronic physiologic changes, is a common condition that is a major predictor of heart attacks, strokes, and other conditions. Despite strong evidence, care teams and patients are inconsistently adherent to HBP guideline recommendations. Patient-facing clinical decision support (CDS) could help improve recommendation adherence but must also be acceptable to clinicians and patients. OBJECTIVE: This study aimed to partly address the challenge of developing a patient-facing CDS application, we sought to understand provider variations and rationales related to HBP guideline recommendations and perceptions regarding patient role and use of digital tools. METHODS: We engaged hypertension experts and primary care respondents to iteratively develop and implement a pilot survey and a final survey which presented five clinical cases that queried clinicians' attitudes related to actions; variations; prioritization; patient input; importance; and barriers for HBP diagnosis, monitoring, and treatment. Analysis of Likert's scale scores was descriptive with content analysis for free-text answers. RESULTS: Fifteen hypertension experts and 14 providers took the pilot and final version of the surveys, respectively. The majority (>80%) of providers felt the recommendations were important, yet found them difficult to follow-up to 90% of the time. Perceptions of relative amounts of patient input and patient work for effective HBP management ranged from 22 to 100%. Stated reasons for variation included adverse effects of treatment, patient comorbidities, shared decision-making, and health care cost and access issues. Providers were generally positive toward patient use of electronic CDS applications but worried about access to health care, nuance of recommendations, and patient understanding of the tools. CONCLUSION: At baseline, provider management of HBP is heterogeneous. Providers were accepting of patient-facing CDS but reported preferences for that CDS to capture the complexity and nuance of guideline recommendations.

Generating and Reporting Electronic Clinical Quality Measures from Electronic Health Records: Strategies from EvidenceNOW Cooperatives.

BACKGROUND: Electronic clinical quality measures (eCQMs) from electronic health records (EHRs) are a key component of quality improvement (QI) initiatives in small-to-medium size primary care practices, but using eCQMs for QI can be challenging. Organizational strategies are needed to effectively operationalize eCQMs for QI in these practice settings. OBJECTIVE: This study aimed to characterize strategies that seven regional cooperatives participating in the EvidenceNOW initiative developed to generate and report EHR-based eCQMs for QI in small-to-medium size practices. METHODS: A qualitative study comprised of 17 interviews with representatives from all seven EvidenceNOW cooperatives was conducted. Interviewees included administrators were with both strategic and cooperative-level operational responsibilities and external practice facilitators were with hands-on experience helping practices use EHRs and eCQMs. A subteam conducted 1-hour semistructured telephone interviews with administrators and practice facilitators, then analyzed interview transcripts using immersion crystallization. The analysis and a conceptual model were vetted and approved by the larger group of coauthors. RESULTS: Cooperative strategies consisted of efforts in four key domains. First, cooperative adaptation shaped overall strategies for calculating eCQMs whether using EHRs, a centralized source, or a "hybrid strategy" of the two. Second, the eCQM generation described how EHR data were extracted, validated, and reported for calculating eCQMs. Third, practice facilitation characterized how facilitators with backgrounds in health information technology (IT) delivered services and solutions for data capture and quality and practice support. Fourth, performance reporting strategies and tools informed QI efforts and how cooperatives could alter their approaches to eCQMs. CONCLUSION: Cooperatives ultimately generated and reported eCQMs using hybrid strategies because they determined neither EHRs alone nor centralized sources alone could operationalize eCQMs for QI. This required cooperatives to devise solutions and utilize resources that often are unavailable to typical small-to-medium-sized practices. The experiences from EvidenceNOW cooperatives provide insights into how organizations can plan for challenges and operationalize EHR-based eCQMs.

An Exploratory Review of Potential Adjunct Therapies for the Treatment of Coronavirus Infections.

OBJECTIVE: The purpose of this exploratory review was to examine vitamin D, zinc, vitamin A, elderberry (Sambucus nigra), garlic (Allium sativum), licorice (Glycyrrhiza glabra), stinging nettle (Urtica dioica), N-acetylcysteine, quercetin, and selenium as potential adjunct therapies for the treatment of coronavirus infections. METHODS: A search of PubMed was performed for articles published from 2005 to 2021. Keywords searched were "zinc," "vitamin A," "vitamin D," "Sambucus nigra," "Allium sativum," "Glycyrrhiza glabra," "Urtica dioica," "N-acetylcysteine," "quercetin," "selenium," and "coronavirus." RESULTS: There were 47 articles selected for this review. Findings included that vitamin D, zinc, vitamin A, S. nigra, A. sativum, G. glabra, U. dioica, N-acetylcysteine, quercetin, and selenium have been shown to produce antiinflammatory, immunostimulatory, or antiviral effects that may enhance the actions of standard therapeutics for the treatment of coronavirus infections. Specific to effects against COVID-19, we found research articles related to the effects of only vitamin D, zinc, G. glabra, quercetin, and selenium. CONCLUSION: We identified nonpharmaceutical supplements (vitamin D, zinc, vitamin A, S. nigra, A. sativum, G. glabra, and U. dioica) which may have potential to provide support for those with coronavirus infections. However, rigorous clinical studies need to be performed before any clinical recommendations can be made.

Molecular analysis of the 2012 Bundibugyo virus disease outbreak.

Bundibugyo virus (BDBV) is one of four ebolaviruses known to cause disease in humans. Bundibugyo virus disease (BVD) outbreaks occurred in 2007-2008 in Bundibugyo District, Uganda, and in 2012 in Isiro, Province Orientale, Democratic Republic of the Congo. The 2012 BVD outbreak resulted in 38 laboratory-confirmed cases of human infection, 13 of whom died. However, only 4 BDBV specimens from the 2012 outbreak have been sequenced. Here, we provide BDBV sequences from seven additional patients. Analysis of the molecular epidemiology and evolutionary dynamics of the 2012 outbreak with these additional isolates challenges the current hypothesis that the outbreak was the result of a single spillover event. In addition, one patient record indicates that BDBV's initial emergence in Isiro occurred 50 days earlier than previously accepted. Collectively, this work demonstrates how retrospective sequencing can be used to elucidate outbreak origins and provide epidemiological contexts to a medically relevant pathogen.

Assessing Data Adequacy for High Blood Pressure Clinical Decision Support: A Quantitative Analysis.

OBJECTIVE: This study examines guideline-based high blood pressure (HBP) and hypertension recommendations and evaluates the suitability and adequacy of the data and logic required for a Fast Healthcare Interoperable Resources (FHIR)-based, patient-facing clinical decision support (CDS) HBP application. HBP is a major predictor of adverse health events, including stroke, myocardial infarction, and kidney disease. Multiple guidelines recommend interventions to lower blood pressure, but implementation requires patient-centered approaches, including patient-facing CDS tools. METHODS: We defined concept sets needed to measure adherence to 71 recommendations drawn from eight HBP guidelines. We measured data quality for these concepts for two cohorts (HBP screening and HBP diagnosed) from electronic health record (EHR) data, including four use cases (screening, nonpharmacologic interventions, pharmacologic interventions, and adverse events) for CDS. RESULTS: We identified 102,443 people with diagnosed and 58,990 with undiagnosed HBP. We found that 21/35 (60%) of required concept sets were unused or inaccurate, with only 259 (25.3%) of 1,101 codes used. Use cases showed high inclusion (0.9-11.2%), low exclusion (0-0.1%), and missing patient-specific context (up to 65.6%), leading to data in 2/4 use cases being insufficient for accurate alerting. DISCUSSION: Data quality from the EHR required to implement recommendations for HBP is highly inconsistent, reflecting a fragmented health care system and incomplete implementation of standard terminologies and workflows. Although imperfect, data were deemed adequate for two test use cases. CONCLUSION: Current data quality allows for further development of patient-facing FHIR HBP tools, but extensive validation and testing is required to assure precision and avoid unintended consequences.

Development, Phenotypic Characterization and Genomic Analysis of a Francisella tularensis Panel for Tularemia Vaccine Testing.

Francisella tularensis is one of several biothreat agents for which a licensed vaccine is needed to protect against this pathogen. To aid in the development of a vaccine protective against pneumonic tularemia, we generated and characterized a panel of F. tularensis isolates that can be used as challenge strains to assess vaccine efficacy. Our panel consists of both historical and contemporary isolates derived from clinical and environmental sources, including human, tick, and rabbit isolates. Whole genome sequencing was performed to assess the genetic diversity in comparison to the reference genome F. tularensis Schu S4. Average nucleotide identity analysis showed >99% genomic similarity across the strains in our panel, and pan-genome analysis revealed a core genome of 1,707 genes, and an accessory genome of 233 genes. Three of the strains in our panel, FRAN254 (tick-derived), FRAN255 (a type B strain), and FRAN256 (a human isolate) exhibited variation from the other strains. Moreover, we identified several unique mutations within the Francisella Pathogenicity Island across multiple strains in our panel, revealing unexpected diversity in this region. Notably, FRAN031 (Scherm) completely lacked the second pathogenicity island but retained virulence in mice. In contrast, FRAN037 (Coll) was attenuated in a murine pneumonic tularemia model and had mutations in pdpB and iglA which likely led to attenuation. All of the strains, except FRAN037, retained full virulence, indicating their effectiveness as challenge strains for future vaccine testing. Overall, we provide a well-characterized panel of virulent F. tularensis strains that can be utilized in ongoing efforts to develop an effective vaccine against pneumonic tularemia to ensure protection is achieved across a range F. tularensis strains.

Computationally modeling mammalian succinate dehydrogenase kinetics identifies the origins and primary determinants of ROS production.

Succinate dehydrogenase (SDH) is an inner mitochondrial membrane protein complex that links the Krebs cycle to the electron transport system. It can produce significant amounts of superoxide ([Formula: see text]) and hydrogen peroxide (H2O2); however, the precise mechanisms are unknown. This fact hinders the development of next-generation antioxidant therapies targeting mitochondria. To help address this problem, we developed a computational model to analyze and identify the kinetic mechanism of [Formula: see text] and H2O2 production by SDH. Our model includes the major redox centers in the complex, namely FAD, three iron-sulfur clusters, and a transiently bound semiquinone. Oxidation state transitions involve a one- or two-electron redox reaction, each being thermodynamically constrained. Model parameters were simultaneously fit to many data sets using a variety of succinate oxidation and free radical production data. In the absence of respiratory chain inhibitors, model analysis revealed the 3Fe-4S iron-sulfur cluster as the primary [Formula: see text] source. However, when the quinone reductase site is inhibited or the quinone pool is highly reduced, [Formula: see text] is generated primarily by the FAD. In addition, H2O2 production is only significant when the enzyme is fully reduced, and fumarate is absent. Our simulations also reveal that the redox state of the quinone pool is the primary determinant of free radical production by SDH. In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective.