Distinct ecological fitness factors coordinated by a conserved Escherichia coli regulator during systemic bloodstream infection.

The ability of bacterial pathogens to adapt to host niches is driven by the carriage and regulation of genes that benefit pathogenic lifestyles. Genes that encode virulence or fitness-enhancing factors must be regulated in response to changing host environments to allow rapid response to challenges presented by the host. Furthermore, this process can be controlled by preexisting transcription factors (TFs) that acquire new roles in tailoring regulatory networks, specifically in pathogens. However, the mechanisms underlying this process are poorly understood. The highly conserved Escherichia coli TF YhaJ exhibits distinct genome-binding dynamics and transcriptome control in pathotypes that occupy different host niches, such as uropathogenic E. coli (UPEC). Here, we report that this important regulator is required for UPEC systemic survival during murine bloodstream infection (BSI). This advantage is gained through the coordinated regulation of a small regulon comprised of both virulence and metabolic genes. YhaJ coordinates activation of both Type 1 and F1C fimbriae, as well as biosynthesis of the amino acid tryptophan, by both direct and indirect mechanisms. Deletion of yhaJ or the individual genes under its control leads to attenuated survival during BSI. Furthermore, all three systems are up-regulated in response to signals derived from serum or systemic host tissue, but not urine, suggesting a niche-specific regulatory trigger that enhances UPEC fitness via pleiotropic mechanisms. Collectively, our results identify YhaJ as a pathotype-specific regulatory aide, enhancing the expression of key genes that are collectively required for UPEC bloodstream pathogenesis.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Assessing the acceptability and feasibility of remote spirometric monitoring for rural patients with interstitial lung disease: a multimethod approach.

INTRODUCTION: Interstitial lung disease encompasses a group of rare lung conditions causing inflammation and scarring of lung tissue. The typical method of monitoring disease activity is through pulmonary function tests performed in a hospital setting. However, accessing care can be difficult for rural patients due to numerous barriers. This study assesses the feasibility and acceptability of home spirometry telemonitoring using MIR-Spirometers and the patientMpower home-monitoring platform for rural patients with interstitial lung disease. METHODS: Unblinded, uncontrolled, prospective, multiple-methods study of the feasibility and utility of remote monitoring of 20 rural subjects with interstitial lung disease. Study assessments include adherence to twice weekly spirometry for 3 months in addition to mMRC dyspnea and EQ-5D-5L health-related quality of life questionnaires with each spirometry maneuver. Upon completion, subjects were encouraged to complete an 11-question satisfaction survey and participate in semi-structured qualitative interviews to further explore expectations and perceptions of rural patients to telehealth and remote patient monitoring. RESULTS: 19 subjects completed the 3-month study period. Adherence to twice weekly spirometry was mean 53% ± 38%, with participants on average performing 2.26 ± 1.69 maneuvers per week. The median (Range) number of maneuvers per week was 2.0 (0.0, 7.0). The majority of participants responded favorably to the patient satisfaction survey questions. Themes regarding barriers to access included: lack of local specialty care, distance to center with expertise, and time, distance, and high cost associated with travel. Remote monitoring was well perceived amongst subjects as a way to improve access and overcome barriers. CONCLUSIONS: Remote spirometry monitoring through web-based telehealth is acceptable and feasible for rural patients. Perceived benefits include overcoming access barriers like time, distance, and travel costs. However, cost, reimbursement, and internet access must be addressed before implementing it widely. Future studies are needed to ensure long-term feasibility and to compare outcomes with usual care.

Cytotoxicity and toxicoproteomics analysis of thiazolidinedione exposure in human-derived cardiomyocytes.

Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5-dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.

Learning from women veterans who navigate invisible injuries, caregiving, and reintegration challenges.

BACKGROUND: As women comprise a greater proportion of military service members, there is growing recognition of how their experiences in the early phase of military to civilian transitions have an important influence on their health and reintegration outcomes. Qualitative accounts of women veterans can inform programs that support transitioning service members. OBJECTIVES: We examined narratives of civilian reintegration among women veterans to understand their experiences of adjusting to community life while coping with mental health challenges. METHODS/PARTICIPANTS: We interviewed 16 post-911 era women who were within 5 years of separating from military service and developed a case study based on three participants. MAIN APPROACH: Interviews were audio-recorded and transcribed verbatim. Inductive thematic analysis was conducted to establish categories about reintegration. Immersion/crystallization techniques were used to identify exemplary cases that illustrated salient themes. KEY RESULTS: Women veterans identified establishing a future career direction, drawing on social support, and navigating health care services as major factors influencing how they adjusted to civilian life. In addition, participants also highlighted the navigation of complex and intersecting identities (i.e., wife, mother, employee, friend, veteran, patient, etc.), further magnified by gender inequalities. These women performed emotional labor, which is often rendered invisible and oriented toward their family and loved ones, while simultaneously monitoring self-care activities. During the early period of reintegration, they described how they felt marginalized in terms of accessing healthcare compared to their military spouses and male veteran peers. CONCLUSIONS: Our case study suggests that there are key gaps in addressing healthcare and readjustment needs for women servicemembers, a high priority VA group, as they transition into post-military life. It is important to consider innovative ways to address specific needs of women in veteran-focused policies and programs.

A developmental formative evaluation of a pilot participatory music program for veterans with housing insecurity.

BACKGROUND: Interventions are needed to improve well-being and promote community reintegration among Veterans with housing insecurity. The objective was to conduct a developmental formative evaluation of a participatory music program. METHODS: This single-site, pilot study implemented a participatory music program at a U.S. Department of Veterans Affairs (VA) Homeless Domiciliary that included one-hour sessions (group music instruction and ensemble playing), 3 times per week for 3 months. Intervention development was guided by the Model of Human Occupation (MOHO). Evaluation was guided by the MOHO and the Consolidated Framework for Implementation Evaluation (CFIR). Qualitative data were collected via semi-structured interviews from participants and non-participants, and were analyzed using an interdisciplinary, constant comparison qualitative analysis technique. RESULTS: Sixteen program participants and 8 non-participants were enrolled, age range 26-59 (mean 41; standard deviation, 11) years; 75% were White. The sample for this study (N = 12) included five participants and seven non-participants. Semi-structured interview responses produced three salient themes illuminating Veterans' perspectives: (1) key characteristics of the intervention (the relative advantage of the participatory program over other problem-focused programs; the importance of a supportive, encouraging teaching; the group setting; the role of music); (2) the therapeutic power of the program (based on it being enjoyable; and serving as an escape from preoccupations); and (3) the context and culture (which included Veterans supporting each other and the Domiciliary setting). CONCLUSIONS: Veterans described the benefits of a participatory music intervention compared to problem-based groups, which included enjoyment, skill acquisition facilitating pride, escape, reconnecting with their identity prior to current problems, and experiencing positive aspects of Veteran culture such as mutual support and discipline. These data support ongoing research about participatory music programs to support Veterans with housing insecurity.

Investigation of frailty markers including a novel biomarker panel in emergency laparotomy: protocol of a prospective cohort study.

BACKGROUND: Emergency laparotomy (EmLAP) is one of the commonest emergency operations performed in the United Kingdom (approximately 30, 000 laparotomies annually). These potentially high-risk procedures can be life changing with frail patients and/ or older adults (≥ 65 years) having the poorest outcomes, including mortality. There is no gold standard of frailty assessment and no clinical chemical biomarkers existing in practice. Early detection of subclinical changes or deficits at the molecular level are essential in improving our understanding of the biology of frailty and ultimately improving patient outcomes. This study aims primarily to compare preoperative frailty markers, including a blood-based biomarker panel, in their ability to predict 30 and 90-day mortality post-EmLAP. The secondary aim is to analyse the influence of perioperative frailty on morbidity and quality of life post-EmLAP. METHODS: A prospective single centred observational study will be conducted on 150 patients ≥ 40 years of age that undergo EmLAP. Patients will be included according to the established NELA (National Emergency Laparotomy Audit) criteria. The variables collected include demographics, co-morbidities, polypharmacy, place of residence, indication and type of surgery (as per NELA criteria) and prognostic NELA score. Frailty will be assessed using: a blood sample for ultra-high performance liquid chromatography mass spectrometry analysis; preoperative CT abdomen pelvis (sarcopenia) and Rockwood Clinical Frailty Scale (CFS). Patients will be followed up for 90 days. Variables collected include blood samples (at post operative day 1, 7, 30 and 90), place of residence on discharge, morbidity, mortality and quality of life (EQ-5D-5 L). The frailty markers will be compared between groups of frail (CFS ≥ 4) and non-frail using statistical methods such as regression model and adjusted for appropriate confounding factors. DISCUSSION: This study hypothesises that frailty level changes following EmLAP in frail and non- frail patients, irrespective of age. We propose that non- frail patients will have better survival rates and report better quality of life compared to the frail. By studying the changes in metabolites/ biomarkers in these patients and correlate them to frailty status pre-surgery, this highly novel approach will develop new knowledge of frailty and define a new area of clinical biomolecular research. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05416047. Registered on 13/06/2022 (retrospectively registered).

Untargeted Molecular Analysis of Exhaled Breath as a Diagnostic Test for Ventilator-Associated Lower Respiratory Tract Infections (BreathDx).

Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015.

"I Don't Want to Spend the Rest of my Life Only Going to a Gender Wellness Clinic": Healthcare Experiences of Patients of a Comprehensive Transgender Clinic.

BACKGROUND: Transgender individuals are less likely to have had a primary care visit in the last year than cisgender individuals. While the importance of multidisciplinary clinics for transgender care has been established, little is known about the healthcare experiences of transgender patients with these clinics. OBJECTIVE: To describe how patients experience transgender clinics and how these experiences compare to those experiences in other settings. PARTICIPANTS: Twenty-one adult patients of a gender health program. DESIGN AND APPROACH: Semi-structured interviews of transgender patients. The interviews focused on two domains: healthcare experiences and relationships with healthcare providers. KEY RESULTS: Overall, transgender patients expressed a need for healthcare services, particularly for primary care, that are partially met by the comprehensive care clinic model. Limitations in access included the lack of willing providers, where the patients live, and long wait times for appointments. Participants recounted a range of experiences, both positive and negative, with providers outside of the transgender clinic, but only positive experiences to share about providers from the transgender clinic. CONCLUSION: Outside specialty transgender settings, many patients had negative experiences with providers who were unwilling or unable to provide care. This study speaks to the need for primary care providers who can and will treat transgender patients, as well as the need for healthcare spaces that feel safe to transgender patents.

Evaluation of the role of KPNA2 mutations in breast cancer prognosis using bioinformatics datasets.

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data-driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions.We report the application of a bioinformatics-based approach probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing clinical data available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival.Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents.In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer.

The Perils of a "My Work Here is Done" perspective: a mixed methods evaluation of sustainment of an evidence-based intervention for transient ischemic attack.

BACKGROUND: To evaluate quality improvement sustainment for Transient Ischemic Attack (TIA) and identify factors influencing sustainment, which is a challenge for Learning Healthcare Systems. METHODS: Mixed methods were used to assess changes in care quality across periods (baseline, implementation, sustainment) and identify factors promoting or hindering sustainment of care quality. PREVENT was a stepped-wedge trial at six US Department of Veterans Affairs implementation sites and 36 control sites (August 2015-September 2019). Quality of care was measured by the without-fail rate: proportion of TIA patients who received all of the care for which they were eligible among brain imaging, carotid artery imaging, neurology consultation, hypertension control, anticoagulation for atrial fibrillation, antithrombotics, and high/moderate potency statins. Key informant interviews were used to identify factors associated with sustainment. RESULTS: The without-fail rate at PREVENT sites improved from 36.7% (baseline, 58/158) to 54.0% (implementation, 95/176) and settled at 48.3% (sustainment, 56/116). At control sites, the without-fail rate improved from 38.6% (baseline, 345/893) to 41.8% (implementation, 363/869) and remained at 43.0% (sustainment, 293/681). After adjustment, no statistically significant difference in sustainment quality between intervention and control sites was identified. Among PREVENT facilities, the without-fail rate improved ≥2% at 3 sites, declined ≥2% at two sites, and remained unchanged at one site during sustainment. Factors promoting sustainment were planning, motivation to sustain, integration of processes into routine practice, leadership engagement, and establishing systems for reflecting and evaluating on performance data. The only factor that was sufficient for improving quality of care during sustainment was the presence of a champion with plans for sustainment. Challenges during sustainment included competing demands, low volume, and potential problems with medical coding impairing use of performance data. Four factors were sufficient for declining quality of care during sustainment: low motivation, champion inactivity, no reflecting and evaluating on performance data, and absence of leadership engagement. CONCLUSIONS: Although the intervention improved care quality during implementation; performance during sustainment was heterogeneous across intervention sites and not different from control sites. Learning Healthcare Systems seeking to sustain evidence-based practices should embed processes within routine care and establish systems for reviewing and reflecting upon performance. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02769338 ).

Development of an Accessible Gene Expression Bioinformatics Pipeline to Study Driver Mutations of Colorectal Cancer.

Colorectal cancer (CRC) is a global cause of cancer-related mortality driven by genetic and environmental factors which influence therapeutic outcomes. The emergence of next-generation sequencing technologies enables the rapid and extensive collection and curation of genetic data for each cancer type into clinical gene expression biobanks. We report the application of bioinformatics tools for investigating the expression patterns and prognostic significance of three genes that are commonly dysregulated in colon cancer: adenomatous polyposis coli (APC); B-Raf proto-oncogene (BRAF); and Kirsten rat sarcoma viral oncogene homologue (KRAS). Through the use of bioinformatics tools, we show the patterns of APC, BRAF and KRAS genetic alterations and their role in patient prognosis. Our results show mutation types, the frequency of mutations, tumour anatomical location and differential expression patterns for APC, BRAF and KRAS for colorectal tumour and matched healthy tissue. The prognostic value of APC, BRAF and KRAS genetic alterations was investigated as a function of their expression levels in CRC. In the era of precision medicine, with significant advancements in biobanking and data curation, there is significant scope to use existing clinical data sets for evaluating the role of mutational drivers in carcinogenesis. This approach offers the potential for studying combinations of less well-known genes and the discovery of novel biomarkers, or for studying the association between various effector proteins and pathways.

Seeding Structures for a Community of Practice Focused on Transient Ischemic Attack (TIA): Implementing Across Disciplines and Waves.

BACKGROUND: The Community of Practice (CoP) model represents one approach to address knowledge management to support effective implementation of best practices. OBJECTIVE: We sought to identify CoP developmental strategies within the context of a national quality improvement project focused on improving the quality for patients receiving acute transient ischemic attack (TIA) care. DESIGN: Stepped wedge trial. PARTICIPANTS: Multidisciplinary staff at six Veterans Affairs medical facilities. INTERVENTIONS: To encourage site implementation of a multi-component quality improvement intervention, the trial included strategies to improve the development of a CoP: site kickoff meetings, CoP conference calls, and an interactive website (the "Hub"). APPROACH: Mixed-methods evaluation included data collected through a CoP attendance log; semi-structured interviews with site participants at 6 months (n = 32) and 12 months (n = 30), and CoP call facilitators (n = 2); and 22 CoP call debriefings. KEY RESULTS: The critical seeding structures that supported the cultivation of the CoP were the kickoffs which fostered relationships (key to the community element of CoPs) and provided the evidence base relevant to TIA care (key to the domain element of CoPs). The Hub provided the forum for sharing quality improvement plans and other tools which were further highlighted during the CoP calls (key to the practice element of CoPs). CoP calls were curated to create a positive context around participants' work by recognizing team successes. In addition to improving care at their local facilities, the community created a shared set of tools which built on their collective knowledge and could be shared within and outside the group. CONCLUSIONS: The PREVENT CoP advanced the mission of the learning healthcare system by successfully providing a forum for shared learning. The CoP was grown through seeding structures that included kickoffs, CoP calls, and the Hub. A CoP expands upon the learning collaborative implementation strategy as an effective implementation practice.

UbiX is a flavin prenyltransferase required for bacterial ubiquinone biosynthesis.

Ubiquinone (also known as coenzyme Q) is a ubiquitous lipid-soluble redox cofactor that is an essential component of electron transfer chains. Eleven genes have been implicated in bacterial ubiquinone biosynthesis, including ubiX and ubiD, which are responsible for decarboxylation of the 3-octaprenyl-4-hydroxybenzoate precursor. Despite structural and biochemical characterization of UbiX as a flavin mononucleotide (FMN)-binding protein, no decarboxylase activity has been detected. Here we report that UbiX produces a novel flavin-derived cofactor required for the decarboxylase activity of UbiD. UbiX acts as a flavin prenyltransferase, linking a dimethylallyl moiety to the flavin N5 and C6 atoms. This adds a fourth non-aromatic ring to the flavin isoalloxazine group. In contrast to other prenyltransferases, UbiX is metal-independent and requires dimethylallyl-monophosphate as substrate. Kinetic crystallography reveals that the prenyltransferase mechanism of UbiX resembles that of the terpene synthases. The active site environment is dominated by π systems, which assist phosphate-C1' bond breakage following FMN reduction, leading to formation of the N5-C1' bond. UbiX then acts as a chaperone for adduct reorientation, via transient carbocation species, leading ultimately to formation of the dimethylallyl C3'-C6 bond. Our findings establish the mechanism for formation of a new flavin-derived cofactor, extending both flavin and terpenoid biochemical repertoires.

New cofactor supports α,ß-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition.

The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis or microbial biodegradation of aromatic compounds, respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear. Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad1. Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry, we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation.

Acceptability of a complex team-based quality improvement intervention for transient ischemic attack: a mixed-methods study.

BACKGROUND: The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurologic Symptoms (PREVENT) program was a complex quality improvement (QI) intervention targeting transient ischemic attack (TIA) evidence-based care. The aim of this study was to evaluate program acceptability among the QI teams and factors associated with degrees of acceptability. METHODS: QI teams from six Veterans Administration facilities participated in active implementation for a one-year period. We employed a mixed methods study to evaluate program acceptability. Multiple data sources were collected over implementation phases and triangulated for this evaluation. First, we conducted 30 onsite, semi-structured interviews during active implementation with 35 participants at 6 months; 27 interviews with 28 participants at 12 months; and 19 participants during program sustainment. Second, we conducted debriefing meetings after onsite visits and monthly virtual collaborative calls. All interviews and debriefings were audiotaped, transcribed, and de-identified. De-identified files were qualitatively coded and analyzed for common themes and acceptability patterns. We conducted mixed-methods matrix analyses comparing acceptability by satisfaction ratings and by the Theoretical Framework of Acceptability (TFA). RESULTS: Overall, the QI teams reported the PREVENT program was acceptable. The clinical champions reported high acceptability of the PREVENT program. At pre-implementation phase, reviewing quality data, team brainstorming solutions and development of action plans were rated as most useful during the team kickoff meetings. Program acceptability perceptions varied over time across active implementation and after teams accomplished actions plans and moved into sustainment. We observed team acceptability growth over a year of active implementation in concert with the QI team's self-efficacy to improve quality of care. Guided by the TFA, the QI teams' acceptability was represented by the respective seven components of the multifaceted acceptability construct. CONCLUSIONS: Program acceptability varied by time, by champion role on QI team, by team self-efficacy, and by perceived effectiveness to improve quality of care aligned with the TFA. A complex quality improvement program that fostered flexibility in local adaptation and supported users with access to data, resources, and implementation strategies was deemed acceptable and appropriate by front-line clinicians implementing practice changes in a large, national healthcare organization. TRIAL REGISTRATION: clinicaltrials.gov : NCT02769338 .

Building cohesion in distributed telemedicine teams: findings from the Department of Veterans Affairs National Telestroke Program.

BACKGROUND: As telemedicine adoption increases, so does the importance of building cohesion among physicians in telemedicine teams. For example, in acute telestroke services, stroke specialists provide rapid remote stroke assessment and treatment to patients at hospitals without stroke specialty care. In the National Telestroke Program (NTSP) of the U.S. Department of Veterans Affairs, a virtual (distributed) hub of stroke specialists throughout the country provides 24/7 consultations nationwide. We examined how these specialists adapted to distributed teamwork, and we identified cohesion-related factors in program development and support. METHODS: We studied the virtual hub of stroke specialists employed by the NTSP. Semi-structured, confidential interviews with stroke specialists in the virtual hub were recorded and transcribed. We explored the extent to which these specialists had developed a sense of shared identity and team cohesion, and we identified factors in this development. Using a qualitative approach with constant comparison methods, two researchers coded each interview transcript independently using a shared codebook. We used matrix displays to identify themes, with special attention to team cohesion, communication, trust, and satisfaction. RESULTS: Of 13 specialists with at least 8 months of NTSP practice, 12 completed interviews; 7 had previously practiced in telestroke programs in other healthcare systems. Interviewees reported high levels of trust and team cohesion, sometimes even more with their virtual colleagues than with co-located colleagues. Factors facilitating perceived team cohesion included a weekly case conference call, a sense of transparency in discussing challenges, engagement in NTSP development tasks, and support from the NTSP leadership. Although lack of in-person contact was associated with lower cohesion, annual in-person NTSP meetings helped mitigate this issue. Despite technical challenges in establishing a new telehealth system within existing national infrastructure, providers reported high levels of satisfaction with the NTSP. CONCLUSION: A virtual telestroke hub can provide a sense of team cohesion among stroke specialists at a level comparable with a standard co-located practice. Engaging in transparent discussion of challenging cases, reviewing new clinical evidence, and contributing to program improvements may promote cohesion in distributed telemedicine teams.

Beyond Discharge Summaries: Communication Preferences in Care Transitions Between Hospitalists and Primary Care Providers Using Electronic Medical Records.

BACKGROUND: Ineffective transitions of care continue to be a source of risk for patients. Although there has been widespread implementation of electronic medical record (EMR) systems, little is currently known about hospitalists' and primary care providers' (PCPs) direct communication preferences at discharge using messaging capabilities in a shared EMR system. OBJECTIVE: We examined how hospitalists and PCPs with a shared EMR prefer to directly communicate at the time of hospital discharge by identifying preferred modes, information prioritization, challenges, facilitators, and proposed solutions. DESIGN: A sequential, explanatory mixed methods study with surveys and semi-structured interviews. PARTICIPANTS: Thirty-eight academic hospitalists and 63 PCPs working in outpatient clinics in a single safety net hospital system with a shared EMR. MAIN APPROACH: Descriptive statistics were used to analyze survey responses. Interviews were analyzed using immersion/crystallization and a mixture of inductive and deductive thematic analysis. KEY RESULTS: PCPs preferred direct communication at discharge through a message within the EMR while hospitalists preferred a message within the EMR and email. Qualitative results identified key themes related to patient care and direct communication: value of direct communication, safety, social determinants of health, and clinical judgment. Both groups prioritized direct communication for high-risk medications, pending and follow-up studies, and high-risk patients that hospitalists were concerned about. Overall, both hospitalists and PCPs reported that ensuring patient safety, flagging patients with social challenges, and expressing concerns about patients based on clinical judgment were key communication priorities. CONCLUSIONS: Hospitalists and primary care providers report considerable overlap in preferences for direct communication at the time of hospital discharge through a shared EMR. Specifically, both groups reported similar concerns regarding patient safety and continuity during transitions. Direct messaging within the EMR could enable "closed loop" communication that helps ensure safe transitions of care for high-risk patients.

Empowering Implementation Teams with a Learning Health System Approach: Leveraging Data to Improve Quality of Care for Transient Ischemic Attack.

BACKGROUND: Questions persist about how learning healthcare systems should integrate audit and feedback (A&F) into quality improvement (QI) projects to support clinical teams' use of performance data to improve care quality. OBJECTIVE: To identify how a virtual "Hub" dashboard that provided performance data for patients with transient ischemic attack (TIA), a resource library, and a forum for sharing QI plans and tools supported QI activities among newly formed multidisciplinary clinical teams at six Department of Veterans Affairs (VA) medical centers. DESIGN: An observational, qualitative evaluation of how team members used a web-based Hub. PARTICIPANTS: External facilitators and multidisciplinary team members at VA facilities engaged in QI to improve the quality of TIA care. APPROACH: Qualitative implementation process and summative evaluation of observational Hub data (interviews with Hub users, structured field notes) to identify emergent, contextual themes and patterns of Hub usage. KEY RESULTS: The Hub supported newly formed multidisciplinary teams in implementing QI plans in three main ways: as an information interface for integrated monitoring of TIA performance; as a repository used by local teams and facility champions; and as a tool for team activation. The Hub enabled access to data that were previously inaccessible and unavailable and integrated that data with benchmark and scientific evidence to serve as a common data infrastructure. Led by champions, each implementation team used the Hub differently: local adoption of the staff and patient education materials; benchmarking facility performance against national rates and peer facilities; and positive reinforcement for QI plan development and monitoring. External facilitators used the Hub to help teams leverage data to target areas of improvement and disseminate local adaptations to promote resource sharing across teams. CONCLUSIONS: As a dynamic platform for A&F operating within learning health systems, hubs represent a promising strategy to support local implementation of QI programs by newly formed, multidisciplinary teams.

Evaluating the feasibility of implementing a Telesleep pilot program using two-tiered external facilitation.

BACKGROUND: Obstructive sleep apnea (OSA) can negatively impact patients' health status and outcomes. Positive airway pressure (PAP) reverses airway obstruction and may reduce the risk of adverse outcomes. Remote monitoring of PAP (as opposed to in-person visits) may improve access to sleep medicine services. This study aimed to evaluate the feasibility of implementing a clinical program that delivers treatment for OSA through PAP remote monitoring using external facilitation as an implementation strategy. METHODS: Participants included patients with OSA at a Veteran Affairs Medical Center (VAMC). PAP adherence and clinical disease severity on treatment (measured by the apnea hypopnea index [AHI]) were the preliminary effectiveness outcomes across two delivery models: usual care (in-person) and Telehealth nurse-delivered remote monitoring. We also assessed visit duration and travel distance. A prospective, mixed-methods evaluation examined the two-tiered external facilitation implementation strategy. RESULTS: The pilot project included N = 52 usual care patients and N = 38 Telehealth nurse-delivered remote monitoring patients. PAP adherence and disease severity were similar across the delivery modalities. However, remote monitoring visits were 50% shorter than in-person visits and saved a mean of 72 miles of travel (median = 45.6, SD = 59.0, mode = 17.8, range 5.4-220). A total of 62 interviews were conducted during implementation with a purposive sample of 12 clinical staff involved in program implementation. Weekly external facilitation delivered to both front-line staff and supervisory physicians was necessary to ensure patient enrollment and treatment. Synchronized, "two-tiered" facilitation at the executive and coordinator levels proved crucial to developing the clinical and administrative infrastructure to support a PAP remote monitoring program and to overcome implementation barriers. CONCLUSIONS: Remote PAP monitoring had similar efficacy to in-person PAP services in this Veteran population. Although external facilitation is a widely-recognized implementation strategy in quality improvement projects, less is known about how multiple facilitators work together to help implement complex programs. Two-tiered facilitation offers a model well-suited to programs where innovations span disciplines, disrupt professional hierarchies (such as those between service chiefs, clinicians, and technicians) and bring together providers who do not know each other, yet must collaborate to improve access to care.