Assessment of EHR Efficiency Tools and Resources Associated with Physician Time Spent on the Inbox.

BACKGROUND: Physicians are experiencing an increasing burden of messaging within the electronic health record (EHR) inbox. Studies have called for the implementation of tools and resources to mitigate this burden, but few studies have evaluated how these interventions impact time spent on inbox activities. OBJECTIVE: Explore the association between existing EHR efficiency tools and clinical resources on primary care physician (PCP) inbox time. DESIGN: Retrospective, cross-sectional study of inbox time among PCPs in network clinics affiliated with an academic health system. PARTICIPANTS: One hundred fifteen community-based PCPs. MAIN MEASURES: Inbox time, in hours, normalized to eight physician scheduled hours (IB-Time8). KEY RESULTS: Following adjustment for physician sex as well as panel size, age, and morbidity, we observed no significant differences in inbox time for physicians with and without message triage, custom inbox QuickActions, encounter specialists, and message pools. Moreover, IB-Time8 increased by 0.01 inbox hours per eight scheduled hours for each additional staff member resource in a physician's practice (p = 0.03). CONCLUSIONS: Physician inbox time was not associated with existing EHR efficiency tools evaluated in this study. Yet, there may be a slight increase in inbox time among physicians in practices with larger teams.

Longitudinal Monitoring of Clinician-Patient Video Visits During the Peak of the COVID-19 Pandemic: Adoption and Sustained Challenges in an Integrated Health Care Delivery System.

BACKGROUND: Numerous prior opinion papers, administrative electronic health record data studies, and cross-sectional surveys of telehealth during the pandemic have been published, but none have combined assessments of video visit success monitoring with longitudinal assessments of perceived challenges to the rapid adoption of video visits during the pandemic. OBJECTIVE: This study aims to quantify (1) the use of video visits (compared with in-person and telephone visits) over time during the pandemic, (2) video visit successful connection rates, and (3) changes in perceived video visit challenges. METHODS: A web-based survey was developed for the dual purpose of monitoring and improving video visit implementation in our health care system during the COVID-19 pandemic. The survey included questions regarding rates of in-person, telephone, and video visits for clinician-patient encounters; the rate of successful connection for video visits; and perceived challenges to video visits (eg, software, hardware, bandwidth, and technology literacy). The survey was distributed via email to physicians, advanced practice professionals, and clinicians in May 2020. The survey was repeated in March 2021. Differences between the 2020 and 2021 responses were adjusted for within-respondent correlation across surveys and tested using generalized estimating equations. RESULTS: A total of 1126 surveys were completed (511 surveys in 2020 and 615 surveys in 2021). In 2020, only 21.7% (73/336) of clinicians reported no difficulty connecting with patients during video visits and 28.6% (93/325) of clinicians reported no difficulty in 2021. The distribution of the percentage of successfully connected video visits ("Over the past two weeks of scheduled visits, what percentage did you successfully connect with patients by video?") was not significantly different between 2020 and 2021 (P=.74). Challenges in conducting video visits persisted over time. Poor connectivity was the most common challenge reported by clinicians. This response increased over time, with 30.5% (156/511) selecting it as a challenge in 2020 and 37.1% (228/615) in 2021 (P=.01). Patients not having access to their electronic health record portals was also a commonly reported challenge (109/511, 21.3% in 2020 and 137/615, 22.3% in 2021, P=.73). CONCLUSIONS: During the pandemic, our health care delivery system rapidly adopted synchronous patient-clinician communication using video visits. As experience with video visits increased, the reported failure rate did not significantly decline, and clinicians continued to report challenges related to general network connectivity and patient access to technology.

Implementing a Second-Level Observation Unit at a Large Academic Medical Center.

Supplemental digital content is available in the text.

Food Insecurity Is Associated with an Increased Prevalence of Comorbid Medical Conditions in Obese Adults: NHANES 2007-2014.

BACKGROUND: Numerous studies have examined if food insecurity (FI) leads to increased weight gain, but little is known about how FI affects obese participants. OBJECTIVE: Our objective was to determine if obese, food-insecure adults are more likely to have medical comorbidities than obese, food-secure adults. DESIGN: We conducted a cross-sectional study using the 2007-2014 National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: All obese participants (≥ 20 years) in NHANES were eligible. Participants who were pregnant or missing FI data were excluded. MAIN MEASURES: The primary exposure was household FI, and the primary outcome was the total number of obesity-related comorbidities. Secondary outcomes evaluated the association between FI and individual comorbidities. Propensity score weighting was used to improve covariate balance. We used negative binomial regression to test the association between FI and the total number of comorbidities. We used logistic regression to test the association between FI and individual comorbidities. KEY RESULTS: Of the 9203 obese participants, 15.6% were food insecure. FI (ß = 0.09, 95% CI: 0.02, 0.15; p = 0.01) and very low food security (ß = 0.17, 95% CI: 0.07, 0.28; p = 0.003) were associated with an increased number of comorbidities. In secondary analyses, FI was associated with increased odds of coronary artery disease (OR: 1.5, 95% CI: 1.1, 2.0) and asthma (OR: 1.3, 95% CI: 1.1, 1.6). Very low food security was associated with increased odds of coronary artery disease, diabetes, and asthma. CONCLUSION: Obese adults living in food-insecure households were more likely to have an increased number of comorbid conditions than obese adults living in food-secure households. Clinicians should be aware of the association between FI and comorbid medical conditions when treating patients with obesity.

Epidemiology of lower extremity peripheral artery disease in veterans.

OBJECTIVE: The objective of this study was to describe the epidemiology, clinical features, outcomes, and predictors of mortality in veterans with peripheral artery disease (PAD). METHODS: We used national data from the Veterans Health Administration from fiscal years 2009 to 2011 to identify patients with a new diagnosis of PAD. Within this cohort, we describe characteristics of the patients, use of recommended medications, and clinical outcomes during a 3-year follow-up (fiscal year 2014). We used Cox proportional hazards regression to examine predictors of mortality and adverse limb outcomes (amputation and hospitalization for critical limb ischemia [CLI]) during follow-up. RESULTS: A total of 175,865 patients with a new diagnosis of PAD were included. The mean age was 69.9 years; 97.8% were male, and 67.7% were white. Nearly 77% of patients had hypertension, 46.5% had diabetes, 23% had chronic obstructive pulmonary disease, and 12.9% had renal failure. A prescription for statins was filled by 60.8%, and 34.9% received high-intensity statins within 90 days of PAD diagnosis. At 1 year, 2.6% underwent revascularization, 1.3% developed CLI, and 1.1% underwent amputation. During a median follow-up of 3.8 years, a total of 28.6% patients died (6.7% at 1 year), and 3.7% developed a limb outcome (2.0% at 1 year). Predictors of mortality included advanced age, comorbidities, and CLI or amputation at presentation. In contrast, prescription with statins was associated with lower mortality. Similar findings were present with regard to predictors of adverse limb outcomes, except that older age was associated with a lower risk of amputation or CLI. CONCLUSIONS: We found that veterans with PAD have a high prevalence of comorbid conditions and have a significant risk of mortality and limb loss. A substantial proportion of veterans with PAD are not prescribed recommended medications, especially statin therapy. Our data highlight important opportunities for improving care of veterans with PAD.

Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory.

BACKGROUND: The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. METHODS: To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. RESULTS: In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. CONCLUSION: A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

Gatekeepers as Care Providers: The Care Work of Patient-centered Medical Home Clerical Staff.

International implementation of the patient-centered medical home (PCMH) model for delivering primary care has dramatically increased in the last decade. A majority of research on PCMH's impact has emphasized the care provided by clinically trained staff. In this article, we report our ethnographic analysis of data collected from Department of Veterans Affairs staff implementing PACT, the VA version of PCMH. Teams were trained to use within-team delegation, largely accomplished through attention to clinical licensure, to differentiate staff in providing efficient, patient-centered care. In doing so, PACT may reinforce a clinically defined culture of care that countermands PCMH ideals. Such competing rubrics for care are brought into relief through a focus on the care work performed by clerks. Ethnographic analysis identifies clerks' care as a kind of emotional dirty work, signaling important areas for future anthropological study of the relationships among patient-centered care, stigma, and clinical authority.

The Critical Role of Clerks in the Patient-Centered Medical Home.

Research evaluating the effectiveness, function, and implementation of patient-centered medical homes (PCMHs) has found major socioprofessional transformations and contributions of primary care physicians and, to a lesser degree, nurses. Our longitudinal ethnographic research with teams implementing PCMH in Veterans Health Administration (VHA) primary care identifies the important but largely underutilized contributions of clerks to PCMH outcomes. Although the relationship of high-performing clerical staff to patient satisfaction is widely acknowledged, PCMH can be further enhanced by enabling clerks to use administrative tasks as conduits for investing in long-term personalized relationships with patients that foster trust in the PCMH and the broader health care organization. Such relationships are engendered through the care-coordination activities clerks perform, which may be bolstered by organizational investment in clerks as skilled health care team members.

Insurance status and the transfer of hospitalized patients: an observational study.

BACKGROUND: There is little objective evidence to support concerns that patients are transferred between hospitals based on insurance status. OBJECTIVE: To examine the relationship between patients' insurance coverage and interhospital transfer. DESIGN: Data analyzed from the 2010 Nationwide Inpatient Sample. PATIENTS: All patients aged 18 to 64 years discharged alive from U.S. acute care hospitals with 1 of 5 common diagnoses (biliary tract disease, chest pain, pneumonia, septicemia, and skin or subcutaneous infection). MEASUREMENTS: For each diagnosis, the proportion of hospitalized patients who were transferred to another acute care hospital based on insurance coverage (private, Medicare, Medicaid, or uninsured) was compared. Logistic regression was used to estimate the odds of transfer for uninsured patients (reference category, privately insured) while patient- and hospital-level factors were adjusted for. All analyses incorporated sampling and poststratification weights. RESULTS: Among 315 748 patients discharged from 1051 hospitals with any of the 5 diagnoses, the percentage of patients transferred to another acute care hospital varied from 1.3% (skin infection) to 5.1% (septicemia). In unadjusted analyses, uninsured patients were significantly less likely to be transferred for 3 diagnoses (P 0.05). In adjusted analyses, uninsured patients were significantly less likely to be transferred than privately insured patients for 4 diagnoses: biliary tract disease (odds ratio, 0.73 [95% CI, 0.55 to 0.96]), chest pain (odds ratio, 0.63 [CI, 0.44 to 0.89]), septicemia (odds ratio, 0.76 [CI, 0.64 to 0.91]), and skin infections (odds ratio, 0.64 [CI, 0.46 to 0.89]). Women were significantly less likely to be transferred than men for all diagnoses. LIMITATION: This analysis relied on administrative data and lacked clinical detail. CONCLUSION: Uninsured patients (and women) were significantly less likely to undergo interhospital transfer. Differences in transfer rates may contribute to health care disparities. PRIMARY FUNDING SOURCE: National Institutes of Health.

Racial disparities in outcomes after cardiac surgery: the role of hospital quality.

Patients from racial and ethnic minorities experience higher mortality after cardiac surgery compared to white patients, both during the early postoperative phase as well as long term. A number of factors likely explain poor outcomes in black and minority patients, which include differences in biology, comorbid health conditions, socioeconomic background, and quality of hospital care. Recent evidence suggests that a major factor underlying excess mortality in these groups is due to their over-representation in low-quality hospitals, where all patients regardless of race have worse outcomes. In this review, we examine the factors underlying racial disparities in outcomes after cardiac surgery, with a primary focus on the role of hospital quality.

Implications of the Patient-Centered Medical Home for Nursing Practice.

OBJECTIVE: The experiences of RNs and licensed practical nurses (LPNs) implementing a patient-centered medical home (PCMH) in the Department of Veterans Affairs (VA) primary care clinics were examined to understand model implications for nursing practice and professional identity. BACKGROUND: National implementation of the PCMH model, called patient-aligned care teams (PACTs) in VA, emphasizes areas of nursing expertise, yet little is known about the effect of medical homes on the day-to-day work of nurses. METHODS: As part of a formative evaluation to identify barriers and facilitators to PACT implementation, we interviewed 18 nurses implementing PACT. RESULTS: Challenges to nurse's organizational and professional roles were experienced differently by RNs and LPNs in the following areas: (1) diversified modes of care and expanded clinical duties, (2) division of labor among PACT nurses, and (3) interprofessional status in the team. CONCLUSIONS: Healthcare managers implementing PCMH should consider its inherent cultural and practice transformations.

Racial disparities in knee and hip total joint arthroplasty: an 18-year analysis of national Medicare data.

OBJECTIVE: To examine whether racial disparities in usage and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time. METHODS: We used data from the US Medicare Program (MedPAR data) for years 1991-2008 to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardised arthroplasty usage rates for Caucasian and African-American Medicare beneficiaries for each calendar year, and examined changes in disparities over time. We examined unadjusted and adjusted outcomes (30-day readmission rate, discharge disposition etc.) for Caucasians and African-Americans, and whether disparities decreased over time. RESULTS: In 1991, the use of primary TKA was 36% lower for African-Americans compared with Caucasians (20.6 per 10,000 for African-Americans; 32.1 per 10,000 for Caucasians; p<0.0001); in 2008, usage of primary TKA was 40% lower for African-Americans (41.5 per 10,000 for African-Americans; 68.8 per 10,000 for Caucasians; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 1991-2008 among three patient cohorts. For example in 1991 30-day readmission rates for African-Americans receiving primary TKA were 6% higher than for Caucasians; by 2008 readmission rates for African-Americans were 24% higher (p<0.05 for change in disparity). Similarly, black-white disparities in the proportion of patients discharged to home after surgery increased across the study period for all cohorts (p<0.05). CONCLUSIONS: In an 18-year analysis of US Medicare data, we found little evidence of declines in racial disparities for joint arthroplasty usage or outcomes.

Structuring payment to medical homes after the affordable care act.

The Patient-Centered Medical Home (PCMH) is a leading model of primary care reform, a critical element of which is payment reform for primary care services. With the passage of the Affordable Care Act, the Accountable Care Organization (ACO) has emerged as a model of delivery system reform, and while there is theoretical alignment between the PCMH and ACOs, the discussion of physician payment within each model has remained distinct. Here we compare payment for medical homes with that for accountable care organizations, consider opportunities for integration, and discuss implications for policy makers and payers considering ACO models. The PCMH and ACO are complementary approaches to reformed care delivery: the PCMH ultimately requires strong integration with specialists and hospitals as seen under ACOs, and ACOs likely will require a high functioning primary care system as embodied by the PCMH. Aligning payment incentives within the ACO will be critical to achieving this integration and enhancing the care coordination role of primary care in these settings.

The role of pragmatic clinical trials in the evolution of learning health systems.

Pragmatic clinical trials (PCTs) test clinical interventions (eg, treatments, diagnostic tests, delivery strategies) that are widely used in practice and for which there is often clinical equipoise. Similar to traditional explanatory trials of novel therapeutics, PCTs use randomization to decrease selection bias. In contrast, PCTs rely on extant data sources (eg, electronic medical records [EMRs]) and test interventions that can be implemented with minimal research infrastructures. Thus, PCTs have drawn interest as vehicles for decreasing the cost of clinical research and for creating learning health systems, which, as articulated by the Institute of Medicine, seek to generate new knowledge as an integral by-product of the delivery experience. However, realizing this vision for PCTs will require innovative approaches for engaging clinicians, improving the efficiency of subject recruitment, improving the reliability of EMR data, and new paradigms for the regulatory review of low-risk trials to decrease unncessary hurdles to practice-based knowledge generation.

Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation.

BACKGROUND: S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma. METHODS: Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings. RESULTS: N6022 attenuated AHR (ED50 of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh. CONCLUSIONS: The significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease.

Patterns of illness explaining the associations between posttraumatic stress disorder and the use of CT.

PURPOSE: To examine the relationship between posttraumatic stress disorder (PTSD) and computed tomography (CT) utilization and to determine whether there were patterns of comorbid illness that could explain the relationship. MATERIALS AND METHODS: The study was approved by the University of Iowa Institutional Review Board and the Iowa City Veterans Affairs Medical Center Research and Development Committee. By using a retrospective cohort design, a national sample of new veteran enrollees aged 18-35 years was studied. Associations were examined between the presence of PTSD, receipt of at least one and multiple CT scans, comorbid medical conditions (eg, abdominal pain, headaches), and measures of health care utilization (eg, primary care, emergency room, and mental health visits) and the daily probability of the receipt of at least one CT scan before and after a diagnosis of PTSD. Analyses included sequential multivariable generalized linear mixed models to examine the independent relationship between PTSD and CT scan utilization. RESULTS: Among the full cohort, 13.0% (10 018 of 76 812) received at least one CT scan. PTSD was identified in 21.1% (16 182 of 76 812) of the cohort, and 22.9% (3711 of 16 182) of veterans with PTSD received at least one CT scan as compared with 10.4% (6307 of 60 630) of veterans without PTSD (P < .0001). In sequential modeling, comorbid factors explaining the relationship between CT scans and PTSD were traumatic brain injury (odds ratio, 3.54; P < .0001), abdominal pain (odds ratio, 4.01; P < .0001), and headaches (odds ratio, 3.07; P < .0001). Associations were also strong for high levels of emergency room (odds ratio, 2.73; P < .0001) and primary care (odds ratio, 2.38; P < .0001) utilization. The daily chance of receiving a CT scan was seven times higher prior to the recognition of PTSD (daily chance, 0.007 before vs 0.001 after; P < .0001). CONCLUSION: Young veterans with PTSD are receiving more CT scans compared with those without PTSD; the daily probability of receiving CT scans is higher prior to recognition of PTSD. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121593/-/DC1.

Associations between reduced hospital length of stay and 30-day readmission rate and mortality: 14-year experience in 129 Veterans Affairs hospitals.

BACKGROUND: Reducing length of stay (LOS) has been a priority for hospitals and health care systems. However, there is concern that this reduction may result in increased hospital readmissions. OBJECTIVE: To determine trends in hospital LOS and 30-day readmission rates for all medical diagnoses combined and 5 specific common diagnoses in the Veterans Health Administration. DESIGN: Observational study from 1997 to 2010. SETTING: All 129 acute care Veterans Affairs hospitals in the United States. PATIENTS: 4,124,907 medical admissions with subsamples of 2 chronic diagnoses (heart failure and chronic obstructive pulmonary disease) and 3 acute diagnoses (acute myocardial infarction, community-acquired pneumonia, and gastrointestinal hemorrhage). MEASUREMENTS: Unadjusted LOS and 30-day readmission rates with multivariable regression analyses to adjust for patient demographic characteristics, comorbid conditions, and admitting hospitals. RESULTS: For all medical diagnoses combined, risk-adjusted mean hospital LOS decreased by 1.46 days from 5.44 to 3.98 days, or 2% annually (P < 0.001). Reductions in LOS were also observed for the 5 specific common diagnoses, with greatest reductions for acute myocardial infarction (2.85 days) and community-acquired pneumonia (2.22 days). Over the 14 years, risk-adjusted 30-day readmission rates for all medical diagnoses combined decreased from 16.5% to 13.8% (P < 0.001). Reductions in readmissions were also observed for the 5 specific common diagnoses, with greatest reductions for acute myocardial infarction (22.6% to 19.8%) and chronic obstructive pulmonary disease (17.9% to 14.6%). All-cause mortality 90 days after admission was reduced by 3% annually. Of note, hospitals with mean risk-adjusted LOS that was lower than expected had a higher readmission rate, suggesting a modest tradeoff between hospital LOS and readmission (6% increase for each day lower than expected). LIMITATIONS: This study is limited to the Veterans Health Administration system; non-Veterans Affairs admissions were not available. No measure of readmission preventability was used. CONCLUSION: Veterans Affairs hospitals demonstrated simultaneous improvements in hospital LOS and readmissions over 14 years, suggesting that as LOS improved, hospital readmission did not increase. This is important because hospital readmission is being used as a quality indicator and may result in payment incentives. Future work should explore these relationships to see whether a tipping point exists for LOS reduction and hospital readmission. PRIMARY FUNDING SOURCE: Office of Rural Health and the Health Services Research & Development Service, Veterans Health Administration, U.S. Department of Veterans Affairs.

The Academic Learning Health System: A Framework for Integrating the Multiple Missions of Academic Medical Centers.

The learning health system (LHS) has emerged over the past 15 years as a concept for improving health care delivery. Core aspects of the LHS concept include: promoting improved patient care through organizational learning, innovation, and continuous quality improvement; identifying, critically assessing, and translating knowledge and evidence into improved practices; building new knowledge and evidence around how to improve health care and health outcomes; analyzing clinical data to support learning, knowledge generation, and improved patient care; and engaging clinicians, patients, and other stakeholders in processes of learning, knowledge generation, and translation. However, the literature has paid less attention to how these LHS aspects may integrate with the multiple missions of academic medical centers (AMCs). The authors define an academic learning health system (aLHS) as an LHS built around a robust academic community and central academic mission, and they propose 6 features that emphasize how an aLHS differs from an LHS. An aLHS capitalizes on embedded academic expertise in health system sciences; engages the full spectrum of translational investigation from mechanistic basic sciences to population health; builds pipelines of experts in LHS sciences and clinicians with fluency in practicing in an LHS; applies core LHS principles to the development of curricula and clinical rotations for medical students, housestaff, and other learners; disseminates knowledge more broadly to advance the evidence for clinical practice and health systems science methods; and addresses social determinants of health, creating community partnerships to mitigate disparities and improve health equity. As AMCs evolve, the authors expect that additional differentiating features and ways to operationalize the aLHS will be identified and hope this article stimulates further discussion around the intersection of the LHS concept and AMCs.

Mechanism of inhibition for N6022, a first-in-class drug targeting S-nitrosoglutathione reductase.

N6022 is a novel, first-in-class drug with potent inhibitory activity against S-nitrosoglutathione reductase (GSNOR), an enzyme important in the metabolism of S-nitrosoglutathione (GSNO) and in the maintenance of nitric oxide (NO) homeostasis. Inhibition of GSNOR by N6022 and related compounds has shown safety and efficacy in animal models of asthma, chronic obstructive pulmonary disease, and inflammatory bowel disease [Sun, X., et al. (2011) ACS Med. Chem. Lett. 2, 402-406]. N6022 is currently in early phase clinical studies in humans. We show here that N6022 is a tight-binding, specific, and fully reversible inhibitor of GSNOR with an IC(50) of 8 nM and a K(i) of 2.5 nM. We accounted for the fact that the NAD(+)- and NADH-dependent oxidation and reduction reactions, catalyzed by GSNOR are bisubstrate in nature in our calculations. N6022 binds in the GSNO substrate binding pocket like a competitive inhibitor, although in kinetic assays it behaves with a mixed uncompetitive mode of inhibition (MOI) toward the GSNO substrate and a mixed competitive MOI toward the formaldehyde adduct, S-hydroxymethylglutathione (HMGSH). N6022 is uncompetitive with cofactors NAD(+) and NADH. The potency, specificity, and MOI of related GSNOR inhibitor compounds are also reported.

Structure-activity relationship of pyrrole based S-nitrosoglutathione reductase inhibitors: carboxamide modification.

The enzyme S-nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, gastrointestinal, and cardiovascular systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently in clinical development for acute asthma. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogs of N6022 focusing on carboxamide modifications on the pendant N-phenyl moiety. We have identified potent and novel GSNOR inhibitors that demonstrate efficacy in an ovalbumin (OVA) induced asthma model in mice.