Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains.

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin's binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R2=0.82). In a blind prediction for an isoform (Myh7b) whose blebbistatin sensitivity was unknown, we find good agreement between predicted and measured IC50s (0.67 µM vs. 0.36 µM). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets.

The importance of hydrology in routing terrestrial carbon to the atmosphere via global streams and rivers.

SignificanceStream/river carbon dioxide (CO2) emission has significant spatial and seasonal variations critical for understanding its macroecosystem controls and plumbing of the terrestrial carbon budget. We relied on direct fluvial CO2 partial pressure measurements and seasonally varying gas transfer velocity and river network surface area estimates to resolve reach-level seasonal variations of the flux at the global scale. The percentage of terrestrial primary production (GPP) shunted into rivers that ultimately contributes to CO2 evasion increases with discharge across regions, due to a stronger response in fluvial CO2 evasion to discharge than GPP. This highlights the importance of hydrology, in particular water throughput, in terrestrial-fluvial carbon transfers and the need to account for this effect in plumbing the terrestrial carbon budget.

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome.

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

Declining greenness in Arctic-boreal lakes.

The highest concentration of the world's lakes are found in Arctic-boreal regions [C. Verpoorter, T. Kutser, D. A. Seekell, L. J. Tranvik, Geophys. Res. Lett. 41, 6396-6402 (2014)], and consequently are undergoing the most rapid warming [J. E. Overland et al., Arctic Report Card (2018)]. However, the ecological response of Arctic-boreal lakes to warming remains highly uncertain. Historical trends in lake color from remote sensing observations can provide insights into changing lake ecology, yet have not been examined at the pan-Arctic scale. Here, we analyze time series of 30-m Landsat growing season composites to quantify trends in lake greenness for >4 × 105 waterbodies in boreal and Arctic western North America. We find lake greenness declined overall by 15% from the first to the last decade of analysis within the 6.3 × 106-km2 study region but with significant spatial variability. Greening declines were more likely to be found in areas also undergoing increases in air temperature and precipitation. These findings support the hypothesis that warming has increased connectivity between lakes and the land surface [A. Bring et al., J. Geophys. Res. Biogeosciences 121, 621-649 (2016)], with implications for lake carbon cycling and energy budgets. Our study provides spatially explicit information linking climate to pan-Arctic lake color changes, a finding that will help target future ecological monitoring in remote yet rapidly changing regions.

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome.

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.1 seconds of the viral proteome. Our simulations capture dramatic opening of the apo Spike complex, far beyond that seen experimentally, which explains and successfully predicts the existence of 'cryptic' epitopes. Different Spike homologues modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also observe dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

Improving Well-Being Among Trainees: A Partnership to Reduce Barriers to Primary Care Services.

BACKGROUND: Improved well-being is a focus for graduate medical education (GME) programs. Residents and fellows often express difficulty with visiting primary care physicians, and this issue has not been thoroughly investigated. OBJECTIVE: We reported implementation and utilization of a primary care concierge scheduling service and a primary care video visit service for GME trainees. METHODS: GME leaders collaborated with Duke Primary Care to offer trainees a concierge scheduling service and opportunity for primary care video visits. This quantitative evaluation included (1) analysis of the institutional GME survey results pre- and post-intervention, and (2) review of use of the concierge scheduling line. RESULTS: Comparison of the 2018 and 2019 internal GME surveys showed a decrease in perceived barriers accessing primary care (58% to 31%, P < .0001), a decrease in perceived delays to access primary care (27% to 21%, P = .023), and an increase in respondents who reported needing health care services in the past year (37% to 62%, P < .0001). Although increased need for health services was reported, there was no difference in the proportion reporting use of health services (63% and 65%, P = .43). Of the 142 concierge line calls reviewed, 127 (87%) callers requested clinic appointments, and 15 (10%) callers requested video appointments. Of callers requesting clinic appointments, 99 (80%) were scheduled. CONCLUSIONS: Providing resources to connect trainees to primary care greatly reduces their perception of barriers to health care and may provide a convenient mechanism to schedule flexible primary care appointments.

What's in a Name? Role Clarity Goes Well Beyond a Simple Title.

BACKGROUND: Role clarity is important for patient care but challenging in graduate medical education (GME). METHODS: Badge buddies were integrated for all GME trainees at a single institution, and surveys were conducted prior to and 5 months following implementation. RESULTS: There were 932 pre- and 498 postimplementation respondents. Following implementation, both trainees and nurses reported improved awareness of GME training level, but there were no changes in patient/family perceptions. CONCLUSIONS: Badge buddies improved caregiver awareness of GME training level but did not impact patient/family perception. Patients appear to be focused primarily on relationships with caregivers and communication skills rather than a provider's specific role.

Pharmacist Involvement in Population Health Management for a Pediatric Managed Medicaid Accountable Care Organization.

Accountable care organizations (ACOs) have emerged as an effective healthcare delivery model for managing quality and cost at a population level. Within ACOs, pharmacists are critical for the delivery of high-value health care, offering patients and health care providers medication-related training, resources, and guidance that can improve quality of care at lower costs. Partners For Kids (PFK), one of the oldest and largest pediatric ACOs in the country, has successfully leveraged pharmacists to provide population health management and medication management to promote health outcomes for individual patients and the overall population it serves. This review explores how the inclusion of pharmacists in the development and execution of various quality improvement initiatives within PFK has positively impacted outcomes for patients while also lowering overall spend. A catalog of interventions is provided to offer various ways that pharmacists can intersect as providers in the triad of patient/family, payor, and provider. By providing enhanced training and education, on-site guidance, medication management, and population-level data analysis, pharmacists are able to identify and improve inefficiencies in care. Moving forward, ongoing engagement of pharmacists in health care operations will be a necessary feature to maximize health care value.

Delayed Neuromuscular Blockade Reversal With Sugammadex After Vecuronium, Desflurane, and Magnesium Administration: A Case Report.

A variety of factors are known to prolong neuromuscular blockade, including several medications commonly used in anesthetic practice. We present a patient who underwent general anesthesia using desflurane, vecuronium, and magnesium infusion with delayed neuromuscular blockade reversal after sugammadex administration. A higher than anticipated total dose of sugammadex was required for adequate reversal, and quantitative neuromuscular monitoring was essential to ensuring complete neuromuscular recovery before extubation in this case.

Standardized documentation workflow within an electronic health record to track pharmacists' interventions in pediatric ambulatory care clinics.

OBJECTIVES: To describe the implementation of a standardized documentation workflow within an electronic health record (EHR) and to track pharmacists' interventions in pediatric ambulatory care clinics. SETTING: Ambulatory care clinics and a transitions-of-care (TOC) service within a pediatric health care system in central Ohio. PRACTICE DESCRIPTION: Ambulatory clinical pharmacists work as integrated members of the health care team in 7 pediatric ambulatory care clinics and a TOC service to achieve the best medication-related outcomes for patients. PRACTICE INNOVATION: A standardized documentation workflow was established among ambulatory clinical pharmacists to document the interventions made in their practice settings with the use of a tool in the EHR. A weekly report from the EHR was run by a technician to gather intervention data, identify reimbursable opportunities, and document and bill via a separate Internet-based medication therapy management platform. EVALUATION: The success of the new documentation workflow was evaluated, and continuous feedback was gathered from the pharmacists and the billing technician. Updates were provided to the ambulatory clinical pharmacist at monthly staff meetings and workflow changes implemented as needed. RESULTS: A total of 5210 interventions were documented by the pharmacists in various intervention categories. The 3 most common intervention categories included patient and medication education (1765), medication reconciliations (1170), and compliance assessments (795). CONCLUSION: A standardized documentation workflow allowed for consistent tracking of interventions across ambulatory care clinics and a TOC service. Key elements to the successful implementation of this new documentation workflow included proper training and continuous feedback to the ambulatory clinical pharmacists, assistance from a billing technician, and consistent documentation by the ambulatory clinical pharmacists.

Spatial patterns of enzymatic activity in large water bodies: Ship-borne measurements of beta-D-glucuronidase activity as a rapid indicator of microbial water quality.

This study used automated enzymatic activity measurements conducted from a mobile research vessel to detect the spatial variability of beta­d­glucuronidase (GLUC) activity in large freshwater bodies. The ship-borne observations provided the first high-resolution spatial data of GLUC activity in large water bodies as rapid indication of fecal pollution and were used to identify associations with hydrological conditions and land use. The utility of this novel approach for water quality screening was evaluated by surveys of the Columbia River, the Mississippi River and the Yahara Lakes, covering up to a 500 km river course and 50 km2 lake area. The ship-borne measurements of GLUC activity correlated with standard E. coli analyses (R2 = 0.71) and revealed the effects of (1) precipitation events and urban run-off on GLUC activity in surface waters, (2) localized point inlets of potential fecal pollution and (3) increasing GLUC signals along gradients of urbanization. We propose that this ship-borne water quality screening to be integrated into future water inventory programs as an initial or complementary tool (besides established fecal indicator parameters), due to its ability to provide near real-time spatial information on potential fecal contamination of large surface water resources and therefore being helpful to greatly reduce potential human health risks.

Implementation of a medication therapy management collaborative within a pediatric health system.

OBJECTIVES: To describe the implementation of a medication therapy management (MTM) collaborative within a pediatric health system to ensure the safe use of medication. SETTING: Outpatient pharmacies and clinics within a pediatric health system in Central Ohio. PRACTICE DESCRIPTION: The outpatient pharmacies conducted the daily operations of a community pharmacy following a standard, 4-point workflow. The ambulatory clinical pharmacists served on interdisciplinary teams within outpatient clinics to ensure the appropriate use of medication. PRACTICE INNOVATION: A collaborative model was developed to offer MTM services to patients within outpatient pharmacies and clinics throughout the health system. The pharmacist responsibilities varied, with outpatient pharmacists focused on targeted medication reviews (TMRs) and ambulatory clinical pharmacists focused on comprehensive medication reviews (CMRs) and TMRs. EVALUATION: The use of multiple plan-do-study-act cycles allowed for program improvements throughout implementation. Data collection included a pharmacy staff perception survey, mapping of MTM opportunities, and a quantitative report on the number, type, and intervention rate of all MTM activities. RESULTS: Four hundred nine MTM interventions, 349 TMRs (70 clinic based and 279 pharmacy based) and 60 CMRs, were completed throughout the first 6 months. Two hundred thirty-eight of the TMRs were pharmacist-initiated interventions that allowed pharmacists to provide medication counseling and follow-up with patients beginning new therapy. Ambulatory clinical pharmacists identified and resolved drug-related problems in greater than one-half of the CMRs completed. The intervention rates were 39% for CMRs and 44% for TMRs. CONCLUSION: The implementation of a collaborative MTM model provided an opportunity to address drug-related problems to ensure the appropriate use of medication. The model consisted of pharmacy staff members within 2 different patient care environments working together to complete MTM services for patients throughout the health system. The key elements of the program included the use of training sessions tailored to the pharmacy staff member's role in MTM, incorporation of technician champions, and creation of pharmacist-initiated interventions.

Pharmacy technician involvement in community pharmacy medication therapy management.

OBJECTIVES: To assess the impact of technician involvement on the completion of medication therapy management (MTM) services in a community pharmacy setting and to describe pharmacists' and technicians' perceptions of technician involvement in MTM-related tasks and their satisfaction with the technician's role in MTM. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: In the fall of 2015, pharmacists and selected technicians from 32 grocery store-based community pharmacies were trained to use technicians within MTM services. MAIN OUTCOME MEASURES: Completed MTM claims were evaluated at all pharmacies for 3 months before training and 3 months after training. An electronic survey, developed with the use of competencies taught in the training and relevant published literature, was distributed via e-mail to trained employees 3 months after training. RESULTS: The total number of completed MTM claims at the 32 pharmacy sites was higher during the posttraining time period (2687 claims) versus the pretraining period (1735 claims). Of the 182 trained participants, 112 (61.5%) completed the survey. Overall, perceived technician involvement was lower than expected. However, identifying MTM opportunities was the most commonly reported technician MTM task, with 62.5% of technicians and 47.2% of pharmacists reporting technician involvement. Nearly one-half of technicians (42.5%) and pharmacists (44.0%) agreed or strongly agreed they were satisfied with the technician's role in MTM services, and 40.0% of technicians agreed that they were more satisfied with their work in the pharmacy after involvement in MTM. CONCLUSION: Three months after initial training of technicians in MTM, participation of technicians was lower than expected. However, the technicians involved most often reported identifying MTM opportunities for pharmacists, which may be a focus for future technician trainings. In addition, technician involvement in MTM services may increase satisfaction with many aspects of work for actively involved technicians.

Improving Resident and Fellow Engagement in Patient Safety Through a Graduate Medical Education Incentive Program.

BACKGROUND: Collaboration between graduate medical education (GME) and health systems is essential for the success of patient safety initiatives. One example is the development of an incentive program aligning trainee performance with health system quality and safety priorities. OBJECTIVE: We aimed to improve trainee safety event reporting and engagement in patient safety through a GME incentive program. METHODS: The incentive program was implemented to provide financial incentives to drive behavior and engage residents and fellows in safety efforts. Safety event reporting was measured beginning in the 2014-2015 academic year. A training module was introduced and the system reporting link was added to the institution's Resident Management System homepage. The number of reports by trainees was tracked over time, with a target of 2 reports per trainee per year. RESULTS: Baseline data for the year prior to implementation of the incentive program showed less than 0.5% (74 of 16 498) of safety reports were submitted by trainees, in contrast with 1288 reports (7% of institutional reports) by trainees in 2014-2015 (P < .0001). A total of 516 trainees (57%), from 37 programs, received payment for the metric, based on a predefined program target of a mean of 2 reports per trainee. In 2015-2016 and 2016-2017 the submission rate was sustained, with 1234 and 1350 reports submitted by trainees, respectively. CONCLUSIONS: An incentive program as part of a larger effort to address safety events is feasible and resulted in increased reporting by trainees.

A structured patient identification model for medication therapy management services in a community pharmacy.

OBJECTIVES: To describe the development and implementation of a structured patient identification model for medication therapy management (MTM) services within traditional dispensing activities of a community pharmacy to facilitate pharmacist-provided completion of MTM services. DESIGN: A daily clinical opportunity report was developed as a structured model to identify MTM opportunities daily for all MTM-eligible patients expecting to pick up a prescription. Pharmacy staff was trained and the standardized model was implemented at study sites. SETTING AND PARTICIPANTS: One hundred nineteen grocery store-based community pharmacies throughout Ohio, West Virginia, and Michigan. OUTCOME MEASURES: A structured patient identification model in a community pharmacy consists of reviewing a clinical opportunity report, identifying interventions for MTM-eligible patients, and possibly collaborating with an interdisciplinary team. This model allows pharmacists to increase MTM cases performed by providing a structured process for identifying MTM-eligible patients and completing MTM services. RESULTS: The development and implementation of a structured patient identification model in the community pharmacy was completed and consists of pharmacists reviewing a clinical opportunity report to identify MTM opportunities and perform clinical interventions for patients. In a 3-month pre- and post-implementation comparison, there was a 49% increase in the number of MTM services provided by pharmacists (P < 0.001). CONCLUSION: A structured patient identification model in the community pharmacy was associated with an increase in the amount of MTM services provided by pharmacists. This method could be a useful tool at a variety of community pharmacies to solve challenges associated with MTM completion.

Self-care as a professional imperative: physician burnout, depression, and suicide.

PURPOSE: Burnout has been identified in approximately half of all practicing physicians, including anesthesiologists. In this narrative review, the relationship between burnout, depression, and suicide is explored, with particular attention to the anesthesiologist. Throughout this review, we highlight our professional imperative regarding this epidemic. SOURCE: The authors searched the existing English language literature via PubMed from 1986 until present using the search terms physician burnout, depression, and suicide, with particular attention to studies regarding anesthesiologists and strategies to address these problems. PRINCIPAL FINDINGS: Burnout and depression have increased among physicians, while the rate of suicide has remained relatively the same. There are many factors associated with burnout and depression as well as many causes. Certain individual factors include sex, amount of social support, and mental health history. Systems factors that play a role in burnout and depression include work compression, demands of electronic health records, production pressure, and lack of control over one's professional life. Medical license applications include questions that reinforce the stigma of psychological stresses and discourage physicians from seeking appropriate care. CONCLUSION: The concept of physician well-being is multidimensional and includes factors related to each physician as an individual as well as to the working environment. Anesthesiologists must actively engage in self-care. Anesthesiology practices and healthcare organizations should evaluate the balance between demands they place on physicians and the resources provided to sustain an engaged, productive, and satisfied physician workforce. National efforts must be rallied to support physicians seeking help for physical and psychological health problems.

Mystery behind the match: an undergraduate medical education-graduate medical education collaborative approach to understanding match goals and outcomes.

BACKGROUND: There is a paucity of information regarding institutional targets for the number of undergraduate medical education (UME) graduates being matched to graduate medical education (GME) programs at their home institutions. At our institution, the Duke University, the number of UME graduates matched to GME programs declined dramatically in 2011. To better understand why this decline may have happened, we sought to identify perceived quality metrics for UME and GME learners, evaluate trends in match outcomes and educational program characteristics, and explore whether there is an ideal retention rate for UME graduates in their home institutions' GME programs. METHODS: We analyzed the number of Duke University UME graduates remaining at Duke for GME training over the past 5 years. We collected data to assess for changing characteristics of UME and GME, and performed descriptive analysis of trends over time to investigate the potential impact on match outcomes. RESULTS: A one-sample t-test analysis showed no statistically significant difference in the number of Duke UME graduates who stayed for GME training. For both UME and GME, no significant changes in the characteristics of either program were found. DISCUSSION: We created a process for monitoring data related to the characteristics or perceived quality of UME and GME programs and developed a shared understanding of what may impact match lists for both UME graduates and GME programs, leaving the Match somewhat less mysterious. While we understand the trend of graduates remaining at their home institutions for GME training, we are uncertain whether setting a goal for retention is reasonable, and so some mystery remains. We believe there is an invaluable opportunity for collaboration between UME and GME stakeholders to facilitate discussion about setting shared institutional goals.