Single Ion Pair Is Essential for Stabilizing SHP2's Open Conformation.

Src-homology-2-domain-containing PTP-2 (SHP2) is a widely expressed signaling enzyme whose misregulation is associated with multiple human pathologies. SHP2's enzymatic activity is controlled by a conformational equilibrium between its autoinhibited ("closed") state and its activated ("open") state. Although SHP2's closed state has been extensively characterized, the putative structure of its open form has only been revealed in the context of a highly activated mutant (E76K), and no systematic studies of the biochemical determinants of SHP2's open-state stabilization have been reported. To identify amino-acid interactions that are critical for stabilizing SHP2's active state, we carried out a mutagenic study of residues that lie at potentially important interdomain interfaces of the open conformation. The open/closed equilibria of the mutants were evaluated, and we identified several interactions that contribute to the stabilization of SHP2's open state. In particular, our findings establish that an ion pair between glutamate 249 on SHP2's PTP domain and arginine 111 on an interdomain loop is the key determinant of SHP2's open-state stabilization. Mutations that disrupt the R111/E249 ion pair substantially shift SHP2's open/closed equilibrium to the closed state, even compared to wild-type SHP2's basal-state equilibrium, which strongly favors the closed state. To the best of our knowledge, the ion-pair variants uncovered in this study are the first known SHP2 mutants in which autoinhibition is augmented with respect to the wild-type protein. Such "hyperinhibited" mutants may provide useful tools for signaling studies that investigate the connections between SHP2 inhibition and the suppression of human disease progression.

Inquiry for the win: Fostering curiosity through a BINGO exercise in a longitudinally integrated clerkship.

EDUCATIONAL CHALLENGE: As technological advancements challenge the current roles healthcare workers fill, curiosity and lifelong learning are becoming increasingly important. However, descriptions of specific curricular interventions that successfully develop these attitudes and skills remain limited. PROPOSED SOLUTION: We aimed to promote curiosity and advance practical application of evidenced-based medicine through a longitudinal, gamified learning activity within a longitudinal integrated clerkship (LIC). Thirty-seven students across two inquiry-themed LICs based at a university hospital and a community-based integrated healthcare delivery system used BINGO cards containing various assignments designed to develop the skill of asking and answering clinical questions. Assignments included: engaging experts, using evidence-based medical resources, attending education events, utilizing medical library resources, and Phone-a-Scientist. Students shared their experiences in a group setting and wrote a reflection for each assignment that was qualitatively analyzed to determine the perceived educational outcomes according to the Kirkpatrick Evaluation Model. LESSONS LEARNED: Results suggest that Inquiry BINGO fosters curiosity and builds skill in applied evidenced-based medicine early in clinical training. Most assignments prompted students to engage in opportunities they might not have otherwise explored. All but three students reported a change in behavior as a result of the assignment and 57% reported positive clinical or research results. NEXT STEPS: Future iterations of this activity should be evaluated by obtaining patient and/or preceptor feedback as well as longitudinal evaluations of student behavior to ensure higher level educational outcomes are being met.

Characterization of Distinctive Teaching Practices in Longitudinal Integrated Clerkships: Perspectives From Students and Faculty.

Phenomenon: Longitudinal integrated clerkships (LICs) are novel curricula that place medical students in long-term learning and coaching relationships with faculty and require adaptation of teaching practices on the behalf of faculty to maximize learning outcomes. An understanding of how teaching in an LIC model differs from teaching trainees in more traditional models is critical to ensuring curricular innovation success through faculty development. Approach: A qualitative approach was used to describe the teaching practices of faculty and learning experiences of student participants in longitudinal integrated clerkships in different clinical and community settings. Forty-five faculty and 20 students participated in focus groups. Thematic analysis of focus group data was used to identify differences and similarities between groups, sites, and specialties. Findings: Two groupings of themes emerged in thematic analysis: (1) precepting strategies distinctive to the longitudinal integrated clerkship model and (2) precepting strategies enhanced when employed in the LIC model. Distinct to the LIC model, preceptors and students described the importance of understanding the curricular structure and supporting students in longitudinal care of patients. Enhanced in the LIC model are the strategies of relationship-based teaching, support of autonomy, feedback, and support of longitudinal growth in skills. Insights: Students and faculty across LIC sites were broadly aligned in their opinions of best practices for teaching in an LIC model. The longitudinal relationship between student and faculty in an LIC distinguishes this model from traditional block rotations and a distinctive approach to successful teaching is demonstrated. Preceptors use time afforded to build trusting relationships with students, which created opportunity for novel teaching approaches and enhanced otherwise effective teaching strategies. A focus on orientation to the curricular model and support of longitudinal relationships with patients may serve as an anchor for faculty development efforts in the development of an LIC.

How to implement a "standard of care" regulatory model for pharmacists.

National pharmacy associations have increasingly explored regulation according to a "standard of care." In such a model, pharmacists can provide a wide range of clinical services aligned with their education and training. Based on Idaho's experience implementing this model, there are five critical steps states must take to enact a standard of care: 1) Adopt a broad definition of "practice of pharmacy;" 2) Allow elasticity for practice innovation over time; 3) Decide which limited instances still necessitate prescriptive regulation; 4) Eliminate all unnecessary regulations; and 5) Strengthen accountability for deviations from the standard of care. States wishing to adopt a standard of care approach can follow this five-step process to enhance patient care and mitigate the lag that is otherwise constant between laws and practice.

A value analysis of longitudinal integrated clerkships: consideration of costs and benefits.

Longitudinal Integrated Clerkships (LICs) prioritise longitudinal relationships with faculty, patients, and place. Research shows that LICs benefit students and faculty, but most medical schools have limited LIC programmes. This is likely due to perceptions that LICs are more costly and complex than traditional block rotations (TBRs). The perceived cost versus evidence-based value related to clerkship education has not been examined in detail. Until recently, no 'All-LIC' medical school exemplars existed in the US, limiting the value of this model as well as the ability to examine relative cost and complexity. In this paper, we draw on our experience launching three 'All-LIC' medical schools in the United States - schools in which the entire clerkship class participates in a comprehensive clerkship-year LIC. We propose that the known benefits of LICs coupled with cost-mitigation strategies related to running an 'All LIC' model for core clinical clerkships, rather than block and LIC models simultaneously, results in a higher value for medical schools.

Resource pulses shape seasonal and individual variation in the diet of an omnivorous carnivore.

Resource pulses are ecologically important phenomenon that occur in most ecosystems globally. Following optimal foraging theory, many consumers switch to pulsatile foods when available, examples of which include fruit mast and vulnerable young prey. Yet how the availability of resource pulses shapes the ecology of predators is still an emerging area of research; and how much individual variation there is in response to pulses is not well understood. We hypothesized that resource pulses would lead to dietary convergence in our population, which we tested by tracking both population-level and individual coyote diets for 3 years in South Carolina, USA. We (1) described seasonal dietary shifts in relation to resource pulses; (2) compared male and female diets across seasons; and (3) tested this dietary convergence hypothesis by quantifying individual dietary variation both across and within periods when resource pulses were available. We found that pulses of white-tailed deer fawns and blackberries composed over half of coyote diet in summer, and persimmon fruits were an important component in fall. Male and female coyotes generally had similar diets, but males consumed more deer in fall, perhaps driven by scavenging more. We found support for our dietary convergence hypothesis, where individuals had more similar diets during resource pulses compared to a non-pulse period. We also found that this convergence happened before peak availability, suggesting a non-symmetric response to pulse availability. We show that nearly all coyotes eat fawns, suggesting that targeted efforts to remove "fawn killers" would be in vain. Instead, given how quickly coyotes collectively converge on resource pulses, our findings show that resource pulses could potentially be used by managers to alter the behavior of apex predators. More broadly, we open a new line of inquiry into how variation in individual foraging decisions scales up to shape the effects of resource pulses on ecological communities.

Genetic analysis of harvest samples reveals population structure in a highly mobile generalist carnivore.

Delineating wildlife population boundaries is important for effective population monitoring and management. The bobcat (Lynx rufus) is a highly mobile generalist carnivore that is ecologically and economically important. We sampled 1225 bobcats harvested in South Dakota, USA (2014-2019), of which 878 were retained to assess genetic diversity and infer population genetic structure using 17 microsatellite loci. We assigned individuals to genetic clusters (K) using spatial and nonspatial Bayesian clustering algorithms and quantified differentiation (F ST and GST″) among clusters. We found support for population genetic structure at K = 2 and K = 4, with pairwise F ST and GST″ values indicating weak to moderate differentiation, respectively, among clusters. For K = 2, eastern and western clusters aligned closely with historical bobcat management units and were consistent with a longitudinal suture zone for bobcats previously identified in the Great Plains. We did not observe patterns of population genetic structure aligning with major rivers or highways. Genetic divergence observed at K = 4 aligned roughly with ecoregion breaks and may be associated with environmental gradients, but additional sampling with more precise locational data may be necessary to validate these patterns. Our findings reveal that cryptic population structure may occur in highly mobile and broadly distributed generalist carnivores, highlighting the importance of considering population structure when establishing population monitoring programs or harvest regulations. Our study further demonstrates that for elusive furbearers, harvest can provide an efficient, broad-scale sampling approach for genetic population assessments.

Practice Makes Perfect: Objective Structured Clinical Examinations Across the UME-to-GME Continuum Improve Care of Transgender Simulated Patients.

Background Residents lack confidence in caring for transgender individuals. More exposure and practice throughout training is needed. Objective To explore whether and how prior exposure to transgender health skills during medical school impacted competency with these skills during residency. Methods In 2022, all 101 internal medicine residents at New York University Grossman School of Medicine participated in an objective structured clinical examination (OSCE) station as part of their annual formative assessment where they cared for a standardized patient (SP) who identified as transgender. Three SPs who were members of the transgender community were recruited through online and social media forums. Two resident groups (continuum vs noncontinuum) differed in their prior experiences with transgender OSCEs during medical school. We analyzed SPs' ratings of resident performance using checklist data and SP open-ended feedback to compare performance between groups and resident post-OSCE evaluations to understand residents' perceptions of the educational value of the case. Results Residents with prior experience with transgender SPs (continuum) were more frequently recommended by SPs (88% [21 of 24] vs 70% [54 of 77]) to a family member or friend, were all rated professional (100% [24 of 24] vs 94% [72 of 94]) and scored better in pain information-gathering (92% vs 65%, mean summary score) and gender-affirming care skills (67% vs 52%, mean summary score). Noncontinuum residents lacked experience, missed opportunities to ask about gender identity, and needed work on demonstrating comfort and using proper language. Most residents completing a post-OSCE evaluation (80%, 41 of 51) rated the case as "very valuable." Conclusions Spaced practice and feedback through early exposure to transgender OSCEs were valuable for skill acquisition, giving continuum residents a learning advantage compared to noncontinuum residents.

Efficacy and Implementation Planning Across the Veterans Affairs Polytrauma System of Care: Protocol for the REACH Intervention for Caregivers of Veterans and Service Members With Traumatic Brain Injury.

BACKGROUND: The responsibility of care for Veterans and Service Members (V/SMs) with traumatic brain injury (TBI) often defaults to informal family caregivers. Caregiving demands considerable knowledge, skill, and support to facilitate the health and well-being of V/SMs and themselves. Persistent and common TBI caregiver issues include strain, depression, and anxiety. While evidence-based, brief interventions have been developed and implemented for family caregivers in Veteran neurodegenerative populations, few interventions have been developed, adapted, or tested to support the unique needs of caregivers of V/SMs with TBI. OBJECTIVE: This study will adapt and test an evidence-based, personalized, 6-session telehealth caregiver intervention, "Resources for Enhancing All Caregivers' Health" (REACH), to meet the unique needs of caregivers of V/SMs with TBI. If successful, a community-based participatory research team will develop an implementation plan to roll out REACH TBI across the national Veterans Affairs Polytrauma System of Care. METHODS: This mixed methods, crossover waitlist control clinical trial will use a Type 1 Hybrid Effectiveness-Implementation approach to adapt and then test the effects of REACH TBI on key TBI caregiver outcomes. RESULTS: This study was funded by the Department of Defense in September 2023. Participant enrollment and data collection will begin in 2024. CONCLUSIONS: If effective, REACH TBI will be the first evidence-based intervention for caregivers of V/SMs with TBI that can be scaled to implement across the Veterans Affairs Polytrauma System of Care and fill a notable gap in clinical services. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/57692.

Outbreak of multidrug-resistant Salmonella infections in people linked to pig ear pet treats, United States, 2015-2019: results of a multistate investigation.

Background: International distribution of contaminated foods can be a source of Salmonella infections in people and can contribute to the spread of antimicrobial-resistant bacteria across countries. We report an investigation led by the United States Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and state governmental officials into a multistate outbreak of salmonellosis linked to pig ear pet treats. Methods: Pig ear treats and companion dogs were tested for Salmonella by state officials and the FDA. Products were traced back to the country of origin when possible. Cases were defined as outbreak illnesses in people associated with one of seven Salmonella serotypes genetically related to samples from pig ear pet treats, with isolation dates from June 2015 to September 2019. Whole genome sequencing (WGS) of isolates was used to predict antimicrobial resistance. Findings: The outbreak included 154 human cases in 34 states. Of these, 107 of 122 (88%) patients reported dog contact, and 65 of 97 (67%) reported contact with pig ear pet treats. Salmonella was isolated from 137 pig ear treats, including some imported from Argentina, Brazil, and Colombia, and from four dogs. WGS predicted 77% (105/137) of human and 43% (58/135) of pig ear treat isolates were resistant to ≥3 antimicrobial classes. Interpretation: This was the first documented United States multistate outbreak of Salmonella infections linked to pig ear pet treats. This multidrug-resistant outbreak highlights the interconnectedness of human health and companion animal ownership and the need for zoonotic pathogen surveillance to prevent human illness resulting from internationally transported pet food products. Funding: Animal Feed Regulatory Program Standards award. Animal and product testing conducted by FDA Vet-LIRN was funded by Vet-LIRN infrastructure grants (PAR-22-063).