The proprotein convertase BLI-4 promotes collagen secretion prior to assembly of the Caenorhabditis elegans cuticle.

Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.

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.

An investigation of an outbreak of Salmonella Typhimurium infections linked to cantaloupe - United States, 2022.

In 2022, the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and state health and regulatory partners investigated an outbreak of Salmonella enterica serovar Typhimurium infections linked to cantaloupes from southwest Indiana, resulting in 87 ill persons and 32 hospitalizations reported in 11 states. Epidemiologic and traceback evidence confirmed cantaloupe as the vehicle for these infections. Based on records collected by FDA, traceback of cantaloupe exposures for 14 ill people converged on a packing house in southwest Indiana, which supplied cantaloupe to eight of the 11 points of service where ill people purchased cantaloupe. Salmonella isolates were recovered from environmental samples collected by FDA from three growers and a packing house in southwest Indiana. Whole genome sequencing analyses of these isolates found that isolates collected from one grower matched the Salmonella Typhimurium outbreak strain, and samples collected from the other two growers and the packing house matched a 2020 Salmonella Newport outbreak strain. State and federal public health and agricultural partners identified potential conditions and practices that could have possibly resulted in the contamination of cantaloupe, including the presence of Salmonella spp. in on-farm, post-harvest, and off-farm environments. This is the third outbreak of salmonellosis confirmed to be linked to melons, sourced from southwest Indiana in the last decade. The 2012, 2020, and 2022 outbreaks of reoccurring and persisting strains of Salmonella illustrate the need for additional efforts to determine the source and extent of environmental contamination in the melon growing region of southwest Indiana and for outreach and education to help promote practices to reduce contamination of melons.

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.

Human Salmonellosis Outbreak Linked to Salmonella Typhimurium Epidemic in Wild Songbirds, United States, 2020-2021.

Salmonella infection causes epidemic death in wild songbirds, with potential to spread to humans. In February 2021, public health officials in Oregon and Washington, USA, isolated a strain of Salmonella enterica serovar Typhimurium from humans and a wild songbird. Investigation by public health partners ultimately identified 30 illnesses in 12 states linked to an epidemic of Salmonella Typhimurium in songbirds. We report a multistate outbreak of human salmonellosis associated with songbirds, resulting from direct handling of sick and dead birds or indirect contact with contaminated birdfeeders. Companion animals might have contributed to the spread of Salmonella between songbirds and patients; the outbreak strain was detected in 1 ill dog, and a cat became ill after contact with a wild bird. This outbreak highlights a One Health issue where actions like regular cleaning of birdfeeders might reduce the health risk to wildlife, companion animals, and humans.

Revisiting Feed Forward: Promoting a Student-Centered Approach to Education Handoffs, Remediation, and Clerkship Success.

Issue: Throughout medical school, and especially during clerkships, students experience changing work and learning environments and are exposed to new academic, interpersonal, and professional challenges unique to clinical learning. Given the siloed nature of clinical rotations, students often "fall through the cracks" and may repeatedly struggle through clerkships without support and coaching from which they would otherwise benefit. Many institutions have grappled with creating feed forward processes, that is, educational handoffs in which information is shared among faculty about struggling students with the intention of providing longitudinal support to ensure their success, while protecting students from negative bias that may follow them throughout the remainder of their medical school tenure. Evidence: Here, the authors describe the feed forward processes of four medical schools. Each school's process relies on close collaboration between course directors and deans to identify students and develop intervention plans. Course leadership and administration are typically the primary drivers for long-term follow-up with students. The number of participants in the process varies, with only one school directly involving students. Two schools hold larger, regularly scheduled meetings with up to 12 faculty present in their institution's feed forward process. Across these institutions, students can "graduate" from the feed forward process once they achieve competency in the areas of concern. Implications: The authors believe the most important outcome achieved is the formalization and adherence to a feed forward process. Thus, risk to students in the form of negative bias is mitigated by the flow of information, the extent to which information is available, and permitting students to be part of the process. These exemplars give insight into variable approaches to feed forward systems adopted by medical schools and demonstrate highly visible methodologies by which educational leadership empower students and educators toward a shared goal of student progress and achievement.

Revisiting the continuum of pharmacist prescriptive authority.

Pharmacists in all states have prescriptive authority in some form. We identify two broad categories of pharmacist prescribing: dependent and independent. There are gradients within these broad categories that allow us to chart pharmacist prescribing on a continuum from most restrictive to least restrictive. Independent prescribing has seen the most innovation in recent years at the state level, with at least three states adopting a "standard of care" prescribing framework that allows pharmacists to exercise broad prescriptive authority including for conditions that require a diagnosis. Each of the approaches to pharmacist prescriptive authority have perceived advantages and disadvantages as it relates to improving patient care.

Opportunities for pharmacist prescriptive authority of buprenorphine following passage of the Mainstreaming Addiction Treatment (MAT) Act.

In December 2022, Congress passed the Mainstreaming Addiction Treatment Act, which removed the federal legal barrier to pharmacist buprenorphine prescribing. As a result, each state can now decide whether or not to allow pharmacists to prescribe buprenorphine as an additional access point to reduce fatal opioid overdoses. At least 10 states allow pharmacists to prescribe controlled substances under collaborative practice agreements. Two states (California and Idaho) have also created pathways for independent prescribing of buprenorphine by pharmacists. Additional states should seek to enable pharmacists to prescribe buprenorphine to increase access to a proven beneficial treatment and help reduce fatal opioid overdoses.

Battling professional self-sabotage: Embracing standard of care as the future of pharmacy regulation.

Laws and regulations are intended to protect the public; however, overregulation of the profession can block initiatives focused on patient safety and public health. This article discusses the 3 main regulatory approaches to pharmacy practice: standard of care (SOC), bright line, and right touch. An SOC regulatory model supports practitioners delivering patient care within their scope of practice and clinical training. Patient safety is maintained by measuring care against other practitioners within the same practice setting while supporting practitioners practicing at the top of their clinical ability. Compared with bright line and right touch approaches, the SOC regulatory model provides the adaptability needed to respond to different practice scenarios and settings, thus increasing access to health care and opportunities for innovation. To have a lasting impact on the profession and support patients, all pharmacy professionals must be fluent in regulatory approaches and advocate for states to transition to SOC regulatory models.

"I Don't Trust It": Use of a Routine OSCE to Identify Core Communication Skills Required for Counseling a Vaccine-Hesitant Patient.

BACKGROUND: Vaccine hesitancy is challenging for clinicians and of increasing concern since COVID-19 vaccination rollout began. Standardized patients (SPs) provide an ideal method for assessing resident physicians' current skills, providing opportunity to practice and gain immediate feedback, while also informing evaluation of curriculum and training. As such, we designed and implemented an OSCE station where residents were tasked with engaging and educating a vaccine-hesitant patient. AIM: Describe residents' vaccine counseling practices, core communication and interpersonal skills, and effectiveness in meeting the objectives of the case. Explore how effectiveness in overcoming vaccine hesitancy may be associated with communication and interpersonal skills in order to inform educational efforts. SETTING: Annual OSCE at a simulation center. PARTICIPANTS: 106 internal medicine residents (51% PGY1, 49% PGY2). PROGRAM DESCRIPTION: Residents participated in an annual residency-wide, multi-station OSCE, one of which included a Black, middle-aged, vaccine-hesitant male presenting for a routine video visit. Residents had 10 min to complete the encounter, during which they sought to educate, explore concerns, and make a recommendation. After each encounter, faculty gave residents feedback on their counseling skills and reviewed best practices for effective communication on the topic. SPs completed a behaviorally anchored checklist (30 items across 7 clinical skill domains and 2 measures of trust in the vaccine's safety and resident) which will inform future curriculum. PROGRAM EVALUATION: Fifty-five percent (SD: 43%) of the residents performed well on the vaccine-specific education domain. PGY2 residents scored significantly higher on two of the seven domains compared to PGY1s (patient education/counseling-PGY1: 35% (SD: 36%) vs. PGY2: 52% (SD: 41%), p = 0.044 and activation-PGY1: 37% (SD: 45%) vs. PGY2: 59% (SD: 46%), p = 0.016). In regression analyses, education/counseling and vaccine-specific communication skills were strongly, positively associated with trust in the resident and in the vaccine's safety. A review of qualitative data from the SPs' perspective suggested that low performers did not use patient-centered communication skills. DISCUSSION: This needs assessment suggests that many residents needed in-the-moment feedback, additional education, and vaccine-specific communication practice. Our program plans to reinforce evidence-based practices physicians can implement for vaccine hesitancy through ongoing curriculum, practice, and feedback. This type of needs assessment is replicable at other institutions and can be used, as we have, to ultimately shed light on next steps for programmatic improvement.

A case of annular erythema of infancy accompanied by elevated tryptase.

Annular erythema of infancy (AEI) is characterized by self-limited eruptions of erythematous, annular to polycyclic patches and plaques, the etiology of which is thought to involve a hypersensitivity reaction to an unknown antigen. We present a case of AEI mistaken for systemic mastocytosis due to elevated serum tryptase. We were unable to find prior reports of an association between AEI and elevated tryptase in the literature.

Initial single surgeon evaluation comparing C-arm fluoroscopy with the Cirq robotic assistance device for instrumentation of the thoracolumbar spine.

OBJECTIVE: To compare our experience with pedicle screw insertion of the thoracolumbar spine utilizing the Cirq robot assistance device compared with traditional paradigm using fluoroscopy. METHODS: We prospectively collected data of patients undergoing pedicle screw instrumentation in the thoracolumbar spine performed by a single surgeon at three different centers. One center took delivery of the Cirq robotic assistance device. Remaining two centers used C-arm fluoroscopy. Demographic information, diagnosis, total OR time, intraoperative complications, unexpected return to the operating room, and hospital readmissions within 90 days was compared between the two cohorts. RESULTS: A total of 166 screws were placed during the study period. Forty percent were placed using the Cirq. Two thirds the patients had traumatic diagnoses with remaining degenerative spine disease. There were no misplaced pedicle screws in either group. While total OR time was longer in the Cirq cohort by 123 min (p = 0.04), actual procedural time was not statistically different (p = 0.11). Nonetheless there were also more hospital readmissions in the Cirq cohort compared with the C arm group (p = 0.04). CONCLUSIONS: Thoracolumbar screws inserted using C-arm fluoroscopy utilize less total operating room time with similar accuracy compared with the Cirq robotic assistance device. Further studies are warranted.

Pharmacy technician-administered immunizations: A five-year review.

In October 2020, the U.S. Department of Health and Human Services (HHS) issued guidance authorizing trained pharmacy technicians in all states to administer immunizations. Given that this action is temporary, it will be necessary for states to adopt their own legislation or regulations to sustain these efforts beyond the coronavirus pandemic. At least 11 different immunization administration training programs have emerged for pharmacy technicians. An increasing number of publications have emerged on pharmacy technician immunization administration, demonstrating the ability to train technicians and have them safely administer immunizations in practice. Supervising pharmacists reported initial hesitancy but strong acceptance of delegating this task after experience in practice. States should look to expand and make permanent the authority of pharmacy technicians to ensure these benefits can continue to be realized after the HHS guidance expires.

Developing sustainable workflows for community pharmacy-based SARS-CoV-2 testing.

BACKGROUND: The coronavirus disease Rapid Antigen Testing Expansion Program (Program) employed a drive-thru model to maximize pharmacy staff and the public's safety. OBJECTIVES: To quickly design, implement, and disseminate a pharmacy-based point-of-care testing program during a public health crisis. PRACTICE DESCRIPTION: Community pharmacies in Idaho were engaged in the state's public health efforts to boost severe acute respiratory syndrome coronavirus 2 testing statewide. Geographic location was a major recruitment factor. Two recruitment periods were held to extend the Program's reach into more remote underserved communities. PRACTICE INNOVATION: Program and pharmacy staff developed workflows and materials in an iterative process. Pharmacies received testing supplies. Program staff created e-Care plans for documentation and reimbursement and designed a Web portal for state reporting of positive rapid antigen test results. EVALUATION METHODS: Testing data (pharmacy location, patient insurance status, test type and results, number of submitted Medicaid claims) were captured in an online form. RESULTS: From September to December 2020, 13 pharmacies opted into a drive-thru, rapid antigen point-of-care testing and nasal swab for offsite testing program. A total of 2425 tests were performed. Approximately 29.4% of point-of-care tests were positive, and 70.6% required backup polymerase chain reaction confirmatory analysis. Patient insurance breakdown was 72.1% private, 8% Medicare, 11.4% Medicaid, and 8.5% uninsured. On average, pharmacies tested patients an average of 2.3 hours/day and 2.6 days/week. As a group, they provided 77.5 hours of testing per week statewide. Program pharmacies accounted for an average of 5.1% of testing across the entire state at the end of December 2020. CONCLUSION: Independent community-based pharmacies should be considered as partners in public health initiatives.

Organophosphate Esters in the Canadian Arctic Ocean.

Eleven organophosphate esters (OPEs) were detected in surface water and sediment samples from yearly sampling (2013-2018) in the Canadian Arctic. In water samples, ∑chlorinated-OPEs (Cl-OPEs) concentrations exceeded ∑non-chlorinated-OPEs (non-Cl-OPEs) with median concentrations of 10 ng L-1 and 1.3 ng L-1, respectively. In sediment samples, ∑Cl-OPEs and ∑nonchlorinated-OPEs had median concentrations of 4.5 and 2.5 ng g-1, respectively. High concentrations of OPEs in samples from the Mackenzie River plume suggest riverine discharge as an OPE source to the Canadian Arctic. The prevalence of OPEs at other sites is consistent with long-range transport. The OPE inventory of the Canadian Arctic Ocean representative of years 2013-2018 was estimated at 450-16,000 tonnes with a median ∑11OPE mass of 4100 tonnes with >99% of the OPE inventory estimated to be in the water column. These results highlight the importance of OPEs as water-based Arctic contaminants subject to long-range transport and local sources. The high OPE inventory in the water column of the Canadian Arctic Ocean points to the need for international regulatory mechanisms for persistent and mobile organic contaminants (PMOCs) that are not covered by the risk assessment criteria of the Stockholm Convention.

Gianotti-crosti syndrome in the setting of recent coronavirus disease-19 infection.

Since the onset of the COVID-19 pandemic, the growing body of literature has largely focused on the adult population. Reported symptoms among children appear to be consistent with those in adults, including fever, respiratory symptoms, and gastrointestinal symptoms, though children may experience an overall milder disease course. Viral exanthems with possible association to COVID-19 have been reported in pediatric patients. We describe a 10-month-old boy with Gianotti-Crosti syndrome in the setting of recent SARS-CoV-2 RT-PCR positive testing to increase physician awareness and add to the collection of cutaneous manifestations of COVID-19.

Reimbursement for pharmacist-provided health care services: A multistate review.

OBJECTIVE(S): To better understand individual state approaches to reimbursement for pharmacist-provided health care services, we sought to (1) review existing statutes and regulations on pharmacist reimbursement from select states (Alaska, California, Idaho, New Mexico, Oregon, and Washington) and (2) suggest approaches to changing state statutes and regulations to allow for reimbursement. METHODS: We reviewed approaches taken by 4 states that currently allow for direct reimbursement of pharmacist-provided health services and 2 states that are in process. Washington requires commercial health plans to credential and privilege pharmacists as health care providers deeming reimbursement and coverage disparities among providers as compensation discrimination. RESULTS: Oregon does not require insurers to provide payment but requires pharmacists to contract and credential with each individual insurer, without the mandate for payment. In California, pharmacists receive 85% of the established fee schedule that physicians receive for equivalent services, and payment is issued to the pharmacy, not the individual pharmacist. California and New Mexico both only allow specified pharmacies or pharmacists to bill (advanced credentials or a tiered licensing model). In Alaska, scope and payor regulations align to allow compensation for covered services; however, insurance credentialing portals are not configured to enroll pharmacists as billing providers. In May 2020, pharmacists were added as nonphysician ordering, referring, and prescribing providers in the Idaho Medicaid basic plan regulations, and licensed pharmacists with national provider identification numbers were auto-enrolled. CONCLUSION: The states we reviewed took different approaches on the basis of their established statutes and regulations (pharmacy, public and private insurance), resulting in variability in compensated services and reimbursement. An intentional alignment of statutes, regulations, and scope of practice is required to support reimbursement and sustainability of services.