The Effects of poly-GA and poly-PR C9orf72 Dipeptide Repeats on Sleep Patterns in Drosophila melanogaster.

C9orf72 is the most common familial gene associated with amyotrophic lateral sclerosis (ALS). Dipeptide repeats (DPRs) encoded by an expanded nucleotide repeat sequence in the C9orf72 gene were found in the sleep-related neurons of patients, indicating a role of DPRs in ALS-associated sleep disruptions. Poly-GA or poly-PR DPRs were expressed in male Drosophila melanogaster to study their effect on sleep . Poly-PR expression caused sleep disruptions while poly-GA expression did not. This study validates the use of Drosophila as an in vivo model system for exploring the roles of DPRs in perturbing the underlying molecular mechanisms in sleep regulation.

Practicing Confidence: An Autoethnographic Exploration of the First Years as Physicians.

Phenomenon: Every year is heralded with a cohort of newly-minted medical school graduates. Through intense residency training and supervision, these learners gradually develop self-assurance in their newfound skills and ways of practice. What remains unknown, however, is how this confidence develops and on what it is founded. This study sought to provide an insider view of this evolution from the frontline experiences of resident doctors. Approach: Using an analytic collaborative autoethnographic approach, two resident physicians (Internal Medicine; Pediatrics) documented 73 real-time stories on their emerging sense of confidence over their first two years of residency. A thematic analysis of narrative reflections was conducted iteratively in partnership with a staff physician and a medical education researcher, allowing for rich, multi-perspective input. Reflections were analyzed and coded thematically and the various perspectives on data interpretation were negotiated by consensus discussion. Findings: In the personal stories and experiences shared, we take you through our own journey and development of confidence, which we have come to appreciate as a layered and often non-linear process. Key moments include fears in the face of the unknown; the shame of failures (real or perceived); the bits of courage gained by everyday and mundane successes; and the emergence of our personal sense of growth and physicianship. Insights: Through this work, we - as two Canadian resident physicians - have ventured to describe a longitudinal trajectory of confidence from the ground up. Although we enter residency with the label of 'physician,' our clinical acumen remains in its infancy. We graduate from residency still as physicians, but decidedly different in terms of our knowledge, attitudes, and skills. We sought to capitalize on the vulnerability and authenticity inherent in autoethnography to enrich our collective understanding of confidence acquisition in the resident physician and its implications for the practice of medicine.

Thresholds of becoming: an exploration of threshold concepts as a means to support professional identity formation in competency-based curricula.

Inherent in every clinical preceptor's role is the ability to understand the learning needs of individual trainees, enabling them to meet their potential. Competency-based medical education frameworks have been developed to this end, but efforts to identify behaviours and activities that define competence are based on mapping knowledge, skills and ability, which can be difficult to integrate into a comprehensive picture of who the trainee is becoming. Professional identity formation, in contrast, prioritizes attention to who trainees are becoming, but provision of detailed guidance to preceptors on how to best support this form of development is challenging. The tension that results limits our ability to optimally support learners as strengths in competency development may mask professional identity development gaps and vice versa. To address this tension, this paper examines how the theory of threshold concepts - troublesome ideas that, once appreciated, fundamentally change how you understand and approach a particular activity - can shine light on professional identity formation and its relationship with developing competence. The recognition and identification of threshold concepts is offered as a means to improve our ability to identify, discuss and support behaviours and actions that impact the learner's capacity to act competently as they develop their identity at various stages of training.

A multiadjuvant polysaccharide-amino acid-lipid (PAL) subunit nanovaccine generates robust systemic and lung-specific mucosal immune responses against SARS-CoV-2 in mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, which are essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters could overcome the shortcomings of parenteral vaccines and enhance pre- existing systemic immunity. Here we present a new protein subunit nanovaccine using multiadjuvanted (e.g. RIG-I: PUUC, TLR9: CpG) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL- NPs, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lung, and showed robust systemic humoral immunity. Interestingly, as a purely intranasal vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. Our data suggest that PUUC+CpG PAL-NP subunit vaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung.

Messenger RNA has now been used to vaccinate millions of people. However, the diversity of pulmonary pathologies, including infections, genetic disorders, asthma and others, reveals the lung as an important organ to directly target for future RNA therapeutics and preventatives. Here we report the screening of 166 polymeric nanoparticle formulations for functional delivery to the lungs, obtained from a combinatorial synthesis approach combined with a low-dead-volume nose-only inhalation system for mice. We identify P76, a poly-ß-amino-thio-ester polymer, that exhibits increased expression over formulations lacking the thiol component, delivery to different animal species with varying RNA cargos and low toxicity. P76 allows for dose sparing when delivering an mRNA-expressed Cas13a-mediated treatment in a SARS-CoV-2 challenge model, resulting in similar efficacy to a 20-fold higher dose of a neutralizing antibody. Overall, the combinatorial synthesis approach allowed for the discovery of promising polymeric formulations for future RNA pharmaceutical development for the lungs.

Goal co-construction and dialogue in an internal medicine longitudinal coaching programme.

BACKGROUND: Longitudinal coaching in residency programmes is becoming commonplace and requires iterative and collaborative discussions between coach and resident, with the shared development of goals. However, little is known about how goal development unfolds within coaching conversations over time and the effects these conversations have. We therefore built on current coaching theory by analysing goal development dialogues within resident and faculty coaching relationships. METHODS: This was a qualitative study using interpretive description methodology. Eight internal medicine coach-resident dyads consented to audiotaping coaching meetings over a 1-year period. Transcripts from meetings and individual exit interviews were analysed thematically using goal co-construction as a sensitising concept. RESULTS: Two themes were developed: (i) The content of goals discussed in coaching meetings focused on how to be a resident, with little discussion around challenges in direct patient care, and (ii) co-construction mainly occurred in how to meet goals, rather than in prioritising goals or co-constructing new goals. CONCLUSIONS: In analysing goal development in the coach-resident relationships, conversations focused mainly around how to manage as a resident rather than how to improve direct patient care. This may be because academic coaching provides space separate from clinical work to focus on the stage-specific professional identity development of a resident. Going forward, focus should be on how to optimise longitudinal coaching conversations to ensure co-regulation and reflection on both clinical competencies and professional identity formation.

Nanoparticle-delivered TLR4 and RIG-I agonists enhance immune response to SARS-CoV-2 subunit vaccine.

Despite success in vaccinating populations against SARS-CoV-2, concerns about immunity duration, continued efficacy against emerging variants, protection from infection and transmission, and worldwide vaccine availability remain. Molecular adjuvants targeting pattern recognition receptors (PRRs) on antigen-presenting cells (APCs) could improve and broaden the efficacy and durability of vaccine responses. Native SARS-CoV-2 infection stimulates various PRRs, including toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors. We hypothesized that targeting PRRs using molecular adjuvants on nanoparticles (NPs) along with a stabilized spike protein antigen could stimulate broad and efficient immune responses. Adjuvants targeting TLR4 (MPLA), TLR7/8 (R848), TLR9 (CpG), and RIG-I (PUUC) delivered on degradable polymer NPs were combined with the S1 subunit of spike protein and assessed in vitro with isogeneic mixed lymphocyte reactions (isoMLRs). For in vivo studies, the adjuvant-NPs were combined with stabilized spike protein or spike-conjugated NPs and assessed using a two-dose intranasal or intramuscular vaccination model in mice. Combination adjuvant-NPs simultaneously targeting TLR and RIG-I receptors (MPLA+PUUC, CpG+PUUC, and R848+PUUC) differentially induced T cell proliferation and increased proinflammatory cytokine secretion by APCs in vitro. When delivered intranasally, MPLA+PUUC NPs enhanced CD4+CD44+ activated memory T cell responses against spike protein in the lungs while MPLA NPs increased anti-spike IgA in the bronchoalveolar (BAL) fluid and IgG in the blood. Following intramuscular delivery, PUUC NPs induced strong humoral immune responses, characterized by increases in anti-spike IgG in the blood and germinal center B cell populations (GL7+ and BCL6+ B cells) in the draining lymph nodes (dLNs). MPLA+PUUC NPs further boosted spike protein-neutralizing antibody titers and T follicular helper cell populations in the dLNs. These results suggest that protein subunit vaccines with particle-delivered molecular adjuvants targeting TLR4 and RIG-I could lead to robust and unique route-specific adaptive immune responses against SARS-CoV-2.

Genetic analyses of circulating PUFA-derived mediators identifies heritable dihydroxyeicosatrienoic acid species.

Estimates of heritability are the first step in identifying a trait with substantial variation due to genetic factors. Large-scale genetic analyses can identify the DNA variants that influence the levels of circulating lipid species and the statistical technique Mendelian randomisation can use these DNA variants to address potential causality of these lipids in disease. We estimated the heritability of plasma eicosanoids, octadecanoids and docosanoids to identify those lipid species with substantial heritability. We analysed plasma lipid mediators in 31 White British families (196 participants) ascertained for high blood pressure and deeply clinically and biochemically phenotyped over a 25-year period. We found that the dihydroxyeicosatrienoic acid (DHET) species, 11,12-DHET and 14,15-DHET, products of arachidonic acid metabolism by cytochrome P450 (CYP) monooxygenase and soluble epoxide hydrolase (sEH), exhibited substantial heritability (h2 = 33%-37%; Padj<0.05). Identification of these two heritable bioactive lipid species allows for future large-scale, targeted, lipidomics-genomics analyses to address causality in cardiovascular and other diseases.

Monitoring the Sialome on Human Immune Cells.

The sialome or display of sialic acids on the surface of human immune cells can vary according to immune response and activation state. Here, human peripheral blood mononuclear cells (PBMCs) were isolated and activated with anti-CD3 antibody and the cell surface sialome was quantified using a combination of click chemistry, confocal microscopy and flow cytometry techniques. Carbohydrate click chemistry was used to detect and measure the incorporation of an azido-m65odified sialic acid precursor molecule, N-acetylmannosamine (ManNaz) sugar into the PBMC surface sialome. Incorporation of sialic acid into the PBMC glycocalyx was visualized using copper-catalyzed click conjugation of Alexa 488 alkyne and confocal microscopy and further quantified using flow cytometry. The use of these methods indicate that regulating the sialome content on the surface of activated immune cells may be monitored during immunomodulatory responses and anti-inflammatory therapies.

Automated Digital Notification of COVID-19 Diagnoses Through Text and Email Messaging - North Carolina, December 2020-January 2021.

During October 3, 2020-January 9, 2021, North Carolina experienced a 400% increase in daily reported COVID-19 cases (1). To handle the increased number of cases and rapidly notify persons receiving a positive SARS-CoV-2 test result (patients), North Carolina state and local health departments moved from telephone call notification only to telephone call plus automated text and email notification (digital notification) beginning on December 24, 2020. Overall, among 200,258 patients, 142,975 (71%) were notified by telephone call or digital notification within the actionable period (10 days from their diagnosis date)* during January 2021, including at least 112,543 (56%) notified within 24 hours of report to North Carolina state and local health departments, a significantly higher proportion than the 25,905 of 175,979 (15%) notified within 24 hours during the preceding month (p<0.001). Differences in text notification by age, race, and ethnicity were observed. Automated digital notification is a feasible, rapid and efficient method to support timely outreach to patients, provide guidance on how to isolate, access resources, inform close contacts, and increase the efficiency of case investigation staff members.

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat.

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.

Experiential learning, collaboration and reflection: key ingredients in longitudinal faculty development.

BACKGROUND: Longitudinal faculty development (LFD) may allow for increased uptake of teaching skills, especially in a forum where teachers can reflect individually and collectively on the new skills. However, the exact processes by which such interventions are effective need further exploration. METHODS: This qualitative study examined an LFD initiative teaching a novel feedback approach attended by five family practice physicians. The initiative began with two 1.5-hour workshops: Goal-Oriented Feedback (as the teaching skill to be developed) and Narrative Reflection (as the tool to support personal reflection on the skill being learned). Over the subsequent six-months, the five participants iteratively applied the feedback approach in their teaching and engaged in narrative reflection at four 1-hour group sessions. Transcripts from the group discussions and exit interviews were analyzed using thematic analysis. RESULTS: Iteratively trialing, individually reflecting on, and collectively exploring efforts to implement the new feedback approach resulted in the development of a learning community among the group. This sense of community created a safe space for reflection, while motivating ongoing efforts to learn the skill. Individual pre-reflection prepared individuals for group co-reflection; however, written narratives were not essential. CONCLUSION: LFD initiatives should include an emphasis on ensuring opportunities for iterative attempts of teaching skills, guided self-reflection, and collaborative group reflection and learning to ensure sustainable change to teaching practices.

CONTEXTE: La formation professorale longitudinale (FPL) peut faciliter l'acquisition d'habiletés pédagogiques, surtout dans le cadre d'un forum où les enseignants peuvent réfléchir individuellement et collectivement à ces nouvelles habiletés. Cependant, les processus exacts qui rendent ces interventions efficaces doivent être explorés davantage. MÉTHODES: Cette étude qualitative examine une initiative de FPL qui comprend l'enseignement d'une nouvelle approche de rétroaction à laquelle ont participé cinq médecins de famille. L'initiative a commencé avec la tenue de deux ateliers d'une heure et demie, le premier sur la rétroaction axée sur les objectifs (l'habileté d'enseignement à développer) et le deuxième sur la réflexion narrative (comme outil pour soutenir la réflexion personnelle sur cette habileté en apprentissage). Au cours des six mois suivants, les cinq participants ont appliqué de manière itérative l'approche de la rétroaction dans leur enseignement et se sont livrés à une réflexion narrative lors de quatre séances de groupe d'une heure. Des transcriptions des discussions de groupe et des entretiens de clôture ont fait l'objet d'une analyse thématique. RÉSULTATS: L'expérimentation itérative, la réflexion individuelle et l'exploration collective des efforts de mise en œuvre de la nouvelle approche de rétroaction ont permis de développer une communauté d'apprentissage au sein du groupe. Ce sentiment de communauté a créé un environnement sûr pour la réflexion, tout en motivant les efforts continus pour apprendre l'habileté. La préréflexion individuelle préparait les participants à la co-réflexion de groupe; cependant, les récits écrits n'étaient pas essentiels. CONCLUSION: Les initiatives de FPL devraient mettre l'emphase sur les occasions de mise en application itérative des habiletés d'enseignement, d'autoréflexion guidée et de réflexion et d'apprentissage collaboratifs en groupe pour assurer un changement durable des pratiques d'enseignement.

Capturing the Moments: An Autoethnographic Exploration of Self-Preservation in Clerkship.

PhenomenonFor most medical students, clerkship represents a transitional phase into the 'real world' of medicine. This transition is often accompanied by significant mental stressors, burnout, and empathy decline. Educator led resilience curricula designed to support students during this critical period often focus on teaching generalized strategies to promote wellness and lack the student input and perspective in their development. Thus, they may be of minimal value when learners are faced with acute moments of challenge and distress in their day-to-day work. The following project seeks to provide an insider view on the experience, interpretation, and response to these moments of challenge and distress from the frontline perspective of clinical clerks. Approach: Using collaborative autoethnography, two medical students documented 85 reflections on their emerging professional identity over the course of a core clerkship year. A narrative analysis was conducted iteratively in partnership with a staff internist and a medical education researcher experienced in autoethnography, allowing for robust multi-perspective input. Reflections were analyzed and coded thematically; disagreements were resolved by consensus discussion. Findings: A key theme of the reflections was self-preservation, conceptualized within two principal contexts: (i) Clerk-patient relationships, wherein we found ourselves in emotionally difficult situations; and (ii) Clerk-preceptor relationships, in which self-preservation manifested through a series of self-protective mechanisms. Insights: The practice of self-preservation is understood as the conscious act of boundary-setting and psychological defense in situations that pose a real (or perceived) threat to the clerk's wellbeing. At best, self-preservation serves as a temporary compromise to the stressors and burnout of clerkship. We speculate, however, that, left unchecked, acts of self-preservation may lead to habitual selfishness and apathy, qualities that are in diametric opposition to those expected of future physicians, and may manifest later (when these learners progress through the hierarchy) as the unprofessional behaviors that perpetuate the cycle of the hidden curriculum.

STAR particles for enhanced topical drug and vaccine delivery.

Drug delivery to the skin is highly constrained by the stratum corneum barrier layer1. Here, we developed star-shaped particles, termed STAR particles, to dramatically increase skin permeability. STAR particles are millimeter-scale particles made of aluminum oxide or stainless steel with micron-scale projections designed to create microscopic pores across the stratum corneum. After gentle topical application for 10 s to porcine skin ex vivo, delivery of dermatological drugs and macromolecules, including those that cannot be given topically, was increased by 1 to 2 orders of magnitude. In mice treated with topical 5-fluorouracil, use of STAR particles increased the efficacy of the drug in suppressing the growth of subcutaneous melanoma tumors and prolonging survival. Moreover, topical delivery of tetanus toxoid vaccine to mice using STAR particles generated immune responses that were at least as strong as delivery of the vaccine by intramuscular injection, albeit at a higher dose for topical than intramuscular vaccine administration. STAR particles were well tolerated and effective at creating micropores when applied to the skin of human participants. Use of STAR particles provides a simple, low-cost and well-tolerated method for increasing drug and vaccine delivery to the skin and could widen the range of compounds that can be topically administered.

Your Goals, My Goals, Our Goals: The Complexity of Coconstructing Goals with Learners in Medical Education.

Phenomenon: Despite a long-standing recognition of the importance of learning goals in feedback, there has been relatively little research on how to address mismatches between learner goals and preceptor goals in medical education. Our study addresses this gap by reporting on challenges and strategies around goal coconstruction as identified by clinical educators who were learning and attempting to implement a goal-oriented feedback approach in their own teaching contexts. Approach: We employed a qualitative, design-based research methodology to study how 5 clinician educators incorporated goal-oriented feedback into their teaching practice. Participants attended workshops on goal-oriented feedback and reflective writing. They then narratively reflected over a 6-month period on their attempts with goal-oriented feedback and shared these reflections in periodic facilitated group discussions. Themes were developed using iterative thematic analysis of group discussions and individual exit interviews. Findings: Participants identified several benefits of goal setting in all environments. They perceived improved rapport with learners and developed empathy for the vastness of learner goals. However, they experienced several struggles especially when learner and preceptor goals did not match. These included (a) how to address learner goals that were not easily amenable to a coconstruction, (b) how to coconstruct goals while actively running a clinical practice, and (c) how to remain learner centered while raising preceptor goals based on perceived gaps. Insights: Mismatches between learner and preceptor goals are inevitable and frequent. Preceptors must find ways to coconstruct goals with learners in various learning environments. That said, in enacting goal-oriented feedback, preceptors are effectively using feedback throughout the teaching and learning interaction to coconstruct the learning environment, resulting in improved rapport with learners and emphasizing why it is important to focus feedback around goals.

Pharmaceutical jewelry: Earring patch for transdermal delivery of contraceptive hormone.

Lack of adherence to medication dosing schedules is a significant cause of morbidity and mortality with large associated financial costs. This is especially true for contraceptive hormones, which provide almost perfect prevention of pregnancy when used correctly, but have significant failure rates in typical use, due largely to poor adherence. To increase medication acceptability and adherence, we introduce pharmaceutical jewelry, in which a transdermal patch is incorporated into jewelry worn on skin. To demonstrate the approach, we incorporated transdermal patches containing the contraceptive hormone levonorgestrel (LNG) into an earring, a ring, a necklace, and a wrist watch. Transdermal delivery of LNG from earring patches across porcine skin ex vivo achieved a steady state flux of 1.7 µg/cm2·h. Pharmacokinetic analysis in hairless rats yielded LNG delivery rates that maintained serum LNG levels near 1500 pg/ml throughout the 1-week patch application period, which is well above the human contraceptive threshold concentration of 200 pg/ml. When patches were applied cyclically for 16 h on and 8 h off to simulate earring removal at night, serum LNG concentrations dipped during off periods, but remained well above the human contraceptive threshold. Earring patches were well tolerated by the rats. We conclude that pharmaceutical jewelry can provide a novel method of drug delivery, especially for contraceptive hormones, that has the potential to improve acceptability and increase medication adherence.

Rheumatoid arthritis reprograms circadian output pathways.

OBJECTIVE: We applied systems biology approaches to investigate circadian rhythmicity in rheumatoid arthritis (RA). METHODS: We recruited adults (age 16-80 years old) with a clinical diagnosis of RA (active disease [DAS28 > 3.2]). Sleep profiles were determined before inpatient measurements of saliva, serum, and peripheral blood mononuclear leukocytes (PBML). Transcriptome and proteome analyses were carried out by RNA-SEQ and LC-MS/MS. Serum samples were analysed by targeted lipidomics, along with serum from mouse collagen induced-arthritis (CIA). Bioinformatic analysis identified RA-specific gene networks and rhythmic processes differing between healthy and RA. RESULTS: RA caused greater time-of-day variation in PBML gene expression, and ex vivo stimulation identified a time-of-day-specific RA transcriptome. We found increased phospho-STAT3 in RA patients, and some targets, including phospho-ATF2, acquired time-of-day variation in RA. Serum ceramides also gained circadian rhythmicity in RA, which was also seen in mouse experimental arthritis, resulting from gain in circadian rhythmicity of hepatic ceramide synthases. CONCLUSION: RA drives a gain in circadian rhythmicity, both in immune cells, and systemically. The coupling of distant timing information to ceramide synthesis and joint inflammation points to a systemic re-wiring of the circadian repertoire. Circadian reprogramming in response to chronic inflammation has implications for inflammatory co-morbidities and time-of-day therapeutics.

Working in the dead of night: exploring the transition to after-hours duty.

CONTEXT: Transitions, although often difficult, represent integral components of medical training. New postgraduate trainees (first-year residents) find themselves in an especially challenging transition as they are expected to fulfil both learning and service expectations concurrently. Workplace learning theory has been suggested as a lens through which to understand this unique educational, yet service-oriented, role. This tension may be further amplified overnight when residents are on-call with little to no support. OBJECTIVES: The aims of this study were to explore the transition from medical student to resident with respect to the on-call experience, and to provide theory-based suggestions to enhance learning during this unique transition. METHODS: We conducted an interpretivist qualitative study by interviewing eight medical students and 10 first-year residents from six different specialty training programmes across four academic sites. Each semi-structured interview was transcribed verbatim and anonymised. Resident interview transcripts were initially coded for major themes, after which medical student interview transcripts were coded for consistencies and discrepancies. RESULTS: Four interrelated themes were identified in students' and residents' descriptions of on-call experiences: (i) shift in responsibility; (ii) supervisory support; (iii) contextual conditions, and (iv) clarity of expectations. Generally, students were not able to anticipate the challenges they would face as residents on-call, and residents perceived the transition as sudden with little emphasis placed on learning. CONCLUSIONS: First-year residents face multiple challenges during on-call, which may prevent optimal learning in this setting. These challenges are amplified by the large gap between the respective roles of medical students and residents. We identified promoters of and barriers to effective learning in this environment and, by using workplace learning theory, provide recommendations for how we might be able to enhance medical students' preparation for and first-year residents' learning during experiences of being on-call.