Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced 13C and 15N Solid-State NMR Spectroscopy.

Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1H longitudinal relaxation times (T1(1H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

Formed in context: A mixed-methods study of medical students' mindsets in an Eastern culture.

INTRODUCTION: Mindsets have become an important focus in the fields of social and cognitive psychology. When holding a growth mindset, people appear more likely to engage in hard work and effort to foster success, seeing setbacks as necessary for learning. When holding a fixed mindset, in contrast, people tend to believe success comes from innate ability, seeing setbacks as evidence of inability. As such, mindsets affect students' learning, resilience and personal development. There is little empirical evidence, however, regarding how medical students perceive mindsets and the fundamental determinants of mindset formation, especially in non-Western contexts. This study investigated medical students' mindsets and perceptions of mindset formation with the aim of broadening the cross-cultural understanding of self-theories. METHODS: Using a convergent mixed-methods approach at a medical school in China, the authors conducted a survey and four focus groups with medical students in first to third years. Quantitatively, we used the Dweck Mindset Scale to describe medical students' mindsets in the domains of intelligence and talent. Qualitatively, we analysed focus group data using a grounded theory approach to develop a descriptive model. RESULTS: Survey results included 464 responses for quantitative analysis. Multivariable regression found that Year 3 students had more fixed mindsets for intelligence and talent (p < 0.05) compared with Year 1 students. Rural students reported a more mixed mindset for intelligence compared to urban students (p < 0.05). Qualitative analysis of focus group data yielded four major categories: beliefs about mindsets, conceptualization of mindsets, achievement motivation and source of mindset formation. We developed a Mindset Basis Model to depict connections among the factors students perceived to influence mindset formation-intra- and interindividual factors; contextual factors; and micro-, meso- and macro-system factors-and students' motivation regarding achievement. CONCLUSION: The study describes medical students' mindsets for the domains of intelligence and talent and explores how they conceptualised these mindsets. The findings indicate that factors influencing mindsets do not operate in isolation but through intricate interactions among multilevel factors embedded within a context.

Applying self-determination theory to stem medical schools' clinical teacher sustainability crisis.

THE PROBLEM: Medical schools require highly skilled and committed clinical faculty to teach, assess, supervise and mentor students' clinical care. Medical education is facing a crisis in recruiting and sustaining these clinical teachers. Faced with multiple demands and responsibilities in fast-paced clinical environments, teachers may not have the time, resources or stamina to sustain these critical roles. Medical school leaders must commit to and provide structures and processes to attract, sustain and retain clinical teachers. CONCEPTUAL FRAMEWORK: The authors use the lens of self-determination theory to frame approaches to support teacher sustainability. Self-determination theory describes sources of human motivation. The theory and its evidence base characterise three human psychological needs: autonomy, competence, and relatedness. This theory can bridge individual psychological and institutional leadership perspectives to help medical school leaders anticipate and respond to their clinical teachers' needs. The authors propose three practical steps: practices to advance employee-centredness, processes to align individual and institutional values, and restructuring education to support clinical teachers' needs alongside student and patient needs. The authors describe limitations to this relational approach that focuses on leadership actions and consider individual agency as another key factor for sustainability. DISCUSSION: Medical school leaders can develop and apply theory-driven approaches to advance sustainability. Sustainability now and in the future requires careful attention to the needs of clinical teachers and to their relationships with and within medical schools.

Patient outcomes in a Longitudinal Integrated Clerkship: A systematic literature review.

CONTEXT: Patient-student relationships are at the heart of Longitudinal Integrated Clerkships (LICs). Outcomes for students and preceptors are beneficial, but patient outcomes remain unclear. This systematic literature review explored the current evidence base of patient outcomes in an LIC. Patient outcomes were defined as issues related to patient safety, clinical effectiveness or patient experience. METHODS: Seven bibliographic databases were searched. A wider search strategy included a hand search of three medical education journals' previous issues and backward/forward citation searching of included studies and of a relevant systematic review. Included studies were quality appraised and assessed for their strength and level of evidence. A qualitative data synthesis was performed. RESULTS: Databases searches identified 7237 titles. Following the removal of duplicates, titles and abstracts were reviewed against the inclusion criteria. Forty-eight studies had a full-text review. Nineteen met the inclusion criteria. Seven studies were included from the wider search strategy. From the 26 included studies, two major themes were identified. (1) 'A trusting patient-student relationship' contains the sub-themes: 'care and compassion', 'patient education and empowerment' and 'the loss of the student as 'my' doctor'. (2) 'The student acts as an agent of change for the patient' contains the sub-themes: 'patient advocacy', 'supporting the patient to navigate the healthcare system', 'communication between patient and healthcare professional' and 'enhancement of preceptors' care, healthcare services and communities'. CONCLUSIONS: LICs provide educational continuity allowing the creation of a trusting patient-student relationship. This relationship leads to students becoming agents of change for patients by enhancing patient outcomes. This review provides further evidence on the benefits of having an LIC as part of the medical education curricula and implications for its successful delivery. Further research is needed to explore educationally induced benefits for patients and look at objective assessments of patient health outcomes.

An exploratory study of goal orientations of traditional block and longitudinal integrated clerkship students.

BACKGROUND: Achievement goal theory links goal setting, motivation, and learning and describes three orientations: 'mastery' (seeking learning), 'performance' (seeking positive judgments), and 'performance-avoidance' (avoiding negative judgments). Mastery orientation is considered most adaptive. The authors investigated goal orientations of traditional block clerkship (TBC) and longitudinal integrated clerkship (LIC) students. METHODS: This was an exploratory study conducted at one US medical school. Three hundred and twenty students completed an anonymous survey consisting of three tools with validation evidence: Patterns of Adaptive Learning Survey, Task-choice Goal Measures, and Questionnaire Goal Choice Items. The authors analyzed the data using regression analyses, Chi-square, and Wilcoxon's rank-sum tests. RESULTS: While all students rated mastery items most highly on the five-point Likert scale (mean 4.58/5.00), LIC students rated performance-orientation lower (ß = -0.36, p = .04), chose personal mastery-orientation items more frequently (92% vs. 64.4%, p = .005), and perceived their learning environment as promoting less performance (ß = -0.60, p = .002) and performance-avoidance (ß = -0.78, p < .001) compared to TBC students. CONCLUSIONS: LIC and TBC students differed in their report of personal and clerkship goal orientations. These differences may inform educational design and future research to promote students' mastery orientation.

Psychological safety and accountability in longitudinal integrated clerkships: a dual institution qualitative study.

BACKGROUND: Psychological safety and accountability are frameworks to describe relationships in the workplace. Psychological safety is a shared belief by members of a team that it is safe to take interpersonal risks. Accountability refers to being challenged and expected to meet expectations and goals. Psychological safety and accountability are supported by relational trust. Relational continuity is the educational construct underpinning longitudinal integrated clerkships. The workplace constructs of psychological safety and accountability may offer lenses to understand students' educational experiences in longitudinal integrated clerkships. METHODS: We performed a qualitative study of 9 years of longitudinal integrated clerkship graduates from two regionally diverse programs-at Harvard Medical School and the University of North Carolina School of Medicine. We used deductive content analysis to characterize psychological safety and accountability from semi-structured interviews of longitudinal integrated clerkship graduates. RESULTS: Analysis of 20 graduates' interview transcripts reached saturation. We identified 109 discrete excerpts describing psychological safety, accountability, or both. Excerpts with high psychological safety described trusting relationships and safe learning spaces. Low psychological safety included fear and frustration and perceptions of stressful learning environments. Excerpts characterizing high accountability involved increased learning and responsibility toward patients. Low accountability included students not feeling challenged. Graduates' descriptions with both high psychological safety and high accountability characterized optimized learning and performance. CONCLUSIONS: This study used the workplace-based frameworks of psychological safety and accountability to explore qualitatively longitudinal integrated clerkship graduates' experiences as students. Graduates described high and low psychological safety and accountability. Graduates' descriptions of high psychological safety and accountability involved positive learning experiences and responsibility toward patients. The relational lenses of psychological safety and accountability may inform faculty development and future educational research in clinical medical education.

Faculty perspectives on facilitating medical students' longitudinal learning: A mixed-methods study.

INTRODUCTION: Medical students' longitudinal care of patients supports clinical learning and promotes patient-centredness. The literature presents little empirically derived guidance for faculty to facilitate students' longitudinal learning and care. Informed by the conceptual framework of relational learning, this study investigated faculty perspectives about longitudinal teaching, their strategies for facilitating students' longitudinal learning and perceived barriers and enablers. METHODS: Using a convergent mixed-methods approach at a single academic medical centre, the authors conducted a survey and two focus groups in 2018-2019 with faculty members teaching in three longitudinal clinical courses. Quantitative analyses included descriptive statistics and chi-square tests. Qualitative content analysis described deductive categories and identified inductive themes. RESULTS: Forty-three eligible faculty (69%) completed the survey. Ninety-one percent (n = 39) reported that teaching in a longitudinal model enhanced their experience as preceptors. Faculty described activities students performed to provide longitudinal care: spending time with patients independently (n = 38, 88%), making follow-up phone calls (n = 35; 81%) and participating in home- and community-based visits (n = 20, 47%), among others. Twelve faculty participated in two focus groups. Deductive analysis characterised strategies for facilitating students' longitudinal learning and barriers and enablers. Strategies included "encouraging students to follow patients," "faculty adaptability," "offering guidance and setting expectations," and "careful patient selection." Barriers included scheduling limitations, and enablers included student initiative. Inductive analysis identified two themes: faculty goals for students and faculty benefits from teaching. Goals included meaningful engagement with patients and their illness over time. Benefits from teaching included personal gratification, mentorship, and holistic student assessment. DISCUSSION: Our survey and focus group findings demonstrated positive faculty attitudes and experiences, characterised faculty goals and approaches, and identified elements of the educational context that hindered or facilitated longitudinal teaching and learning. This study's faculty perspectives build upon prior investigations of students' and patients' perspectives, offer teaching strategies, and may guide faculty development.

Hydrates of active pharmaceutical ingredients: A 35Cl and 2H solid-state NMR and DFT study.

This study uses 35Cl and 2H solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations to characterize the molecular-level structures and dynamics of hydrates of active pharmaceutical ingredients (APIs). We use 35Cl SSNMR to measure the EFG tensors of the chloride ions to characterize hydrated forms of hydrochloride salts of APIs, along with two corresponding anhydrous forms. DFT calculations are used to refine the crystal structures of the APIs and determine relationships between the 35Cl EFG tensors and the spatial arrangements of proximate hydrogen bonds, which are particularly influenced by interactions with water molecules. We find that the relationship between 35Cl EFG tensors and local hydrogen bonding geometries is complex, but meaningful structure/property relationships can be garnered through use of DFT calculations. Specifically, for every case in which such a comparison could be made, we find that the hydrate has a smaller magnitude of CQ than the corresponding anhydrous form, indicating a chloride ion environment with a ground-state electron density of higher spherical symmetry in the former. Finally, variable-temperature 35Cl and 2H SSNMR experiments on a deuterium-exchanged sample of the API cimetidine hydrochloride monohydrate are used to monitor temperature-dependent influences on the spectra that may arise from motional influences on the 35Cl and 2H EFG tensors. From the 2H SSNMR spectra, we determine that the motions of water molecules are characterized by jump-like motions about their C2 rotational axes that occur on timescales that are unlikely to influence the 35Cl central-transition (+1/2 ↔︎ -1/2) powder patterns (this is confirmed by 35Cl SSNMR). Together, these methods show great promise for the future study of APIs in their bulk and dosage forms, especially variable hydrates in which crystallographic water content varies with external conditions such as humidity.

Coproducing clinical curricula in undergraduate medical education: Student and faculty experiences in longitudinal integrated clerkships.

PURPOSE: Educational coproduction, in which learners partner with educators to create and improve their educational experiences, can facilitate student-centered medical education. Empirical descriptions of best practices for involving students in clinical curricular coproduction are needed. We aimed to understand faculty and student perspectives on methods, perceived benefits, and common barriers and solutions to clinical curricular coproduction. METHODS: We conducted an international mixed-methods study of clinical curricular coproduction in undergraduate medical education and longitudinal integrated clerkships specifically. Faculty and students identified through an international listserv received an electronic survey to identify methods, benefits, and challenges of clinical curricular coproduction. We conducted semi-structured interviews with a subset of survey participants. We present descriptive statistics for survey data and themes derived from inductive qualitative analysis. RESULTS: Two hundred forty-seven individuals (104 faculty; 143 students) representing 52 medical schools in eight countries completed the survey. Methods for clinical curricular coproduction ranged from informal, low-intensity learner involvement (e.g. verbal feedback) to formal, high-intensity learner involvement (e.g. committee membership). Perceived benefits included improvements in student-faculty relationships, program culture and design, and student development. Structural issues (e.g. scheduling) were the most common perceived barriers. CONCLUSIONS: Clinical curricular coproduction among faculty and students is perceived to enhance collaboration, enable curriculum change, and support students' professional development. Our study offers empirical guidance for involving students as partners in clinical curricular coproduction.

Patient perceptions of students in a longitudinal integrated clerkship in Taiwan: a qualitative study.

BACKGROUND: Longitudinal integrated clerkships (LICs) are a model of clinical education growing rapidly in Western contexts. LICs use educational continuity to benefits students' clinical learning and professional identity formation. Patient-centered care is a core component of medical professionalism in the West. To support patient-centered care, education leaders in Taiwan restructured clinical education and implemented the first longitudinal integrated clerkship in East Asia. We aimed to investigate patients' perceptions of longitudinal relationships with the LIC students within Taiwan's Confucian cultural and social context. METHODS: We invited patients or their family members who were cared for longitudinally by a LIC student to participate in the study. Participating patients or their family members undertook semi-structured interviews. We analyzed data qualitatively using a general inductive approach to identify themes in the patients' descriptions of their experiences interacting with the LIC students. RESULTS: Twenty-five patients and family members participated in interviews: 16 patients and 9 family members. Qualitative analysis of interview transcripts identified three themes from patients' experience receiving care from their LIC students: care facilitation, companionship, and empathy. To provide care facilitation, LIC students served as a bridge between the physicians and patients. Students served patients by reminding, consulting, tracking disease progression, and researching solutions for problems. To provide companionship, students accompanied patients interpersonally like a friend or confidant who listens and provides a presence for patients. To provide empathy, patients reported that students showed sincere concern for patients' experience, feelings, and mood. CONCLUSION: In our study, Taiwanese patients' perspectives of LIC students suggested the value of care facilitation, companionship, and empathy. We discuss these themes within the context of Confucian culture and the Taiwanese context of care.

Rapid Characterization of Formulated Pharmaceuticals Using Fast MAS 1H Solid-State NMR Spectroscopy.

Active pharmaceutical ingredients (APIs) can be prepared in many different solid forms and phases that affect their physicochemical properties and suitability for oral dosage forms. The development and commercialization of dosage forms require analytical techniques that can determine and quantify the API phase in the final drug product. 13C solid-state NMR (SSNMR) spectroscopy is widely employed to characterize pure and formulated solid APIs; however, 13C SSNMR experiments on dosage forms with low API loading are often challenging due to low sensitivity and interference from excipients. Here, fast magic angle spinning 1H SSNMR experiments are shown to be applicable for the rapid characterization of low drug load formulations. Diagnostic 1H SSNMR spectra of APIs within tablets are obtained by using combinations of frequency-selective saturation and excitation pulses, two-dimensional experiments, and 1H spin diffusion periods. Selective saturation pulses efficiently suppress the broad 1H SSNMR signals from the most commonly encountered excipients such as lactose and cellulose, allowing observation of high-frequency API 1H NMR signals. 1H SSNMR provides a 1-3 orders of magnitude reduction in experiment time compared to standard 13C SSNMR experiments, enabling diagnostic SSNMR spectra of dilute APIs within tablets to be obtained within minutes. The 1H SSNMR spectra can be used for quantification, provided calibrations are performed on a standard sample with known API loading.

Diffusion of innovation and longitudinal integrated clerkships: Results of the clerkship directors in internal medicine annual survey.

PURPOSE: Longitudinal integrated clerkships (LICs) are innovative educational models that emphasize medical student continuity with patients, preceptors, peers, and health systems. We characterize LIC growth in the US and interpret the growth using Rogers' Diffusion of Innovation Theory. METHODS: In 2015, we surveyed 123 US allopathic medical schools affiliated with Clerkship Directors in Internal Medicine (CDIM). The organization's annual survey was supplemented with questions aimed to quantify the number of current and planned LICs and to determine the intended purpose of starting LICs. RESULTS: Of the 94 (out of 123 possible) schools which were responding, 35 (37%) have at least one LIC of six months or greater; of these 20 are year-long. Nineteen schools are engaged in planning a new LIC or increasing the number of students in an LIC. At least 45 (48%) responding schools will have LICs in future years. Respondents report implementing LICs to foster continuity of care, support patient-centeredness, advance inter-professional education, and address workforce shortages. CONCLUSIONS: The number of LICs is increasing across the US. We considered the data through the lens of Diffusion of Innovation Theory, speculated that LIC growth has reached "critical mass," and considered why the LIC innovation may be self-sustaining.

Quantifying Disproportionation in Pharmaceutical Formulations with 35Cl Solid-State NMR.

Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra-wideline (UW) 35Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. 35Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within ±1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl- anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients.

In Pursuit of Educational Integrity: Professional Identity Formation in the Harvard Medical School Cambridge Integrated Clerkship.

Graduates of Harvard Medical School's Cambridge Integrated Clerkship (CIC) describe several core processes that may underlie professional identity formation (PIF): encouragement to integrate pre-professional and professional identities; support for learner autonomy in discovering meaningful roles and responsibilities; learning through caring relationships; and a curriculum and an institutional culture that make values explicit. The authors suggest that the benefits of educational integrity accrue when idealistic learners inhabit an educational model that aligns with their own core values, and when professional development occurs in the context of an institutional home that upholds these values. Medical educators should clarify and animate principles within curricula and learning environments explicitly in order to support the professional identity formation of their learners.

35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients.

In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H-35Cl broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H-13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.