Multicenter Study of Optional In-Person Visits to Residency Programs After Virtual Interviews.

Background Compared to in-person recruitment, virtual interviewing reduces costs and promotes equity. However, many residency applicants believe that visiting programs helps inform their rank decisions. Objective We assessed the feasibility of and stakeholder opinions about optional in-person visits after virtual interviewing and program rank list finalization. Methods Six internal medicine residency programs conducted virtual recruitment in 2022-2023 and finalized their rank lists 4 weeks before the deadline. Applicants were invited for optional in-person visits after program rank list finalization. Interviewed applicants, program directors, and program administrators were given surveys that included 7-17 questions and employed "skip logic," discrete answers (eg, "yes/no/unsure" or multiple choice), and open-ended questions. Survey questions assessed stakeholders' opinions about the value, equity, and potential downsides of this recruitment process. Results Participating programs interviewed an average of 379 applicants (range 205-534) with 39 (10.3% [39 of 379], range 7.9%-12.8% [33 of 420-51 of 397]) applicants completing in-person visits. Of 1808 interviewed applicants, 464 responded to the survey (26%); 88% (407 of 464) believe a similar optional in-person visit should be offered next year, 75% (347 of 464) found this process equitable, but only 56% (258 of 464) trusted programs not to change their rank lists. Nearly all who attended an in-person visit (96.5%, 109 of 113) found it valuable. All program directors liked the optional in-person visit and believe future applicants should be offered similar in-person visits. Conclusions A large majority of participating applicants and program directors believe that in-person visits should be offered after program rank list finalization. The majority of respondents felt this recruitment process was equitable.

Characterization of myeloproliferative neoplasms in the paediatric and young adult population.

The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%).

Assessing Antigen-Adjuvant Complex Stability Against Physical Stresses By wNMR.

This study applies an emerging analytical technology, wNMR (water proton nuclear magnetic resonance), to assess the stability of aluminum adjuvants and antigen-adjuvant complexes against physical stresses, including gravitation, flow and freeze/thaw. Results from wNMR are verified by conventional analytical technologies, including static light scattering and microfluidic imaging. The results show that wNMR can quickly and noninvasively determine whether an aluminum adjuvant or antigen-adjuvant complex sample has been altered by physical stresses.

Cirrhosis.

Cirrhosis is a chronic condition resulting from inflammation and fibrosis of the liver. Patients with cirrhosis may have a myriad of physical examination findings that reflect the severity of the underlying liver disease. Although many signs and symptoms related to cirrhosis are nonspecific, such as abdominal pain, nausea, and malaise, some findings are more specific and point to complications of liver disease. In this article, key physical findings in patients with cirrhosis, including hepatomegaly, splenomegaly, jaundice, ascites, encephalopathy, dilated abdominal wall veins, spider nevi, palmar erythema, and others, are discussed.

Early Pre-clerkship Clinical Skills Assessments Predict Clerkship Performance.

Introduction: Assessment of medical students' clinical skills (CS) remains a challenge. Little is known about early predictors of future CS performance. This study examines the relationship between students' pre-clerkship clinical skills (PCCS) performance and year 3 clerkship performance measures. Methods: The authors performed a retrospective analysis of four medical student cohorts who matriculated between 2014 and 2017 and participated in a longitudinal pre-clerkship CS curriculum. A total of 440 students were included in the analyses. Students' clinical skills were assessed through a series of PCCS exams, each consisting of a single standardized patient encounter. First-year PCCS exams assessed history taking, physical examination, professionalism, and communication skills; second-year PCCS exams also assessed clinical documentation and clinical reasoning skills. Evaluators assigned a grade of "satisfactory," "borderline," or "unsatisfactory" for each skill set. Regression analyses compared year 3 performance outcomes between students with one or more "unsatisfactory" or "borderline" PCCS skill set grades and students assessed as "satisfactory" for all PCCS skill set assessments. Results: Thirty-two percent (n = 140) of the 440 students had at least one borderline or unsatisfactory (US) PCCS skill set grade. These students performed significantly worse on year 3 National Board of Medical Examiner subject exams, workplace-based clinical performance evaluations, and overall year 3 performance compared to students who passed all PCCS exam components. In addition, a higher percentage of students with PCCS performance deficiencies failed the United States Medical Licensing Examination Step 2 CS exam on the first attempt versus students who passed all PCCS exam components. Conclusions: PCCS exam performance at our institution aligned with future student performance on multiple year 3 clerkship outcome measures. This pre-clerkship performance data can be used to identify at-risk students who would benefit from additional resources to achieve competency in the clerkship environment and future medical training. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01519-8.

HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression.

Myeloproliferative neoplasms (MPNs) transform to myelofibrosis (MF) and highly lethal acute myeloid leukemia (AML), although the actionable mechanisms driving progression remain elusive. Here, we elucidate the role of the high mobility group A1 (HMGA1) chromatin regulator as a novel driver of MPN progression. HMGA1 is upregulated in MPN, with highest levels after transformation to MF or AML. To define HMGA1 function, we disrupted gene expression via CRISPR/Cas9, short hairpin RNA, or genetic deletion in MPN models. HMGA1 depletion in JAK2V617F AML cell lines disrupts proliferation, clonogenicity, and leukemic engraftment. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2V617F mice, decreasing erythrocytosis, thrombocytosis, megakaryocyte hyperplasia, and expansion of stem and progenitors, while preventing splenomegaly and fibrosis within the spleen and BM. RNA-sequencing and chromatin immunoprecipitation sequencing revealed HMGA1 transcriptional networks and chromatin occupancy at genes that govern proliferation (E2F, G2M, mitotic spindle) and cell fate, including the GATA2 master regulatory gene. Silencing GATA2 recapitulates most phenotypes observed with HMGA1 depletion, whereas GATA2 re-expression partially rescues leukemogenesis. HMGA1 transactivates GATA2 through sequences near the developmental enhancer (+9.5), increasing chromatin accessibility and recruiting active histone marks. Further, HMGA1 transcriptional networks, including proliferation pathways and GATA2, are activated in human MF and MPN leukemic transformation. Importantly, HMGA1 depletion enhances responses to the JAK2 inhibitor, ruxolitinib, preventing MF and prolonging survival in murine models of JAK2V617F AML. These findings illuminate HMGA1 as a key epigenetic switch involved in MPN transformation and a promising therapeutic target to treat or prevent disease progression.

Integrating the Electronic Health Record Into Patient Encounters: An Introductory Standardized Patient Exercise for Preclinical Medical Students.

INTRODUCTION: Increasingly, use of the electronic health record (EHR) is interwoven into even the most basic patient care tasks. Accordingly, learning how to utilize the EHR during patient encounters is important for medical students as they develop their clinical skills. Existing EHR curricula have focused primarily on doctor-patient relationship skills. We developed a session for our preclinical students on EHR-related doctor-patient relationship skills as well as on using the EHR to verify data and focus one's history taking. METHODS: We developed student notes, three training videos, four standardized patient (SP) cases, and a simplified, simulated EHR based on these cases. Students reviewed the notes and videos prior to class. During class, students practiced EHR-related communication and data-collection strategies by interviewing an SP while interacting with the simulated EHR. Following each encounter, students received feedback from a small group of peers and faculty. RESULTS: Two-hundred eighty-nine second-year medical students participated this session in 2019 and 2020, and 27 (19%, 2019) and 40 (28%, 2020) students, respectively, completed the postsession evaluation. Most respondents rated the SP activity as extremely or quite effective for practicing doctor-patient relationship strategies while interacting with the EHR (89%, 2019; 83%, 2020) and for practicing verification of EHR data during a patient encounter (81%, 2019; 86%, 2020). DISCUSSION: This training session was effective for introducing preclinical medical students to fundamental concepts and skills related to incorporating the EHR into patient encounters and offers a low-cost approach to teaching early medical students these important skills.

Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.

Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.

Introduction to Health Systems Science: Experiential Learning Through Patient Interviews in the Emergency Department.

Increased complexity in health care delivery is now a problem of national proportions. Traditional medical education fails to sufficiently prepare students for the realities of practicing medicine in the 21st century. To address this critical problem, health systems science (HSS), which focuses on the broader system of care, has emerged as the "third pillar" of undergraduate medical education complementing the basic and clinical sciences. The authors identified a need to increase the amount and quality of HSS education in a way that would engage students and provide a platform to learn how patients interact with the health care system. UNITED (Understanding Needs in the Emergency Department) was thus designed and implemented to introduce preclinical medical students to HSS through patient interactions in the emergency department (ED). EDs serve as America's health care "safety net" and there is no lack of opportunity to learn how the current system of care does and does not work for patients. Qualitative analysis of students' written reflections revealed the following themes of the UNITED experience: 1) medical students question their understanding of the health care system after listening to patients' stories, 2) focused patient interviews about the health care system provides a unique perspective of the patient experience not found elsewhere in the preclinical curriculum, and 3) discussing the realities of being a patient in the U.S. health care system is an emotional experience for students. Based on these data, the authors concluded that asking preclinical students to interview patients about their experience in the health care system leads to emotional activation and a subsequent stated desire to improve care delivery.

Probing Microenvironmental Acidity in Lyophilized Protein and Vaccine Formulations Using Solid-state NMR Spectroscopy.

Biophysical and biochemical instability of therapeutic proteins in the solution state may necessitate the development of products in the solid form, due to their enhanced stability. Lyophilization is a widely used method to ensure dry state stabilization of biological products. A commonly encountered issue is the pH shifts that can occur due to undesired crystallization of a buffer component, resulting in loss of protein activities. However, it is technically challenging to noninvasively investigate the physicochemical environment in the lyophile matrix. In this work, we demonstrate an approach based on solid-state NMR to investigate the microenvironmental acidity in lyophilized protein formulations, using histidine, a commonly used buffer agent, as a molecular probe. The solid-state acidity in the lyophilized matrix can be assessed by monitoring the chemical shift changes of histidine. The protonation and tautomeric states of histidine lyophilized at a range of pH values from 4.5 to 11.0 were identified from full 13C and 15N resonance assignments in one-dimensional and two-dimensional NMR experiments. The results demonstrated a pH-dependence of histidine chemical shift in the amorphous state. Moreover, we successfully applied this protocol to investigate the microenvironmental pH in lyophilized formulations of the HPV vaccine and lactate dehydrogenase protein.

The Simulated Cardiology Clinic: A Standardized Patient Exercise Supporting Medical Students' Biomedical Knowledge and Clinical Skills Integration.

Introduction: Development of cardiac disease-related diagnostic skills-including hypothesis-driven data gathering, heart sound interpretation, and ECG interpretation-is an important component of medical student training. Prior studies indicate trainees' performance of these skills is limited. Simulation provides students with opportunities to practice integrating their developing knowledge in a relevant clinical context. We developed a simulated clinic activity for second-year medical students consisting of standardized patient (SP) cases representing cardiovascular (CV) diseases. Methods: Student small groups rotated through four SP encounters. For each case, one student performed the history, after which the whole small group listened to audio files of heart sounds, interpreted an ECG, and collaboratively developed a prioritized differential diagnosis. The CV course director met with students for a large-group debrief, highlighting key learning points. We collected learners' evaluations of the event through an online survey. Results: Of students, 276 participated in this activity over the course of 2 years. Nearly all students assessed the activity as extremely or quite effective for applying learning content from the CV course (97%, 2018; 93%, 2019), and for practicing how to approach chest pain, shortness of breath, palpitations, and fatigue (100%, 2018; 95%, 2019). The most helpful aspects were reinforcement of CV disease illness scripts, hypothesis-driven data gathering practice, ECG interpretation, and applying knowledge and skills in a realistic context. Discussion: SP encounters representing CV conditions can effectively provide opportunities for students to integrate basic science knowledge and clinical skills. Students assessed the activity as helpful and engaging.

The GI Simulated Clinic: A Clinical Reasoning Exercise Supporting Medical Students' Basic and Clinical Science Integration.

Introduction: Cognitive integration is required to perform clinical decision-making tasks, even in the preclinical curriculum of medical school. Simulation supports students' cognitive integration by providing practical application of basic science knowledge in a relevant clinical context. To address the need for integrative activities in our curriculum, we implemented a simulated clinic exercise with cases representing gastrointestinal diseases for first-year medical students. Methods: Basic science and clinical skills course directors collaborated to design this simulated clinic event, during which student small groups rotated through a series of standardized patient encounters. During each encounter, one student performed the history and physical exam, following which the small group collaboratively developed a prioritized differential diagnosis. Afterwards, the gastroenterology course director debriefed students to highlight key learning points. We collected learner evaluation data following the event. Results: Two hundred eighty first-year medical students participated in the simulated clinic in 2018 and 2019. Students rated these events as effective for learning about clinical features of the diseases presented and for reinforcing skills learned in the clinical skills course. Students agreed that the small-group format, pace, and duration were appropriate and that the problem-solving aspect was intellectually stimulating. The most effective aspects were opportunities to solidify illness scripts, apply knowledge to solve a problem, and encounter diseases in a realistic clinical context. Discussion: This simulated clinic model effectively supported preclinical students' basic and clinical science integration to complete diagnostic reasoning tasks for gastrointestinal gastrointestinal conditions and was evaluated favorably by learners.

Chasing Fevers: An Interactive Exercise for Pediatrics Residents on Triaging and Assessing Inpatients With Fever.

Introduction: Pediatrics residents are frequently tasked with triaging fevers in pediatric inpatients. The variety of clinical scenarios in the inpatient setting-patients with a multitude of diseases and a spectrum of risk for invasive infection-makes this task challenging. To enhance our residents' training on this topic, we developed an activity providing explicit instruction on how to approach these patient scenarios. Methods: The 45-minute activity began with an interactive discussion on approaching pediatric inpatient fevers, followed by a case-based exercise where small groups were assigned one of six clinical scenarios involving inpatients with fever. Learners discovered new information about their patient by drawing paper slips out of a container. Each slip could take their patient's story in a different direction. Small groups discussed decision-making options for their assigned case at each step. Among the potential events were rapid response calls-acute issues requiring immediate assessment-in which learners competed for limited seats to determine who would respond to the call. The activity concluded with a discussion about treatment of inpatient fevers. Results: Respondents to the postevent evaluation rated the activity as highly engaging, effective in helping them achieve its learning objectives, highly relevant to their career, and effective in simulating real-life clinical decision-making situations. Discussion: This instructional technique offers a unique, engaging, case-based approach to teaching about inpatient fever management in which instructors facilitate and support learners' articulation of clinical reasoning. Future directions include using this technique for other common clinical problems and with other learner groups.

Thrombopoietin is required for full phenotype expression in a JAK2V617F transgenic mouse model of polycythemia vera.

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis are hematopoietic stem cell disorders and share driver mutations that either directly activate the thrombopoietin receptor, MPL, or activate it indirectly through gain-of-function mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, MPL surface expression in hematopoietic stem cells is also reduced in the myeloproliferative neoplasms due to abnormal post-translational glycosylation and premature destruction of JAK2, suggesting that the myeloproliferative neoplasms are disorders of MPL processing since MPL is the only hematopoietic growth factor receptor in hematopoietic stem cells. To examine this possibility, we genetically manipulated MPL expression and maturation in a JAK2V617F transgenic mouse model of polycythemia vera. Elimination of MPL expression completely abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could only be partially restored by expression of one MPL allele. Most importantly, elimination of thrombopoietin gene expression abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could be completely restored by expression of a single thrombopoietin allele. These data indicate that polycythemia vera is in part a thrombopoietin-dependent disorder and that targeting the MPL-thrombopoietin axis could be an effective, nonmyelotoxic therapeutic strategy in this disorder.

Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden.

The factors underlying the variable presentation and clinical course of myeloproliferative neoplasms (MPNs) remain unclear. The aim of this study was to evaluate the independent effect of sex on MPN presentation and outcomes. A total of 815 patients with essential thrombocytosis, polycythemia vera, or primary myelofibrosis were evaluated between 2005 and 2019, and the association of sex with presenting phenotype, JAK2 V617F burden, progression, and survival was examined. Men presented more often with primary myelofibrosis vs essential thrombocytosis (relative risk, 3.2; P < .001) and polycythemia vera (relative risk, 2.1; P < .001), had higher rates of transformation to secondary myelofibrosis (hazard ratio [HR], 1.55; P = .013) and acute myeloid leukemia (HR, 3.67; P < .001), and worse survival (HR, 1.63; P = .001) independent of age, phenotype at diagnosis, and MPN-specific mutation. Men had higher JAK2 V617F allele burdens in their CD34+ cells (P = .001), acquired more somatic mutations (P = .012) apart from the MPN-specific mutations, and had an increased frequency of 1 (odds ratio, 2.35; P = .017) and 2 (odds ratio, 20.20; P = .011) high-risk mutations independent of age, phenotype, and driver mutation. Male sex is an independent predictor of poor outcomes in MPNs. This seems to be due to an increased risk of non-MPN-specific somatic mutations, particularly high-risk mutations, rather than MPN-specific mutation allele frequency. Conversely, disease progression in female subjects is more dependent on JAK2 mutation allele burden than on acquisition of other somatic mutations. Sex should be considered in prognostic models and when evaluating therapeutic strategies in MPNs.

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment.

The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM). The aim of this study was to determine preclinically whether intradermal (ID) vaccination with an unadjuvanted 9-valent recombinant HPV vaccine using a first-generation ID delivery device, the Nanopatch™, could enhance vaccine immunogenicity compared with the traditional ID route (Mantoux technique). IM injection of HPV VLPs formulated with Merck & Co., Inc., Kenilworth, NJ, USA Alum Adjuvant (MAA) were included in the rhesus study for comparison. The Nanopatch™ prototype contains a high-density array comprised of 10,000 microprojections/cm2, each 250 µm long. It was hypothesized the higher density array with shallower ID delivery may be superior to the Mantoux technique. To test this hypothesis, HPV VLPs without adjuvant were coated on the Nanopatch™, stability of the Nanopatch™ with unadjuvanted HPV VLPs were evaluated under accelerated conditions, skin delivery was verified using radiolabelled VLPs or FluoSpheres®, and the immune response and skin site reaction with the Nanopatch™ was evaluated in rhesus macaques. The immune response induced by Nanopatch™ administration, measured as HPV-specific binding antibodies, was similar to that induced using the Mantoux technique. It was also observed that a lower dose of unadjuvanted HPV VLPs delivered with the first-generation Nanopatch™ and applicator or Mantoux technique resulted in an immune response that was significantly lower compared to a higher-dose of alum adjuvanted HPV VLPs delivered IM in rhesus macaques. The study also indicated unadjuvanted HPV VLPs could be delivered with the first-generation Nanopatch™ and applicator to the skin in 15 s with a transfer efficiency of approximately 20%. This study is the first demonstration of patch administration in non-human primates with a vaccine composed of HPV VLPs.

Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes.

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of ß-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.

Identifying Information Resources for Patients in the Intensive Care Unit and Their Families.

BACKGROUND: Providing information to patients in intensive care units and their families is challenging. Patients often are admitted unexpectedly and experience stress and uncertainty. One source of stress has been identified as unclear, uncoordinated, or inconsistent communication and information. Despite the need for information, no centrally located, easily accessible, standardized intensive care unit education content exists. OBJECTIVE: To identify educational content for patients in the intensive care unit and their families across 4 different hospitals, develop a general content database, and organize the general content into a framework for education of patients and their families. METHODS: Educational content for patients in the intensive care units of 4 participating hospitals was collected and a gap analysis was performed. RESULTS: Key content format and categories were identified. Educational content was organized into an information pathway divided into 3 phases: intensive care unit arrival; understanding the intensive care unit and partnering in care; and intensive care unit transitions. The gap analysis revealed substantial variation in content format and categories. CONCLUSIONS: Structuring a digital learning center using different stages of the patient's stay in the intensive care unit and placing resources in the context of an information pathway can help coordinate education for these patients and their families, and creates a consistent communication guide for clinicians as well. The optimal digital format should be considered in designing the learning center.