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Background and Objectives: As clinicians increasingly rely on telemedicine, medical students will need to learn how to appropriately use telemedicine in patient care. A formal approach to curriculum development is needed to identify gaps and needs in early medical student performance. Methods: In October 2020, 120 second-year medical students completed a telemedicine visit with a standardized patient with chronic essential hypertension. Students were assessed across five domains (history-gathering, communication, vitals, physical exam, and assessment/management). An anonymous, voluntary survey was distributed to assess self-efficacy in telemedicine skills. Results: Students perform well in history-gathering and communication (98% of student scored 4 or 5 out of 5 on history, 100% of students received a 7 or 8 out of 8 on communication). Students perform poorly in obtaining vital signs (23% scored 3 or 4 out of 4) and assessment/management (14% scored 3 or 4 out of 4). Students received their lowest scores in physical examination (2% score 4 or 5 out of 5). The number of telemedicine visits completed with patients prior to the standardized patient exercise had no impact on student performance during the exercise. Student response rate on the postexercise survey was 88%. Self-efficacy was lowest in physical examination telemedicine skills compared to other domains. Conclusions: Findings suggest that early medical students are able to gather history and communicate over telemedicine, but perform poorly on telemedicine physical examination skills. More robust curriculum development addressing telemedicine physical examinations skills is needed early in medical training.

Background and Objectives: The Association of American Medical Colleges identifies telemedicine competence as an important skill for graduating medical students, but which educational methods are effective in improving student performance is unclear. We aimed to assess the impact of two educational interventions on student performance in telemedicine standardized patient encounters. Methods: Sixty second-year medical students participated in the telemedicine curriculum during their required longitudinal ambulatory clerkship. Students first completed a preintervention telemedicine standardized patient (SP) encounter in October 2020. They subsequently were assigned to two intervention groups (ie, a role-play intervention, N=30; a faculty demonstration, N=30) and completed a teaching case. In December 2020, they completed a postintervention telemedicine SP encounter. Each case was a unique clinical scenario. SPs scored the encounters across six domains based on a standardized performance checklist. We compared the median scores for these domains and the median total score pre- and postintervention (using Wilcoxon signed rank and rank-sum tests) and the difference in median score by intervention type. Results: Students scored highly in history-taking and communication performance but had low physical exam (PE) and assessment/plan scores. Postintervention, median scores in PE (ie, median score difference 2, interquartile ranges [IQR] 1-3.5, P

With an expected shortage of oncologists, primary care providers (PCPs) may need to manage more cancer surveillance and screening, areas where educational resources for PCPs have been limited. The goal of this e-curriculum was for PCPs to learn surveillance and screening for several common cancers. The e-curriculum covered breast and colorectal cancer surveillance and lung cancer screening with (1) a pre-test assessing knowledge, attitudes, practice patterns, and confidence; (2) case vignette-based teaching; and (3) an immediate post-test (with knowledge and confidence items identical to the pre-test) providing feedback. A delayed post-test was administered several months later. The curriculum and test items were developed by content experts and evaluated in a primary care group practice. Of 167 community PCPs, 152 completed the pre-test (91%), 145 completed the immediate post-test (87%), and 63 completed the delayed post-test (37%); 62 PCPs completed all three tests (37%). The median score on the pre-test was 43%, immediate post-test was 93%, and delayed post-test was 70%. For PCPs completing all three tests, the median scores were 50%, 90%, and 70%, respectively (p < 0.0001). The percentage of PCPs confident in their knowledge 4 to 6 months after module completion compared to the pre-test baseline was statistically significant for lung cancer screening but not for cancer surveillance. This curriculum provided concise, effective education for PCPs on 3 common cancers. Limitations include content breadth and lack of data reflecting physician ordering patterns. Curricular strengths include its accessibility, immediate feedback, and effectiveness, with a significant improvement in immediate and delayed post-test knowledge. Given a lack of increased confidence to provide cancer surveillance, PCPs should rely on electronic medical record tools and other resources to guide appropriate surveillance care.

BACKGROUND: Advance care planning (ACP) and involving family are particularly important in dementia, and primary care is a key setting. The purpose of this trial is to examine the impact and implementation of SHARING Choices, an intervention to improve communication for older adults with and without dementia through proactively supporting ACP and family engagement in primary care. METHODS: We cluster-randomized 55 diverse primary care practices across two health systems to the intervention or usual care. SHARING Choices is a multicomponent intervention that aims to improve communication through patient and family engagement in ACP, agenda setting, and shared access to the patient portal for all patients over 65 years of age. The primary outcomes include documentation of an advance directive or medical orders for life-sustaining treatment in the electronic health record (EHR) at 12 months for all patients and receipt of potentially burdensome care within 6 months of death for the subgroup of patients with serious illness. We plan a priori sub-analysis for patients with dementia. Data sources include the health system EHRs and the Maryland health information exchange. We use a mixed-methods approach to evaluate uptake, fidelity and adaptation of the intervention and implementation facilitators and barriers. CONCLUSIONS: This cluster-randomized pragmatic trial examines ACP with a focus on the key population of those with dementia, implementation in diverse settings and innovative approaches to trial design and outcome abstraction. Mixed-methods approaches enable understanding of intervention delivery and facilitators and barriers to implementation in rapidly changing health care systems. ClinicalTrials.gov Identifier: NCT04819191

BACKGROUND A health system's commitment to delivering culturally competent care is essential in creating a culture of respect for patients, clinicians, and administrative staff. As the diversity of the health care workforce grows, gaining an understanding of the perspectives among different health care personnel and the value that they place on organizational cultural competence is a first step in developing more effective team environments. PURPOSE The aim of the study was to determine whether an association exists between perceptions of organizational cultural competence and teamwork climate among employees in a health system. METHODOLOGY/APPROACH One thousand eighty employees in a primary care network consisting of 49 ambulatory practices were surveyed on their perceptions of senior management's efforts in organizational cultural competence and teamwork climate in their own work setting using 5-point Likert scales. Linear regression models were used to evaluate the association between organizational cultural competence and teamwork climate. RESULTS The overall organizational response rate for the survey was 84%. Higher perception of organizational cultural competence was associated with better teamwork climate (coef. = 0.4, p

The safety culture in the workplace may affect event reporting. We evaluated the relationship of safety culture and voluntary event reporting within a large network of ambulatory practices, most of which provided primary care.This study was an observational, retrospective cohort study. Patient safety event reporting rates for 35 ambulatory practices were collected using a standard tool (UHC Patient Safety Net [PSN]) and normalized based on the number of patient visits in each practice. The overall and domain-specific safety culture of each practice was measured with a validated instrument (Safety Attitudes Questionnaire [SAQ]), distributed to 828 employees in 2013. We compared safety culture scores and the average event reporting rates during a 4-month window before and after the survey distribution. Poisson regression analyses were performed to determine the relationship between PSN reporting rates and SAQ results.The SAQ response rate was 87%. Practices varied widely in rates of reporting events, from 0.00 to 6.99 reports per 1000 total patient visits per month. Regression analyses indicated a positive association between PSN reporting rates and SAQ scores for the domains of overall culture (incidence rate ratio [IRR], 1.019; P = 0.004) and 4 safety culture domains: teamwork climate (IRR, 1.016; P = 0.019), safety climate (IRR, 1.018; P = 0.004), working conditions (IRR, 1.017; P = 0.006), and perceptions of local management (IRR, 1.016; P = 0.040).Our work provides new evidence to show that in the ambulatory setting more events and near misses are reported when there is a strong culture of safety.

Background Most medical schools teach a high-value care (HVC) curriculum during the clinical years. Currently, there lacks any research demonstrating the effectiveness of the HVC curriculum taught to students in their first year of medical school. Methods A total of 118 of 466 first-year medical students at Johns Hopkins School of Medicine between 2013 and 2017 enrolled on an HVC course that provided the initial framework necessary to practice cost-conscious clinical medicine. The curriculum was evaluated by comparing the performance of students who completed the course with the performance of students without training, through a standardised patient encounter on musculoskeletal back pain and how to approach a patient's request for imaging. Chi-square testing was used to assess the impact of the course on performance in a standardised patient encounter. Results Students enrolled on the HVC course were more likely, compared with their counterparts, to assure patients that back pain was a simple strain (48 versus 31%), and were less likely to ask for preceptor help on how to proceed with management (11 versus 29%) [χ2 (4, n = 466) = 14.28, p = 0.007]. There were no differences between students enrolled on the HVC course who had not yet received training compared with students taking another elective [χ2 (4, n = 385) = 8.73, p = 0.07]. Discussion This is the first study to assess the effectiveness of an HVC curriculum for first-year medical students, and it demonstrates promise that they can acquire some skill sets necessary for cost-effective practice in a simulated clinical setting. This is the first study to assess the effectiveness of an HVC curriculum for first-year medical students, and it demonstrates promise that they can acquire some skill sets necessary for cost-effective practice.

Changes in the US healthcare economic system are requiring academic health centers (AHCs) to restructure in pursuit of their traditional tripartite missions; engaging the individuals focused on clinical care is becoming more important. We conducted this study to guide our institution's transformation by identifying ways to formally recognize clinicians who are excelling in patient care and understand which forms of acknowledgment would be acceptable and motivating.A survey was developed by a large committee with representation spanning the AHC and was sent electronically in spring 2014 to stakeholders across the institution. Items assessed perceptions of the importance and present state of valuing clinical excellence, the utility of 14 potential metrics to assess clinical excellence, and the meaningfulness of seven potential rewards for clinical excellence. Bivariate and multivariate logistic regression models analyzed differences (P0.05) by respondent sex, ethnicity, academic rank, primary clinical affiliation, and time spent in patient care and research activities.A total of 1716 of 3168 (54%) stakeholders responded, including 1198 of 2151 (56%) individuals from academic hospitals, 114 of 276 (41%) from the outpatient affiliated practices, and 304 of 741 (54%) from satellite locations. Nearly everyone (96%) agreed that clinical accomplishments should be recognized, although a minority (47%) believed that clinicians were already valued. Most respondents selected 7 or more of 14 metrics as valid and reasonable for assessing clinical excellence. Popular metrics (eg, clinical productivity) were not believed to represent clinical excellence as much as others (eg, professionalism). Multivariate analysis found the least agreement among stakeholders on using published scholarship as evidence for clinical excellence, with the widest differences comparing senior faculty versus nonfaculty (88% vs 27%) and those with75% of their time spent in patient care versus others (37% vs 73%). Most (six of seven) types of reward were perceived as meaningful by the majority of respondents, with little variation among subgroups across bivariate and multivariate analyses.This system-wide assessment was successful at identifying new strategies for recognizing clinical excellence. Other AHCs seeking institutional transformation may wish to perform a similar assessment.

As part of a pragmatic trial to reduce hypertension disparities, we conducted a baseline organizational assessment to identify aspects of organizational functioning that could affect the success of our interventions. Through qualitative interviewing and the administration of two surveys, we gathered data about health care personnel’s perceptions of their organization’s orientations toward quality, patient centeredness, and cultural competency. We found that personnel perceived strong orientations toward quality and patient centeredness. The prevalence of these attitudes was significantly higher for these areas than for cultural competency and varied by occupational role and race. Larger percentages of survey respondents perceived barriers to addressing disparities than barriers to improving safety and quality. Health care managers and policy makers should consider how we have built strong quality orientations and apply those lessons to cultural competency.

Johns Hopkins University recently implemented two novel urban health residency training programs (UHR). The programs include increased access programs, community health worker-delivered care, substance abuse screening and treatment, community psychiatry/ mental health programs, case and disease management teams, and interprofessional training. These programs are designed to create well-trained physicians who competently provide care for the underserved inner-city patient.

OBJECTIVE—Although suboptimal glycemic control is known to be common in diabetic adults, few studies have evaluated factors at the level of the physician-patient encounter. Our objective was to identify novel visit-based factors associated with intensification of oral diabetes medications in diabetic adults. RESEARCH DESIGN AND METHODS—We conducted a nonconcurrent prospective cohort study of 121 patients with type 2 diabetes and hyperglycemia (A1C ≥8%) enrolled in an academically affiliated managed-care program. Over a 24-month interval (1999–2001), we identified 574 hyperglycemic visits. We measured treatment intensification and factors associated with intensification at each visit. RESULTS—Provider-patient dyads intensified oral diabetes treatment in only 128 (22%) of 574 hyperglycemic visits. As expected, worse glycemia was an important predictor of intensification. Treatment was more likely to be intensified for patients with visits that were “routine” (odds ratio [OR] 2.55 [95% CI 1.49–4.38]), for patients taking two or more oral diabetes drugs (2.82 [1.74–4.56]), or for patients with longer intervals between visits (OR per 30 days 1.05 [1.00–1.10]). In contrast, patients with less recent A1C measurements (OR >30 days before the visit 0.53 [0.34–0.85]), patients with a higher number of prior visits (OR per prior visit 0.94 [0.88–1.00]), and African American patients (0.59 [0.35–1.00]) were less likely to have treatment intensified. CONCLUSIONS—Failure to intensify oral diabetes treatment is common in diabetes care. Quality improvement measures in type 2 diabetes should focus on overcoming inertia, improving continuity of care, and reducing racial disparities.

In diabetic adults, tight control of risk factors reduces complications. To determine whether failure to make visits, monitor risk factors, or intensify therapy affects control of blood pressure, glucose, and lipids. A non-concurrent, prospective study of data from electronic files and standardized abstraction of hard-copy medical records for the period 1/1/1999–12/31/2001. Three hundred eighty-three adults with diabetes managed in an academically affiliated managed care program. Main exposure variable: Intensification of therapy or failure to intensify, reckoned on a quarterly basis. Main outcome measure: Hemoglobin A1c (A1c), systolic blood pressure (SBP), and LDL-cholesterol at the end of the interval. In this visit-adherent cohort, control of glycemia and lipids showed improvement over 24 months, but many patients did not achieve targets. Only those with the worst blood pressure control (SBP ≥160 mmHg) showed any improvement over 2 years. Failure to intensify treatment in patients who kept visits was the single strongest predictor of sub-optimal control. Compared to their counterparts with no failures of intensification, patients with failures in ≥3 quarters showed markedly worse control of blood glucose (A1c 1.4% higher: 95% CI: 0.7, 2.1); hypertension (SBP 22.2 mmHg higher: 95% CI: 16.6, 27.9) and LDL cholesterol (LDL 43.7 mg/dl higher: 95% CI: 24.1, 63.3). These relationships were strong, graded, and independent of socio-demographic factors, baseline risk factor values, and co-morbidities. Failure to intensify therapy leads to suboptimal control, even with adequate visits and monitoring. Interventions designed to promote appropriate intensification should enhance diabetes care in primary practice.

Clinical skills training for preclinical medical students has traditionally focused on adult patients. As medical education evolves to incorporate earlier exposure to clinical training, there is a need to prepare medical students for the unique aspects of caring for pediatric patients. This medical school curriculum is designed to educate medical students about important pediatric topics at a level appropriate for preclinical students. The materials include four written modules with end-of-module questions and answers, a presentation for an interactive workshop that reviews the material covered in the module on the history and physical exam, an instructor guide to the presentation, a case script for the small-group role-playing, and a white coat card for use by students. We developed this pediatric training curriculum at the Johns Hopkins University School of Medicine. We developed this curriculum to better prepare students to work with pediatric patients as part of the first and second-year longitudinal ambulatory clerkship course. Medical students who had completed the course partnered with the clerkship directors and conducted a needs assessment. Approximately one-third of students worked with pediatric patients and more than half of all students indicated that they believed they could benefit from pediatric modules. After the curriculum was implemented for the first time, 75% of students were satisfied or very satisfied with the orientation workshop.

Nurse-managed anticoagulation is an emerging trend in primary care with the potential to improve the quality, efficiency, and responsiveness of outpatient anticoagulation services. Research indicates that specially trained nurses, using portable international normalized ratio (INR) monitors and decision-support systems, safely and effectively perform independent warfarin-dose adjustment. This article describes the development, implementation, and preliminary evaluation of a nurse-managed anticoagulation program as well as key lessons learned in the process. Factors for success included (a) availability of portable INR monitors, (b) designation of specially trained anticoagulation nurses, (c) use of an effective decision support system, and (d) support from staff and management.

Medication nonadherence is an important public health consideration, affecting health outcomes and overall health care costs. This review considers the most recent developments in adherence research with a focus on the impact of medication adherence on health care costs in the US health system. We describe the magnitude of the nonadherence problem and related costs, with an extensive discussion of the mechanisms underlying the impact of nonadherence on costs. Specifically, we summarize the impact of nonadherence on health care costs in several chronic diseases, such as diabetes and asthma. A brief analysis of existing research study designs, along with suggestions for future research focus, is provided. Finally, given the ongoing changes in the US health care system, we also address some of the most relevant and current trends in health care, including pharmacist-led medication therapy management and electronic (e)-prescribing.

As part of ongoing efforts to improve quality of care through clinical education of our medical assisting staff, we developed a competency-based training and assessment program. At the time of program implementation, we assessed clinical skills of 111 certified medical assistants and found that 10% were unable to accurately measure blood pressure, 9% were unable to correctly perform an intradermal injection, and 48% were unable to correctly draw specified volumes into syringes. More than 10 years after program implementation, we continue to detect and remediate clinical skills in newly hired employees. This case study report describes the evolution of the program and assessment findings.

This article was migrated. The article was not marked as recommended. Background: Family health history (FH) is a useful tool for assessing health risk and improving communication among family members, but remains underutilized in primary care practice. The goals of this study were to assess the utility of a content-driven group reflection on family history on student learning, and to equip them with tools to improve their skills in FH assessment. Methods: A 90-minute pilot Family History and Communication Reflection module was developed and made available to first and second-year medical students completing a longitudinal ambulatory clerkship; a group reflection model was used. 16 students (13% of the first year class) participated and 8 students completed the evaluation form. Results: The majority of students were satisfied with the module, would recommend the module to another student, and felt prepared or very prepared to incorporate FH assessment tools into their clinical practice. Conclusions: The pilot FH module was well-received by first-year medical students as a strategy for emphasizing the importance of assessing FH in a busy primary care setting and providing practical tools for FH. The reflective learning approach was cited as helpful for using and building upon prior clerkship experience.

Increasing the use of electronic medical records (EMR) has been suggested as an important strategy for improving healthcare safety.To sequentially measure, evaluate, and respond to safety culture and practice safety concerns following EMR implementation.Safety culture was assessed using a validated tool (Safety Attitudes Questionnaire; SAQ), immediately following EMR implementation (T1) and at 1.5 (T2) and 2.5 (T3) years post-implementation. The SAQ was supplemented with a practice-specific assessment tool to identify safety needs and barriers.A large medical group practice with a primary care core of 17-18 practices, staffed by clinicians in family medicine, pediatrics, internal medicine.Survey results were used to define and respond to areas of need between assessments with system changes and educational programs.Change in safety culture over time; perceived impact of EMR on practice.Responses were received from 103 of 123 primary care providers in T1 (83.7 % response rate), 122 of 143 in T2 (85.3 %) and 142 of 181 in T3 (78.5 %). Safety culture improved over this period, with statistically significant improvement in all domains except for stress recognition. Time constraints, communications and patient adherence were perceived to be the most important safety issues. The majority of respondents in both T2 (77.9 %) and T3 (85.4 %) surveys agreed that the EMR improved their ability to provide care more safely.Implementation of an EMR in a large primary care practice required redesign of many organizational processes, and was associated with improvements in safety culture. Most primary care providers agreed that the EMR allowed them to provide care more safely.

We describe a method for identifying fibrinogen and fibrin split products using electrophoresis on agarose gel with sodium dodecyl sulfate (SDS) followed by blotting in nitrocellulose paper. Detection of these derivatives after blotting is accomplished with per-oxidase-conjugated rather than by isotopically labeled antibodies. This technique can detect diverse fibrinogen derivatives produced in vivo or in vitro by the combined action of thrombin, plasmin, and factor XIII. This methodology is applicable to plasma, serum, and other body fluids including urine and ascitic fluid. This sensitive and specific assay, distinguishing the products of cross-linked fibrin from those of fibrinogen and detecting fibrin polymers in plasma, can be achieved without the use of radioactivity.

Although tight blood pressure control is crucial in reducing vascular complications of diabetes, primary care providers often fail to appropriately intensify antihypertensive medications.To identify novel visit-based factors associated with intensification of antihypertensive medications in adults with diabetes.Non-concurrent prospective cohort study.A total of 254 patients with type 2 diabetes and hypertension enrolled in an academically affiliated managed care program. Over a 24-month interval (1999-2001), we identified 1,374 visits at which blood pressure was suboptimally controlled (systolic BP/= 140 mmHg or diastolic BP/= 90 mmHg).Intensification of antihypertensive medications at each visit was the primary outcome. Primary care providers intensified antihypertensive treatment in only 176 (13%) of 1,374 visits at which blood pressure was elevated. As expected, higher mean systolic and mean diastolic blood pressures were important predictors of intensification. Treatment was also more likely to be intensified at visits that were "routine" odds ratio (OR) 2.08; 95% Confidence Interval [95% CI] 1.36-3.18), or that paired patients with their usual primary care provider (OR 1.84; 95% CI 1.11-3.06). In contrast, several factors were associated with failure to intensify treatment, including capillary glucose150 mg/dL (OR 0.54; 95% CI 0.31-0.94) and the presence of coronary heart disease (OR 0.61; 95% CI 0.38-0.95). Co-management by a cardiologist accounted partly for this failure (OR 0.65; 95% CI 0.41-1.03).Failure to appropriately intensify antihypertensive treatment is common in diabetes care. Clinical distractions and shortcomings in continuity and coordination of care are possible targets for improvement.

Background African Americans suffer disproportionately from diabetes complications, but little research has focused on how to improve diabetic control in this population. There are also few or no data on a combined primary care and community-based intervention approach. Methods We randomly assigned 186 urban African Americans with type 2 diabetes (76% female, mean A SD age 59 A 9 years) to 1 of 4 parallel arms: (1) usual care only; (2) usual care + nurse case manager (NCM); (3) usual care + community health worker (CHW); (4) usual care + nurse case manager/community health worker team. Using the framework of the Precede–Proceed behavioral model, interventions included patient counseling regarding self-care practices and physician reminders. Results The 2-year follow-up visit was completed by 149 individuals (84%). Compared to the Usual care group, the NCM group and the CHW group had modest declines in HbA 1c over 2 years (0.3 and 0.3%, respectively), and the combined NCM/CHW group had a greater decline in HbA 1c (0.8%. P = 0.137). After adjustment for baseline differences and/or follow-up time, the combined NCM/CHW group showed improvements in triglycerides (−35.5 mg/dl; P = 0.041) and diastolic blood pressure, compared to the usual care group (−5.6 mmHg; P = 0.042). Conclusions Combined NCM/CHW interventions may improve diabetic control in urban African Americans with type 2 diabetes. Although results were clinically important, they did not reach statistical significance. This approach deserves further attention as a means to reduce the excess risk of diabetic complications in African Americans.

The objective of the study was to determine the effectiveness and cost-effectiveness of primary care and community-oriented interventions in managing HbA1c, blood pressure, and lipids, and reducing hospitalizations and emergency room visits over 2 years. We describe an ongoing, randomized controlled trial of 542 urban African-Americans with type 2 diabetes ages 25 years and older who are members of a university-affiliated managed-care organization in Baltimore, MD. The participants are 74% female, have a mean age of 58 years, and 35% have yearly incomes greater than 7500 US dollars. Participants were randomized to one of two intervention groups for a period of 2 years: (1) usual medical care plus minimal telephone intervention implemented by a trained lay health educator (control group) or (2) usual medical care plus intensive intervention implemented by a nurse case manager (NCM)/community health worker (CHW) team. The intensive NCM/CHW team executes individual plans of care using evidence-based algorithms that focus on traditional diabetes self-management, screening and management of diabetes-related complications, and social issues surrounding diabetes care. Face-to-face NCM visits are conducted in the clinic once per year and CHW visits are conducted in the participant's home one to three times per year, both with additional follow-up contacts as needed. Written and verbal feedback (when necessary) is provided to the participant's primary care physician. All participants are expected to attend a 24-month follow-up visit where data are collected by interviewers blinded to intervention assignment. As of May 1, 2003, recruitment is complete, interventions are being fully implemented, and 24-month follow-up visits are beginning. Baseline sociodemographic characteristics, health-care utilization, health behaviors, and clinical characteristics of the study population are reported. This study is designed to test the hypothesis that a primary-care-based NCM plus CHW team approach is an effective, practical, and economically feasible strategy for translating current knowledge about type 2 diabetes into high-quality health care for urban African-Americans.

c-Myc plays a part in the regulation of important cellular processes such as growth, differentiation and neoplastic transformation. Although c-myc gene structure and expression are well characterized, the function and biochemical properties of the protein are less well understood. Human c-myc is a 439-amino acid phosphoprotein which binds DNA in vitro and belongs to a discrete subset of nuclear proteins. Using the human c-myc mutants generated by linker-insertion and deletion mutagenesis, we have defined regions of the protein that are important for its transforming activities and its nuclear localization. Here, we show that human c-myc exists as an oligomer in vitro and use mutant proteins to localize the oligomerization domain to a carboxyl-terminal peptide containing the 'leucine zipper' motif. The 'leucine zipper' describes a structure found in a number of DNA-binding proteins that contains leucines occurring at intervals of every seventh amino acid in a region predicted to be alpha-helical. The 'leucine zipper' might mediate dimerization by intermolecular interdigitation of the leucine side-chains. We show that a c-myc mutant, which is inactive but can oligomerize, dominantly inhibits the cotransforming activity with wild-type c-myc of rat embryo cells, whereas inactive mutants which cannot oligomerize properly because of deletions in the oligomerization domain are recessive.

Hereditary elliptocytosis is a heterogeneous disorder resulting from defects in the erythrocyte membrane skeleton. Although some cases of elliptocytosis result from defects in spectrin, the specific structural abnormality has yet to be identified in the majority of cases. Protein 4.1 plays an essential role in erythrocyte membrane physiology, and deficiencies have been implicated in only a few rare cases of elliptocytosis. By using 4.1 immunoblots and a 4.1 radioimmunoassay we identified distinct variants of protein 4.1 in 15 elliptocytic members of three US white families with the Rh-linked form of elliptocytosis. Elliptocytic members of family G were heterozygotes for a low-molecular weight (mol wt) 4.1 variant (65,000 to 68,000 daltons; normal, 80,000) inherited in linkage with the Rz phenotype. Elliptocytic members of family C expressed a simple partial deficiency of protein 4.1 (63% of the normal level) that was inherited in linkage with the r phenotype. Elliptocytic members of family N were heterozygotes for a high-mol wt 4.1 variant (100,000 daltons) also inherited in linkage with the r phenotype. These studies indicate that mutant forms of protein 4.1 are not uncommon in elliptocytosis among whites and that different kindreds probably express different mutations. The observed linkage of elliptocytosis and Rh blood type most likely results from the close proximities of the 4.1 gene (site of the mutation) and the Rh gene, which is located nearby on the short arm of chromosome 1.