Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.

High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs the survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.

Indirect institutional revenue generated from an academic primary care clinical network.

BACKGROUND AND OBJECTIVES: As the financial performances of US academic health centers have faltered under managed care and the Balanced Budget Act of 1997, increasing attention has been paid to the costs and benefits of operating primary care networks. This study examines the indirect revenues to a university hospital and faculty group practice that result from such a primary care network using a method of abstracting billing data. METHODS: A primary care patient cohort was identified by selecting all patients who generated at least one charge in any of the 10 primary care clinics in the network over a 15-month period. All charges from the hospital and the faculty practice group for this cohort were then examined during a 6-month period, and the total charges generated in the primary care setting were compared with charges generated elsewhere in the health system. RESULTS: The primary care patient cohort included 56,459 patients and generated a total of $7,243,312 in charges for primary care services, $43,559,741 of charges in the hospital billing system for non-primary care services, and $8,825,611 of charges for services from specialty faculty. This cohort accounted for 18.5% of the gross charges for hospital care and 17.6% of charges generated by the specialty physicians. CONCLUSIONS: Using a simple and replicable methodology, this study estimates a substantial financial benefit to the hospital and specialty practices from a primary care network.

Lessons learned from ACGME.

BACKGROUND AND OBJECTIVES: The year 1998 brought to a close our 6 years of service as representatives to the Accreditation Council for Graduate Medical Education. These have been challenging times for graduate medical education (GME), and our time on the council has been an educational experience of the first order. This paper describes our experiences and summarizes the issues we believe lie ahead for GME, particularly for family practice residency programs.

Reflections on internal medicine and family medicine.

The manner in which U.S. medical care is organized and paid for is rapidly changing. These political and financial changes have created an environment that favors collaboration and cooperation among the primary care specialties. ALthough their relationship was once that of referring physician and consultant, the family physician and general internist are becoming peers, and they increasingly have similar needs and interests. Improving collaboration between the practitioners in these two fields requires a respect for important differences in their respective cultures. All family physicians work closely with internists during residency, but many general internists have had little or no experience working with family physicians. This essay reviews the practice style and philosophy of the family physician and suggest ways to improve communication and collaboration between the two disciplines.

Defining the need for faculty in family medicine: results of a national survey.

BACKGROUND: Although numerous anecdotal reports are being offered about the growing number of unfilled faculty positions in US family medicine departments, virtually no literature exists on faculty recruitment. The objective of this study was to define the scope and nature of current faculty recruitment needs in family medicine. METHODS: A national survey was sent to all family medicine department chairs and family practice residency program directors concerning faculty positions unfilled at their sites and positions for which recruitment would occur within the next 5 years. The survey asked for information on currently available positions; academic title of position; percentage of time to be devoted to clinical, educational, administrative, and research activities; primary focus of the position; date when the position became available; and the length of time the position has been unfilled. Similar information was collected on positions anticipated to be available within the next 5 years. RESULTS: A total of 364 surveys were returned, for an overall response rate of 70%. Information from the survey revealed a current, substantial demand for family medicine faculty throughout the country, with an even greater demand anticipated for the near future. Respondents reported 496 currently unfilled positions for family medicine faculty and another 677 positions anticipated to be available within the next 19.5 months on average. A total of 89.7% of those anticipated positions were reported as either "certain" or "somewhat certain," in terms of likelihood of availability. CONCLUSIONS: The demand for family medicine faculty is increasing, and much of the demand is financially motivated. Clinical expectations appear to be higher among departments than for residencies. Finally, it was revealed that most positions had minimal allotments for research time. Family medicine must recommit itself to the development of a scholarly agenda as it recruits new faculty.

Defining the generalist physician's training.

OBJECTIVE: To determine the extent to which various specialties prepare residents in the broad competencies required for primary care practice and to propose guidelines for improving generalist physician training. DATA SOURCES: Leading causes of morbidity and mortality, 1991 National Ambulatory Medical Care Survey data, expert reports, and the special requirements for residency training. DESIGN: From the data sources we identified the common presenting conditions and diagnoses that broadly trained generalist physicians could be expected to manage in primary care practice. We then compiled a list of 60 requisite residency training components grouped according to seven practice criteria for generalist physicians. Using the special requirements for residency training for family practice, internal medicine, pediatrics, obstetrics and gynecology, and emergency medicine, we determined the extent to which the requirements addressed the 60 components and continuity-of-care training. RESULTS: Almost all of the 60 generalist training components were required by family practice (95%), internal medicine (91%), and pediatrics (91%), compared with emergency medicine (42%) and obstetrics and gynecology (47%). Family practice, internal medicine, and pediatric residencies also require lengthy, well-defined continuity-of-care experiences. CONCLUSION: Family practice, internal medicine, and pediatric programs prepare residents in the broad competencies necessary for primary care practice. To train competent generalist physicians, we recommend that residency programs require training in 90% or more of the 60 components, 50% or more of the components in each of the seven categories, and a continuity-of-care experience for a panel of patients during at least 10% of the entire residency training period.

Retraining the subspecialist for a primary care career: four possible pathways.

The degree to which a reformed U.S. health care system relies on an adequate supply of primary care physicians will determine the urgency of change in the composition of the medical workforce. In many areas of the United States, the demand for primary care physicians, particularly in managed care settings, far exceeds the supply. In contrast, reports of reduced practice opportunities for medical and surgical subspecialists in the same settings are increasing. As opportunities for and incomes of primary care physicians are enhanced, some medical subspecialists may seek retraining in primary care. This article provides a context for understanding the development of physician retraining programs, examines precedents for retraining physicians, describes four possible pathways through which medical subspecialists might acquire primary care training, and emphasizes the importance of defining the scope of practice and necessary skills for providing primary care. Obstacles to retraining appear to be economic (Who will pay? Is the cost worth the benefit?) and jurisdictional (Who will define core competencies? Who will credential programs and trainees?). The current absence of demand for such retraining programs suggests either that marketplace-induced changes will not take place or that the notion of a primary care provider shortage and an oversupply of medical subspecialists is overstated. The inclusion of physician retraining programs in proposed health reform legislation suggests that policymakers are convinced that such programs offer one viable solution to the nation's medical workforce needs.

A retrospective study of patient care needs on admission to an inpatient hospice facility.

BACKGROUND: The care and support of dying patients and their families are among the most important skills of a family physician. In this century, an increasing proportion of deaths have occurred in hospitals with resulting medicalization of the dying process. Hospice care has emerged to focus on the relief of suffering rather than the cure of illness. This descriptive study reports information about the diagnoses, care needs, and attending physicians of a cohort of patients admitted to a free-standing, inpatient hospice program. METHODS: We undertook a retrospective chart review of 335 patients admitted to a hospice program during a 26-month period, collecting data recorded on standardized nursing assessment forms. These forms provided information on 19 biologic, functional, and psychosocial symptom groups at the time of admission. RESULTS: Family physicians were the admitting physicians in a minority of hospice admissions. Pain and mobility problems were the most frequent symptoms encountered. Other common issues included bowel, respiratory, and nutritional problems. Emotional difficulties were noted less frequently than these common biomedical problems. CONCLUSIONS: Family physicians should be trained to address core problems encountered in the care of dying patients. Multidisciplinary team approaches are essential in the management of many problems encountered in hospice care.

Fracture care by family physicians.

This report helps characterize fracture management by family physicians. The findings suggest that family physicians can care for a broad range of acute fractures with healing times at least comparable with the standard of care described by orthopedists. A prospective trial would be necessary to assess fully clinical outcomes resulting from specific fracture management. That distal extremity fractures predominated should guide educators in their decision regarding orthopedic training.

Postpartum urinary retention.

BACKGROUND: Urinary retention is a common and frustrating complication in women during the immediate postpartum period. Physiologic changes in the bladder that occur during pregnancy predispose patients to develop symptomatic retention of urine during the first hours to days after delivery. METHODS: The incidence and characteristics of postpartum urinary retention were researched through a literature review and are illustrated by a case report. RESULTS AND CONCLUSIONS: Postpartum urinary retention has a reported incidence ranging from 1.7 to 17.9 percent. Factors associated with postpartum urinary retention include (1) first vaginal delivery, (2) epidural anesthesia, and (3) Cesarean section. Treatment begins with supportive measures to enhance the likelihood of micturition, such as ambulation, privacy, and a warm bath. If these measures are not successful, catheterization can be performed. If the bladder contains more than 700 mL of urine, prophylactic antibiotics may be warranted, because prolonged or repeated catheterization may be necessary.

Trichomonas infections in men.

Trichomonas vaginalis, a common pathogen in the female genital tract, produces a characteristic clinical picture in women. Less well recognized are the manifestations of Trichomonas infestations of the male genital tract, which include urethritis and chronic prostatitis. Multiple-glass urinalysis and selective use of Trichomonas cultures may improve recognition of this organism in the family practice setting.