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Biomedical subjects

J S Weissman

Publications and source records attributed to J S Weissman.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative genetic analysis in Saccharomyces cerevisiae using epistatic miniarray profiles (E-MAPs) and its application to chromatin functions.

The use of the budding yeast Saccharomyces cerevisiae as a simple eukaryotic model system for the study of chromatin assembly and regulation has allowed rapid discovery of genes that influence this complex process. The functions of many of the proteins encoded by these genes have not yet been fully characterized. Here, we describe a high-throughput methodology that can be used to illuminate gene function and discuss its application to a set of genes involved in the creation, maintenance and remodeling of chromatin structure. Our technique, termed E-MAPs, involves the generation of quantitative genetic interaction maps that reveal the function and organization of cellular proteins and networks.

Chromatin↗
PubMed2001

Preparedness for clinical practice: reports of graduating residents at academic health centers.

CONTEXT: Medical educators are seeking improved measures to assess the clinical competency of residents as they complete their graduate medical education. OBJECTIVE: To assess residents' perceptions of their preparedness to provide common clinical services during their last year of graduate medical education. DESIGN, SETTING, AND PARTICIPANTS: A 1998 national survey of residents completing their training in 8 specialties (internal medicine, pediatrics, family practice, obstetrics/gynecology, general surgery, orthopedic surgery, psychiatry, and anesthesiology) at academic health centers in the United States. A total of 2626 residents responded (response rate, 65%). MAIN OUTCOME MEASURES: Residents' reports of their preparedness to perform clinical and nonclinical tasks relevant to their specialties. RESULTS: Residents in all specialties rated themselves as prepared to manage most of the common conditions they would encounter in their clinical career. However, more than 10% of residents in each specialty reported that they felt unprepared to undertake 1 or more tasks relevant to their disciplines, such as caring for patients with human immunodeficiency virus/acquired immunodeficiency syndrome or substance abuse (family practice) or nursing home patients (internal medicine); performance of spinal surgery (orthopedic surgery) or abdominal aortic aneurysm repair (general surgery); and management of chronic pain (anesthesiology). CONCLUSIONS: Overall, residents in their last year of training at academic health centers rate their clinical preparedness as high. However, opportunities for improvement exist in preparing residents for clinical practice.

Academic Medical Centers↗
PubMed2001

Racial differences in cardiac revascularization rates: does "overuse" explain higher rates among white patients?

BACKGROUND: Coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) are well-established treatments for symptomatic coronary artery disease. Previous studies have documented racial differences in rates of use of these cardiac revascularization procedures. Other studies suggest that these procedures are overused: that is, they are done for patients with clinically inappropriate indications. OBJECTIVE: To test the hypothesis that the higher rate of cardiac revascularization among white patients is associated with a higher prevalence of overuse (revascularization for clinically inappropriate indications) among white patients than among African-American patients. DESIGN: Observational cohort study using Medicare claims and medical record review. SETTING: 173 hospitals in five U.S. states. PARTICIPANTS: A stratified, weighted, random sample of 3960 Medicare beneficiaries who underwent coronary angiography during 1991 and 1992; 1692 of these patients underwent 1711 revascularization procedures within 90 days. MEASUREMENTS: The proportion of CABG and PTCA procedures rated appropriate, uncertain, and inappropriate according to RAND criteria, and the multivariate odds of undergoing inappropriate revascularization among African-American patients and white patients. RESULTS: After angiography, rates of PTCA (23% vs. 19%) and CABG surgery (29% vs. 17%) were significantly higher among white patients than among African-American patients. The respective rates of inappropriate PTCA and CABG surgery were 14% and 10%. Among the study states, rates of inappropriate use ranged from 4% to 24% for PTCA and 0% to 14% for CABG surgery. White patients were more likely than African-American patients to receive inappropriate PTCA (15% vs. 9%; difference, 6 percentage points [95% CI, -0.4 to 12.7 percentage points]), and difference by race was statistically significant among men (20% vs. 8%; difference, 12 percentage points [CI, 1.2 to 21.7 percentage points]). Rates of inappropriate CABG surgery did not differ by race (10% in both groups). CONCLUSIONS: Among a large and diverse sample of Medicare beneficiaries in five U.S. states, overuse of PTCA was greater among white men than among other groups, but this difference did not fully account for racial disparities in revascularization. Overuse of cardiac revascularization varied significantly by geographic region.

Aged↗
PubMed2001

Status of clinical research in academic health centers: views from the research leadership.

CONTEXT: The changing state of the health care system in the United States may be adversely affecting clinical research conducted in academic health centers (AHCs). Few formal data have been gathered about the nature and extent of the problems facing clinical research or the effects of remedies undertaken by AHCs. OBJECTIVES: To assess the perceived quality and health of the clinical research enterprise and to determine challenges and adaptations to current environmental pressures. DESIGN, SETTING, AND PARTICIPANTS: Mailed survey conducted between December 1998 and March 1999 of a subsample of department chairs and senior research administrators (SRAs) in all US medical schools. Of the 712 potential respondents, 478 completed a questionnaire, yielding an overall response rate of 67.1% (64.8% for SRAs and 67.8% for department chairs). MAIN OUTCOME MEASURES: Ratings of overall health/robustness of clinical research, quality of research in 5 domains, extent of challenges to performing research, and sense of urgency in responding to research challenges; formal strategies for research-related tasks and their effects. RESULTS: Slightly more than half (52%) of all respondents rated the health of the clinical research enterprise as good or excellent compared with 63% for nonclinical research (P<.001). Respondents were most likely to rate nonclinical research as high in quality (79%) compared with 70% for phase 3 clinical trials, 67% for translational research, 65% for phase 1 and 2 trials, and 57% for health services research (for all comparisons with nonclinical research, P<.001). Pressure on clinical faculty to see patients was perceived as a moderate-to-large problem for clinical research by the largest percentage of respondents (93%), followed by insufficient clinical revenues (89%), recruiting trained researchers (75%), lack of external support for clinical research (72%), competition from contract research organizations (48%), problems introduced by the institutional review board process (38%), and finding research participants (37%). In total, 81% of respondents considered the challenges facing clinical research in AHCs to be urgent or extremely urgent. CONCLUSIONS: Academic leaders perceive clinical research activities in AHCs to be less healthy, of poorer quality, and facing greater challenges than nonclinical research activities. Many AHCs do not have policies or mechanisms to address challenges facing the clinical research mission. Even among those with such policies, more than half do not believe these policies have had large positive effects. Our findings support the view that the clinical research workforce and infrastructure may need to be expanded and strengthened to keep pace with advances in basic research.

Academic Medical Centers↗
PubMed2001

Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI(+)] prion.

The yeast prion [PSI(+)] results from self-propagating aggregates of Sup35p. De novo formation of [PSI(+)] requires an additional non-Mendelian trait, thought to result from a prion form of one or more unknown proteins. We find that the Gln/Asn-rich prion domains of two proteins, New1p and Rnq1p, can control susceptibility to [PSI(+)] induction as well as enhance aggregation of a human glutamine expansion disease protein. [PSI(+)] inducibility results from gain-of-function properties of New1p and Rnq1p aggregates rather than from inactivation of the normal proteins. These studies suggest a molecular basis for the epigenetic control of [PSI(+)] inducibility and may reveal a broader role for this phenomenon in the physiology of protein aggregation.

Amino Acid Sequence↗
PubMed2001

Conformational diversity in a yeast prion dictates its seeding specificity.

A perplexing feature of prion-based inheritance is that prions composed of the same polypeptide can evoke different phenotypes (such as distribution of brain lesions), even when propagated in genetically identical hosts. The molecular basis of this strain diversity and the relationship between strains and barriers limiting transmission between species remain unclear. We have used the yeast prion phenomenon [PSI+]4 to investigate these issues and examine the role that conformational differences may have in prion strains. We have made a chimaeric fusion between the prion domains of two species (Saccharomyces cerevisae and Candida albicans) of Sup35, the protein responsible for [PSI+]. Here we report that this chimaera forms alternate prion strains in vivo when initiated by transient overexpression of different Sup35 species. Similarly, in vitro the purified chimaera, when seeded with different species of Sup35 fibres, establishes and propagates distinct amyloid conformations. These fibre conformations dictate amyloid seeding specificity: a chimaera seeded by S. cerevisiae fibres efficiently catalyses conversion of S. cerevisiae Sup35 but not of C. albicans Sup35, and vice versa. These and other considerations argue that heritable prion strains result from self-propagating conformational differences within the prion protein itself. Moreover, these conformational differences seem to act in concert with the primary structure to determine a prion's propensity for transmission across a species barrier.

Amino Acid Sequence↗
PubMed2001

The ins and outs of GroEL-mediated protein folding.

Two papers recently published in Cell investigate the role of protein encapsulation by GroEL in assisting folding. The first shows how encapsulation can "smooth" the folding landscape, accelerating folding of some proteins. The second defines a confinement-independent pathway, which allows GroEL to assist folding of substrates too large to be encapsulated.

Adenosine Triphosphate↗
PubMed2001

Residents' preferences and preparation for caring for underserved populations.

Access to care by low-income persons and residents of rural and poor inner-city areas is a persistent problem, yet physicians tend to be maldistributed relative to need. The objectives were to describe preferences of resident physicians to locate in underserved areas and to assess their preparedness to provide service to low-income populations. A national survey was made of residents completing their training in eight specialties at 162 US academic health center hospitals in 1998, with 2,626 residents responding. (Of 4,832 sampled, 813 had invalid addresses or were no longer in the residency program. Among the valid sample of 4,019, the response rate was 65%.) The percentage of residents ranking public hospitals, rural areas, and poor inner-city areas as desirable employment locations and the percentage feeling prepared to provide specified services associated with indigent populations were ascertained. Logistic regressions were used to calculate adjusted percentages, controlling for sex, race/ethnicity, international medical graduate (IMG) status, plans to subspecialize, ownership of hospital, specialty, and exposure to underserved patients during residency. Only one third of residents rated public hospitals as desirable settings, although there were large variations by specialty. Desirability was not associated with having trained in a public hospital or having greater exposure to underserved populations. Only about one quarter of respondents ranked rural (26%) or poor inner-city (25%) areas as desirable. Men (29%, P <.01) and noncitizen IMGs (43%, P <.01) were more likely than others to prefer rural settings. Residents who were more likely to rate poor inner-city settings as desirable included women (28%, P =.03), noncitizen IMGs (35%, P =.01), and especially underrepresented minorities (52%, P <.01). Whereas about 90% or more of residents felt prepared to treat common clinical conditions, only 67% of residents in four primary care specialties felt prepared to counsel patients about domestic violence or to care for human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) or substance abuse patients (all 67%). Women were more likely than men to feel prepared to counsel patients about domestic violence (70% vs. 63%, P =.002) and depression (83% vs. 75%, P <.01). Underrepresented minority residents were more likely than other residents to feel prepared to counsel patients about domestic violence (P <.01) and compliance with care (P =.04). Residents with greater exposure to underserved groups were more prepared to counsel patients about domestic violence (P =.01), substance abuse (P =.01), and to treat patients with HIV/AIDS (P =.01) or with substance abuse problems (P <.01). This study demonstrates the need to expose graduate trainees to underserved populations and suggests a continuing role of minorities, women, and noncitizen physicians in caring for low-income populations.

Academic Medical Centers↗
PubMed2001

Understanding the relationship between market competition and students' ratings of the managed care content of their undergraduate medical education.

PURPOSE: The increase in managed care has led to questions about the inadequacy of instruction undergraduate medical students receive in curricular areas related to managed care. This study examined (1) the percentages of graduating medical students who felt they had received inadequate instruction in six curricular content areas (CCAs): primary care, care of ambulatory patients, health promotion and disease prevention, medical care cost control, teamwork with other health professionals, and cost-effective medical practice; and (2) whether the market competitiveness of these students' medical schools affected their reports of inadequacy of instruction in these CCAs. METHOD: Data from the Association of American Medical Colleges' Graduation Questionnaires (GQs) from 1994 to 1997 were analyzed. The GQ asked graduating students to rate the adequacy of instruction they had received in the six CCAs. Students' ratings were collapsed into the dichotomous variables "inadequate" and "not inadequate." The market competitiveness of medical schools was determined using the four-stage Market Evolution Model developed by the University HealthSystem Consortium. Only responses from students graduating from medical schools that could be staged for all four years of the study were analyzed. Statistical analyses were performed to determine trends for each CCA by year, across the entire study period, by market stage, and by market stage across the entire study period. RESULTS: A total of 39,136 respondents from 86 medical schools were used in the study. The percentages of graduating medical students who reported inadequate instruction decreased over the study period for five of the six CCAs: primary care (27.6% in 1994 to 13.7% in 1997), ambulatory care (37.4% to 23. 9%), medical care cost control (62.9% to 52.9%) cost-effectiveness of medical practice (62.7% to 53.9%), and health promotion and disease prevention (44.4% to 23.7%); all at p <0.001. The responses for inadequacy of instruction for teamwork with other health professionals remained steady from 1994 to 1996 (10.2% to 10.6%), then increased 21.8% in 1997. Over the course of the study, students graduating from schools in more competitive markets (Stage 3 or Stage 4) were more likely to report inadequate instruction in three CCAs, primary care, ambulatory care, and health promotion and disease prevention, than were those graduating from schools in less competitive markets (Stage 1 and Stage 2). Conversely, students graduating from schools in the more competitive health care markets were less likely to report inadequate instruction in cost-effectiveness and cost control than were students from schools in less competitive markets. CONCLUSION: Graduating students' reports of inadequacy of instruction decreased over the study period for five of the six CCAs, increasing only for teamwork with other professionals. Findings were mixed with regard to the relationship of medical schools' market competitiveness and graduating students' reports of inadequacy of instruction. More research is needed to confirm graduating students' perceptions of the inadequacy of their instruction in CCAs related to managed care, particularly once they have gained experience treating patients in managed care environments.

Ambulatory Care↗
PubMed2001

Market competition and patient-oriented research: the results of a national survey of medical school faculty.

PURPOSE: To understand the effect of market competition on patient-oriented research at U.S. medical schools and teaching hospitals. METHOD: From a multi-stage stratified, random sample, the authors surveyed 3,804 research faculty at 117 U.S. medical schools. The questionnaire assessed five variables, the type of research conducted by the respondent, changes in patient-oriented and non-clinical research in the preceding three years, amount of time spent on patient care, market stage of the respondent's institution, and research productivity. RESULTS: Of the 2,336 faculty who responded (62%), 84% of those conducting patient-oriented research and 80% of those engaged in non-clinical research reported conducting the same amount of research or more in 1996-1997 than in the preceding three years. However, both patient-oriented and non-clinical researchers in the most competitive health care markets and those with high levels of patient care duties were most likely to report decreases in the amounts of such research conducted in the previous three years. Further, researchers reporting such decreases had been as productive in recent years and over their careers as had those who did not report a decrease. CONCLUSIONS: This study provides additional evidence of the negative relationships that exist between high levels of market competition and patient care services on the patient-oriented and non-clinical research missions of teaching hospitals.

Data Collection↗
PubMed2001

The action of molecular chaperones in the early secretory pathway.

The endoplasmic reticulum (ER) serves as a way-station during the biogenesis of nearly all secreted proteins, and associated with or housed within the ER are factors required to catalyze their import into the ER and facilitate their folding. To ensure that only properly folded proteins are secreted and to temper the effects of cellular stress, the ER can target aberrant proteins for degradation and/or adapt to the accumulation of misfolded proteins. Molecular chaperones play critical roles in each of these phenomena.

Animals↗
PubMed2000

Biochemical basis of oxidative protein folding in the endoplasmic reticulum.

The endoplasmic reticulum (ER) supports disulfide bond formation by a poorly understood mechanism requiring protein disulfide isomerase (PDI) and ERO1. In yeast, Ero1p-mediated oxidative folding was shown to depend on cellular flavin adenine dinucleotide (FAD) levels but not on ubiquinone or heme, and Ero1p was shown to be a FAD-binding protein. We reconstituted efficient oxidative folding in vitro using FAD, PDI, and Ero1p. Disulfide formation proceeded by direct delivery of oxidizing equivalents from Ero1p to folding substrates via PDI. This kinetic shuttling of oxidizing equivalents could allow the ER to support rapid disulfide formation while maintaining the ability to reduce and rearrange incorrect disulfide bonds.

Binding Sites↗
PubMed2000

Racial disparities in access to renal transplantation--clinically appropriate or due to underuse or overuse?

BACKGROUND: Despite abundant evidence of racial disparities in the use of surgical procedures, it is uncertain whether these disparities reflect racial differences in clinical appropriateness or overuse or underuse of inappropriate care. METHODS: We performed a literature review and used an expert panel to develop criteria for determining the appropriateness of renal transplantation for patients with end-stage renal disease. Using data from five states and the District of Columbia on patients who had started to undergo dialysis in 1996 or 1997, we selected a random sample of 1518 patients (age range, 18 to 54 years), stratified according to race and sex. We classified the appropriateness of patients as data on candidates for transplantation and analyzed rates of referral to a transplantation center for evaluation, placement on a waiting list, and receipt of a transplant according to race. RESULTS: Black patients were less likely than white patients to be rated as appropriate candidates for transplantation according to appropriateness criteria based on expert opinion (71 blacks [9.0 percent] vs. 152 whites [20.9 percent]) and were more likely to have had incomplete evaluations (368 [46.5 percent] vs. 282 [38.8 percent], P<0.001 for the overall chi-square). Among patients considered to be appropriate candidates for transplantation, blacks were less likely than whites to be referred for evaluation, according to the chart review (90.1 percent vs. 98.0 percent, P=0.008), to be placed on a waiting list (71.0 percent vs. 86.7 percent, P=0.007), or to undergo transplantation (16.9 percent vs. 52.0 percent, P<0.001). Among patients classified as inappropriate candidates, whites were more likely than blacks to be referred for evaluation (57.8 percent vs. 38.4 percent), to be placed on a waiting list (30.9 percent vs. 17.4 percent), and to undergo transplantation (10.3 percent vs. 2.2 percent, P<0.001 for all three comparisons). CONCLUSIONS: Racial disparities in rates of renal transplantation stem from differences in clinical characteristics that affect appropriateness as well as from underuse of transplantation among blacks and overuse among whites. Reducing racial disparities will require efforts to distinguish their specific causes and the development of interventions tailored to address them.

Adult↗
PubMed2000

Unmet health needs of uninsured adults in the United States.

CONTEXT: In 1998, 33 million US adults aged 18 to 64 years lacked health insurance. Determining the unmet health needs of this population may aid efforts to improve access to care. OBJECTIVE: To compare nationally representative estimates of the unmet health needs of uninsured and insured adults, particularly among persons with major health risks. DESIGN AND SETTING: Random household telephone survey conducted in all 50 states and the District of Columbia through the Behavioral Risk Factor Surveillance System. PARTICIPANTS: A total of 105,764 adults aged 18 to 64 years in 1997 and 117,364 in 1998, classified as long-term (>/=1 year) uninsured (9.7%), short-term (<1 year) uninsured (4.3%), or insured (86.0%). MAIN OUTCOME MEASURES: Adjusted proportions of participants who could not see a physician when needed due to cost in the past year, had not had a routine checkup within 2 years, and had not received clinically indicated preventive services, compared by insurance status. RESULTS: Long-term- and short-term-uninsured adults were more likely than insured adults to report that they could not see a physician when needed due to cost (26.8%, 21.7%, and 8.2%, respectively), especially among those in poor health (69.1%, 51.9%, and 21.8%) or fair health (48.8%, 42.4%, and 15.7%) (P<.001). Long-term-uninsured adults in general were much more likely than short-term-uninsured and insured adults not to have had a routine checkup in the last 2 years (42.8%, 22.3%, and 17.8%, respectively) and among smokers, obese individuals, binge drinkers, and people with hypertension, elevated cholesterol, diabetes, or human immunodeficiency virus risk factors (P<.001). Deficits in cancer screening, cardiovascular risk reduction, and diabetes care were most pronounced among long-term-uninsured adults. CONCLUSIONS: In our study, long-term-uninsured adults reported much greater unmet health needs than insured adults. Providing insurance to improve access to care for long-term-uninsured adults, particularly those with major health risks, could have substantial clinical benefits. JAMA. 2000;284:2061-2069

Adult↗