The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment.

PURPOSE: Idelalisib is a novel, potent inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), which is prominently expressed in cells of hematopoietic origin. Renal excretion plays a minor role in elimination of idelalisib in humans (~15 % of the dose is excreted in urine). This study evaluated the pharmacokinetics (PK) and safety of idelalisib and GS-563117 (its inactive primary metabolite) in subjects with severe renal impairment and healthy subjects. METHODS: Subjects with severe renal impairment were matched in age, sex, and body mass index with healthy subjects who had normal renal function. Each subject received a single oral dose of idelalisib at 150 mg, and safety assessments and PK analyses were performed. RESULTS: Compared with healthy subjects, the geometric least-squares mean ratio of area under the concentration-time curve from zero to last PK observation (AUC(last)), area under the concentration-time curve from zero to infinity (AUC(inf)), and maximum observed plasma concentration (C(max)) were 127, 127, and 105 % for idelalisib and 124, 124, and 96 % for GS-563117, respectively, in subjects with severe renal impairment. CONCLUSIONS: There were no clinically relevant changes of idelalisib or GS-563117 PK in subjects with severe renal impairment versus matched healthy controls. No relevant relationships were identified between idelalisib or GS-563117 exposures and baseline creatinine clearance. Idelalisib dosing was generally well tolerated with most treatment-emergent adverse events and laboratory abnormalities assessed as grade 1 or 2 in severity. Accordingly, dose adjustments for idelalisib are not necessary in subjects with mild, moderate, or severe renal impairment.

Phylogeography of microbial phototrophs in the dry valleys of the high Himalayas and Antarctica.

High-elevation valleys in dry areas of the Himalayas are among the most extreme, yet least explored environments on Earth. These barren, rocky valleys are subjected to year-round temperature fluctuations across the freezing point and very low availability of water and nutrients, causing previous workers to hypothesize that no photoautotrophic life (primary producers) exists in these locations. However, there has been no work using modern biogeochemical or culture-independent molecular methods to test the hypothesis that photoautotrophs are absent from high Himalayan soil systems. Here, we show that although microbial biomass levels are as low as those of the Dry Valleys of Antarctica, there are abundant microbial photoautotrophs, displaying unexpected phylogenetic diversity, in barren soils from just below the permanent ice line of the central Himalayas. Furthermore, we discovered that one of the dominant algal clades from the high Himalayas also contains the dominant algae in culture-independent surveys of both soil and ice samples from the Dry Valleys of Antarctica, revealing an unexpected link between these environmentally similar but geographically very distant systems. Phylogenetic and biogeographic analyses demonstrated that although this algal clade is globally distributed to other high-altitude and high-latitude soils, it shows significant genetic isolation by geographical distance patterns, indicating local adaptation and perhaps speciation in each region. Our results are the first to demonstrate the remarkable similarities of microbial life of arid soils of Antarctica and the high Himalayas. Our findings are a starting point for future comparative studies of the dry valleys of the Himalayas and Antarctica that will yield new insights into the cold and dry limits to life on Earth.

Detection of the intrinsic size of Sagittarius A* through closure amplitude imaging.

We have detected the intrinsic size of Sagittarius A*, the Galactic center radio source associated with a supermassive black hole, showing that the short-wavelength radio emission arises from very near the event horizon of the black hole. Radio observations with the Very Long Baseline Array show that the source has a size of 24 +/- 2 Schwarzschild radii at 7-millimeter wavelength. In one of eight 7-millimeter epochs, we also detected an increase in the intrinsic size of 60(-17)(+25)%. These observations place a lower limit to the mass density of Sagittarius A* of 1.4 x 10(4) solar masses per cubic astronomical unit.

Administration of open-ended test questions by computer in a clerkship final examination.

PURPOSE: To evaluate the reliability, efficiency, and cost of administering open-ended test questions by computer. METHODS: A total of 1,194 students in groups of approximately 30 were tested at the end of a required surgical clerkship from 1993 through 1998. For the academic years 1993--94 and 1994--95, the administration of open-ended test questions by computer was compared experimentally with administration by paper-and-pencil for two years. The paper-and-pencil mode of the test was discontinued in 1995, and the administration of the test by computer was evaluated for all students through 1998. Computerized item analysis of responses was added to the students' post-examination review session in 1996. RESULTS: There was no significant difference in the performances of 440 students (1993--94 and 1994--95) on the different modes of test administration. Alpha reliability estimates were comparable. Most students preferred the computer administration, which the faculty judged to be efficient and cost-effective. The immediate availability of item-analysis data strengthened the post-examination review sessions. CONCLUSION: Routine administration of open-ended test questions by computer is practical, and it enables faculty to provide feedback to students immediately after the examination.

Patients don't present with five choices: an alternative to multiple-choice tests in assessing physicians' competence.

PURPOSE: To evaluate an open-ended, computer-scored testing format designed to overcome certain limitations of multiple-choice questions. METHOD: Test items covering content in family medicine were administered in two different formats to 7,036 resident physicians in 380 training programs, and to 35 experienced, board-certified physicians in conjunction with the In-training Examination of the American Board of Family Practice. Examinees completed a booklet of 40 open-ended, uncued (UnQ) test items by selecting the answer to each item from a list of over 500 responses. Similar items were administered using the standard multiple-choice question (MCQ) format. One year later, another test of 40 UnQ test items dealing with core content in family medicine was administered to 7,138 residents. RESULTS: Examinees completed over 560,000 UnQ responses with high compliance and few errors. Both reliability and validity for the UnQ format were higher than for the MCQ format, and the UnQ items discriminated more accurately among levels of physicians' experience. The UnQ format almost eliminated the possibility that the physicians could answer questions by sight recognition or random guessing, and it was particularly effective in measuring knowledge of core content. CONCLUSIONS: This study supports the feasibility of administering open-ended test items to enhance tests of physicians' competence.

A statewide system to track medical students' careers: the Pennsylvania model.

In 1994 the Commonwealth of Pennsylvania announced a statewide Generalist Physician Initiative (GPI) modeled after The Robert Wood Johnson Foundation's GPI. Three-year grants totaling more than $9 million were awarded to seven of Pennsylvania's medical schools, including two that had already received GPI grants from the foundation. Stimulated by these initiatives, the state's six allopathic and two osteopathic medical schools decided to work together to develop a collaborative longitudinal tracking system to follow the careers of all their students from matriculation into their professional careers. This statewide data system, which includes information for more than 18,000 students and graduates beginning with the entering class of 1982, can be used to evaluate the impact of the Pennsylvania GPI, and it also yielded a local longitudinal tracking system for each medical school. This paper outlines the concept of the system, its technical implementation, and the corresponding implications for other medical schools considering the development of similar outcomes assessment systems.

Who is a generalist? An analysis of whether physicians trained as generalists practice as generalists.

Accurate data on the number of generalist physicians are needed to monitor the physician workforce and to plan for future requirements in the changing health care system. This study assessed the relationship between two frequently used definitions of a generalist physician: completion of graduate medical education (GME) in only a generalist discipline and physician's self-report of practicing as a generalist. Data for 4,808 physician graduates from six Pennsylvania medical schools from 1986 to 1991 were analyzed using information from the GME tracking census of the Association of American Medical Colleges and the Physician Masterfile of the American Medical Association. Of 1,291 physicians trained in a generalist discipline, 1,205 (93%) reported practicing as generalists. Conversely, of the 3,517 not trained in a generalist discipline, 3,358 (95%) were not practicing as generalists. These results indicate GME training is a valid predictor of self-reported practice and provide baseline data to monitor future changes.

Students' satisfaction and perceptions of attending physicians' and residents' teaching role.

BACKGROUND: Changes in the health care system imply that fewer patients will be admitted to hospitals and attending physicians will be devoting more time to clinical activities with less time for student education. METHODS: Surveys of third-year students were conducted for 5 consecutive years at Jefferson Medical College at the end of the required 6-week surgical clerkship at the university hospital or at one of the eight affiliates. RESULTS: The numbers of new inpatients and outpatients encountered by students were not significantly related to students' overall satisfaction. The ratings of teaching rounds and conferences were significant predictors of satisfaction with the clerkship, as were the ratings of residents' teaching. CONCLUSIONS: As medical education shifts to ambulatory settings, didactic teaching such as rounds and conferences should be maintained and efforts to enhance the teaching skills of residents should be encouraged.

Relationship of students' perceptions of faculty to scholastic achievement: are popular instructors better educators?

Student evaluation of the faculty is a standard practice in most medical schools. Implied in these evaluations is the motion that popular instructors (ie, those considered outstanding by the students) are better educators, whose teaching translates into higher scores for their students on examinations. We tested this hypothesis by comparing students' evaluations of the faculty with levels of academic achievement in a second-year pathology course. Objective measures of academic achievement included scores on final comprehensive examinations, final course grade, and performance on the United States Medical Licensing Examination (USMLE). During the 4 years studied (1990 to 1995), students belonging to groups with the highest ratings for their instruction performed no better than those with the poorest ratings. There was no correlation between students' perceptions of quality in teaching and their academic achievement. Our results indicate that students' evaluations of the faculty are subjective and do not correlate with objective results used in the assessment of student knowledge. Popular instructors are not necessarily better educators.

The virtues of extended matching and uncued tests as alternatives to multiple choice questions.

The objectives of this study were to compare the reliability and validity of written test formats that are widely used in medical education (multiple choice, uncued, extended matching, and true/false) and evaluate the effects of uncued examinations on long-term retention of medical knowledge. Uncued tests were introduced into a traditional course in general and systemic pathology (six interim tests). In the following year, students were given eight tests written in the four formats, each being used twice. The academic achievement of students in these 2 years was compared with that of students in 2 previous years, in which multiple choice tests were used. Measures of academic achievement included performance on a final comprehensive examination and the United States Medical Licensing Examination (USMLE). Student performance on uncued tests was consistent over time (i.e., there was no learning curve). Mean scores ranged from 77% to 84%, and coefficient alpha reliability estimates on 100-item tests were excellent (0.79 to 0.90). Extended matching tests were also reliable, with a mean coefficient alpha of 0.90. There was no significant relationship between test format and student performance on subsequent comprehensive examinations. Our results indicate that extended matching and uncued tests have considerable advantages over multiple choice and true/false examinations. They are more reliable, better able to discriminate the well-prepared from the marginal student, and well suited for tested core knowledge. Contrary to our expectation, extended matching questions with 20 choices presented to the student were as statistically reliable and valid as uncued queries with several hundred choices.

Assessment of physicians' interest in primary care training/retraining.

PURPOSE: To assess generalists and specialists interest in primary care training and the factors associated with this interest. METHOD: The study sample was drawn from the alumni of the Jefferson Medical College of Thomas Jefferson University (classes of 1970-1990) who were practicing in Pennsylvania. Family practitioners and general internists were defined as generalists; obstetrician-gynecologists (ob-gyns) and internal medicine subspecialists were defined as specialists. In 1995 a questionnaire was mailed consisting of 46 items assessing the physicians' interest in participating in primary care educational programs, reasons for any such interest, and preferences for content. Two items on the specialists' questionnaire asked about changing careers from specialist to generalist, and two items on the generalists' questionnaire asked about broadening the scope of their practices. RESULTS: The response rate was 54% (381/707). In all, 78% of the physicians expressed interest in primary care training. The generalists were more interested in primary care training than were the specialists (p < .001). The ob-gyns were more interested in primary care training than were the medical subspecialists (p = .01). Few of the medical subspecialists and no ob-gyns were influenced by plans to change careers to primary care. More of the ob-gyns than the medical subspecialists were motivated by plans to shift emphasis to provide more primary care. CONCLUSION: The results suggest (1) that although many specialists have an interest in primary care training, it is rarely motivated by plans to change to primary care practice, and (2) that generalists are very interested in expanding their abilities. Both of these findings should be considered in workforce planning.

Pain and disability in families of chronic noncancer pain patients.

The authors conducted a cross-sectional study to determine the prevalence of chronic noncancer pain or disability in first-degree relatives of patients who had sustained a physically traumatic injury with resultant chronic pain. A control group of general internal medicine patients was also interviewed about existence in their family of chronic pain or of disability, either pain-related or related to nonpainful chronic illness. None of the control patients were themselves experiencing acute or chronic pain. There was no statistically significant difference between the two groups in the prevalence of chronic pain or disability in family members. The study's findings suggest that chronic noncancer pain patients should not be viewed as a uniform group with regard to learned behaviors and/or familial aggregation.

Retrospective study of 2,200 involuntary psychiatric admissions and readmissions.

OBJECTIVE: The authors describe demographic data, the distribution of diagnoses, and comorbid psychoactive substance use in a large sample of patients involuntarily admitted to a psychiatric hospital from multiple crisis centers and explore the relative roles these variables may play in service utilization and admission rates. METHOD: Data on demographic characteristics and comorbid psychoactive substance use in 2,200 consecutive involuntary hospital admissions of 1,755 psychiatric patients were gathered. Pertinent demographic and comorbidity data at first admission for the 1,755 patients, 314 of whom were admitted more than once, were analyzed; then the data for the 1,441 single-admission patients and the data at first admission for the 314 patients who had multiple admissions were compared. Finally, the diagnostic distribution and comorbid psychoactive substance use in all 2,200 admissions were investigated, with attention to a subgroup of 88 high-risk patients (those with three or more admissions) who represented a total of 307 admissions. RESULTS: Specific demographic characteristics were represented in the patient group at a high level of statistical significance. The diagnosis of schizophrenia was significantly overrepresented. Schizophrenia and psychosis not elsewhere classified clustered in the subgroup with a high risk of readmission. CONCLUSIONS: The results suggest a specific profile for the patient with heightened risk of hospital admission: a young, unmarried, African American male who has schizophrenia without comorbid substance abuse. An effect size data analysis identified marital status and a diagnosis of schizophrenia as the variables associated with the greatest likelihood of admission. Unexpectedly, the impact of comorbid psychoactive substance use was relatively modest and showed a uniform distribution among diagnostic groups.

Gender differences among civilly committed schizophrenia subjects.

The authors describe a sample of 815 acutely ill schizophrenia patients hospitalized under a petition for involuntary inpatient treatment and illustrate how this group of patients can be considered as more representative of involuntary commitment status than more traditional "involuntary" patients drawn from State hospitals' wards. Available demographics of the general population from which the sample was drawn are also presented for comparison. The authors then report the gender distribution of several variables--age, marital status, psychoactive substance use, comorbidity, length of stay, and frequency of readmissions--among the study sample and discuss the relevance of these findings.

Primary care and nonprimary care physicians' concerns in practice and perceptions of medical school curriculum.

The purpose of the present study is to address the issue of physicians' concerns in practice and their perception of a medical school's curriculum with an emphasis on comparisons between primary and nonprimary care physicians. The sample consisted of 663 physicians who graduated from Jefferson Medical College (JMC) between 1982 and 1986, and also responded to a mailed questionnaire. Comparisons were made between physicians in primary care (n=234) and in nonprimary care (n=429) specialties on their responses regarding concerns in medical practice and evaluation of the medical school curriculum. Primary care physicians were more concerned about the time for their professional development whereas nonprimary care physicians were more concerned about an oversupply of physicians in their specialties, prospective hospital payment, and malpractice litigation. Regardless of the specialties, the physicians overall seemed very concerned about their personal time. Interpersonal skills were regarded by all respondents as an important aspect of the medical school's curriculum. The importance of psychological, social, and cultural factors in the curriculum was strongly supported by these physicians' responses, particularly among primary care and women physicians.

Students' psychosocial characteristics as predictors of academic performance in medical school.

PURPOSE: To investigate the incremental effects of selected psychosocial measures--beyond the effects of conventional admission measures--in predicting students' academic performances in medical school. METHODS: In 1989-90, 210 second-year students at Jefferson Medical College were each asked to complete 11 psychosocial questionnaires that were then used as predictors of performance measures in medical school. The students' scores on three subtests of the Medical College Admission Test (MCAT) were also used as predictors. Three composite measures of performance were used as the criterion measures: basic science examination grades, clinical examination grades, and ratings of clinical competence. A multiple regression algorithm (general linear model) was used for statistical analysis. RESULTS: The response rate was 83% (175 students). When the psychosocial measures were added to the statistical models in which the common variances of the MCAT scores were already determined, significant increments in the common variances were observed for two of the three performance measures: basic science grades and clinical examination grades. Whereas only 4% of the common variance in the ratings of clinical competence could be accounted for by the MCAT scores, 14% could be accounted for by the psychosocial measures. CONCLUSION: The "noncognitive," or psychosocial, measures increased the magnitude of the relationships between the predictive and criterion measures of the students' academic performances, beyond the magnitude attained when only the conventional admission measures were used. Therefore, psychosocial measures should be considered as significant and unique predictors of performance in medical school.