Training physicians for the future US Health Care System.

Changes in US medical education have not yet paralleled the extraordinary recent advances in biomedical science. This is about to change with recent innovations in undergraduate medical education (UME) pedagogy. These changes include the 'flipped classroom,' new Liaison Committee on Medical Education requirements for learners to function collaboratively on health care teams that include other health professionals, the comprehensive development of professional identity in learning communities and adoption of measurable outcomes, termed 'entrustable professional activities'. These innovations offer the opportunity for a consistent longitudinal educational continuum in the US from UME to Graduate Medical Education (GME) and continuing medical education (CME). Such innovation addresses both individual patient and population health, with the potential for increasing shared decision-making and patient satisfaction. These innovations in US medical education have the potential to address the Institute for Healthcare Improvement's triple aim of improving patient care, improving the health of populations and reducing the per capita cost of health care.

Dimensions of impulsive behavior in obese, overweight, and healthy-weight adolescents.

Impulsivity is a multidimensional construct that has been linked with obesity. To explore profiles of impulsive behavior potentially associated with adolescent weight status, we measured multiple dimensions of impulsivity (delay discounting, sustained attention, and behavioral disinhibition) using laboratory behavioral tasks in a sample of adolescents (N=61). For comparison purposes, we also assessed self-reported impulsive behavior with the BIS-11-A. Participants differed in body mass index: obese (n=21), overweight (n=20), and healthy-weight (n=20). Obese and overweight adolescents were more impulsive on the measure of delay discounting than healthy-weight adolescents, but no difference was found between obese and overweight adolescents on this measure. Obese adolescents also were more impulsive on the measure of inattention compared to overweight and healthy-weight adolescents, who did not differ on this measure. Behavioral disinhibition had no association with weight status, nor did the self-report measure of impulsivity. The additive pattern of these findings for certain laboratory behavioral measures indicates that obese adolescents are more impulsive than their healthy-weight counterparts on two dimensions of behavior, whereas overweight adolescents are more impulsive on only one dimension. Consequently, adolescents who are impulsive on two dimensions of behavior (i.e., delay discounting and sustained attention) may be at greater risk of becoming obese rather than overweight compared to adolescents who are impulsive on only one dimension of behavior (i.e., delay discounting).

Influence of standing estrus before an injection of GnRH during a beef cattle fixed-time AI protocol on LH release, subsequent concentrations of progesterone, and steriodogenic enzyme expression.

Beef cows that exhibit estrus before fixed-time AI have been reported to have increased pregnancy success and increased concentrations of progesterone during the subsequent estrous cycle. Therefore, these experiments were conducted to evaluate if initiation of standing estrus before an injection of GnRH during a fixed-time AI protocol affected LH pulses, subsequent concentrations of progesterone, and luteal steroidogenic enzyme expression. In Experiments 1 and 2, cows were treated with the CO-Synch protocol (100 µg GnRH day -9, 25 mg PGF(2α) day -2, and 100 µg GnRH day 0) and allotted to one of two treatments: 1) cows that initiated estrus before GnRH on day 0 (estrus; n = 5) or 2) cows that did not initiate estrus and were induced to ovulate by the GnRH on day 0 (no estrus; n = 5). In Experiment 1, blood samples were collected at 15-min intervals from 0 to 6 (bleed 1), 12 to 20 (bleed 2), 26 to 34 (bleed 3), and 40 to 48 (bleed 4) h after GnRH. Daily blood samples were collected for 17 d. Initiation of estrus before the GnRH injection had no effect on LH release or the pattern of progesterone increase; however, cows detected in estrus had overall increased (P = 0.002) concentrations of progesterone compared with cows not in estrus. In Experiment 2, estrus was detected with the HeatWatch system. Location and size of the ovulatory follicle was determined on day 0 by transrectal ultrasonography at time of injection with GnRH. Blood samples were collected on days 3, 4, 5, 7, and 9; luteal tissue was collected on day 10 (n = 4 estrus and n = 9 no estrus) from corpus luteum (CL) originating from similar-sized follicles (13.0 to 16.0 mm). Total cellular RNA was extracted, and relative mRNA levels were determined by real-time reverse transcription PCR and corrected for GAPDH. There was no effect of estrus on CL weight or concentrations of progesterone. In addition, there was no effect of estrus, follicle size, or CL weight on luteal expression of LH receptor, StAR, CYP11A1, or 3ßHSD. However, there was a correlation between follicle size and CL weight (P = 0.01; R(2) = 0.43); for every increase of 1 mm in follicle size, CL weight increased by 1.5 g. In summary, estrus did not influence release of LH, CL weight, progesterone concentrations, or expression of steriodogenic enzymes. However, as follicle size increased, CL weight increased; therefore, both follicle size and CL weight were associated with progesterone concentrations.

Identifying and treating persistent tinnitus in CI users.

The study was undertaken within an established cochlear implant (CI) centre, in conjunction with a tertiary Tinnitus Clinic. The primary aim was to identify more readily which CI recipients experience significant tinnitus, by introducing the Tinnitus Handicap Inventory (THI). A secondary aim was to pilot a specialist joint clinic for CI users with tinnitus, involving clinicians from both the implant and the tinnitus teams. This paper reports principally on the level of agreement between the centre's established tinnitus self-report measure and the THI.

Influence of inducing luteal regression before a modified controlled internal drug-releasing device treatment on control of follicular development.

At the initiation of most controlled internal drug-releasing (CIDR) device protocols, GnRH has been used to induce ovulation and reset follicular waves; however, its ability to initiate a new follicular wave is variable and dependent on stage of the estrous cycle. The objectives of the current studies were to determine 1) if inducing luteal regression before the injection of GnRH at time of insertion of a CIDR resulted in increased control of follicular development, and 2) if removing endogenous progesterone by inducing luteal regression before insertion of the CIDR decreased variation in LH pulse frequency. In Exp. 1 and 2, Angus-cross cycling beef heifers (n = 22 and 38, respectively) were allotted to 1 of 2 treatments: 1) heifers received an injection of PGF(2α) on d -3, an injection of GnRH and insertion of a CIDR on d 0, and a PGF(2α) injection and CIDR removal on d 6 (PG-CIDR) or 2) an injection of GnRH and insertion of a CIDR on d 0 and on d 7 an injection of PGF(2α) and removal of CIDR (Select Synch + CIDR). In Exp. 3, Angus-cross beef heifers (n = 15) were assigned to 1 of 3 treatments: 1) PG-CIDR; 2) PGF(2α) on d -3, GnRH on d 0, and PGF(2α) on d 6 (PG-No CIDR); or 3) Select Synch + CIDR. Follicular development and ovulatory response were determined by transrectal ultrasonography. Across all experiments, more (P = 0.02) heifers treated with PG before GnRH initiated a new follicular wave after the injection of GnRH compared with Select Synch + CIDR-treated heifers. In Exp. 1, after CIDR removal, interval to estrus did not differ (P = 0.18) between treatments; however, the variance for the interval to estrus was reduced (P < 0.01) in PG-CIDR heifers compared with Select Synch + CIDR heifers. In Exp. 3, there was a tendency (P = 0.09) for LH pulse frequency to be greater among PG-CIDR and PG-No CIDR compared with the Select Synch + CIDR, but area under the curve, mean LH concentrations, and mean amplitude did not differ (P > 0.76). In summary, induction of luteal regression before an injection of GnRH increased the percentage of heifers initiating a new follicular wave. Removal of endogenous progesterone tended to increase LH pulse frequency, and the modified treatment increased the synchrony of estrus after CIDR removal.

Flux and energy analysis of species in hollow cathode magnetron ionized physical vapor deposition of copper.

To meet the stringent requirements of interconnect metallization for sub-32 nm technologies, an unprecedented level of flux and energy control of film forming species has become necessary to further advance ionized physical vapor deposition technology. Such technology development mandates improvements in methods to quantify the metal ion fraction, the gas∕metal ion ratio, and the associated ion energies in the total ion flux to the substrate. In this work, a novel method combining planar Langmuir probes, quartz crystal microbalance (QCM), and gridded energy analyzer (GEA) custom instrumentation is developed to estimate the plasma density and temperature as well as to measure the metal ion fraction and ion energy. The measurements were conducted in a Novellus Systems, Inc. Hollow Cathode Magnetron (HCM(TM)) physical vapor deposition source used for deposition of Cu seed layer for 65-130 nm technology nodes. The gridded energy analyzer was employed to measure ion flux and ion energy, which was compared to the collocated planar Langmuir probe data. The total ion-to-metal neutral ratio was determined by the QCM combined with GEA. The data collection technique and the corresponding analysis are discussed. The effect of concurrent resputtering during the deposition process on film thickness profile is also discussed.

Violence in youth sports: hazing, brawling and foul play.

By separating hazing, brawling, and foul play and failing to recognise that their connection to sport binds them together into a cohesive subset of sport injury and youth violence, past research has failed to show how sports-related violence is a broad example of interpersonal violence. The acceptance of violence within the sporting culture may, in part, explain why sports-related violence has not yet been widely recognised as a public health concern. This review shows that sports-related violence, including hazing, brawling and foul play, occurs among youth athletes of all ages and in a variety of different sports. The few studies to address this issue have all acknowledged the dangers of sports-related violence; however, no incident tracking method has been developed. Future research must provide accurate national estimates of the incidence of sports-related violence among youth, identify associated risk factors, evaluate preventive interventions and identify effective methods of distributing and implementing evidence-based interventions. Monitoring the magnitude and distribution of the burden of sports-related violence and building the scientific infrastructure necessary to support the development and widespread application of effective sports-related prevention interventions are essential first steps toward a reduction in the incidence of sports-related violence.

Effects of GnRH treatment on initiation of pulses of LH, LH release, and subsequent concentrations of progesterone.

Progesterone is essential for establishment and maintenance of pregnancy. One proposed method to increase progesterone is administering GnRH at insemination. However, this method has resulted in conflicting results. Therefore, 2 experiments were conducted to evaluate how administering GnRH at insemination affected pulses of luteinizing hormone (LH) and subsequent progesterone. In Experiment 1, cows were allotted to 2 treatments: (1) GnRH (100 microg) given approximately 12h after initiation of estrus (n=5); and (2) Control (n=5). Blood samples were collected at 15-min intervals for 6h at 12 (blood sampling period 1), 26 (blood sampling period 2), 40 (blood sampling period 3), 54 (blood sampling period 4), and 68 (blood sampling period 5) h after onset of estrus. Daily blood samples were collected for 17 d. In Experiment 2, cows were allotted into 2 treatments: GnRH administered 10 to 11h (n=10) or 14 to 15 h (n=10) after onset of estrus. Daily blood samples were collected for 17 d. Cows treated with GnRH tended (P

When the rules of the game are broken: what proportion of high school sports-related injuries are related to illegal activity?

OBJECTIVES: To compare sport and gender differences in injury rates and proportions of injuries related to illegal activity and to describe the epidemiology of injuries related to illegal activity. DESIGN: Descriptive epidemiology study. SETTING: 100 US high schools. SUBJECTS: Athletes participating in nine sports: boys' football, soccer, basketball, wrestling, and baseball plus girls' soccer, volleyball, basketball, and softball. MAIN OUTCOME MEASURES: Illegal activity-related injuries were analyzed using data from the 2005-06 and 2006-07 National High School Sports-Related Injury Surveillance Study. RESULTS: Nationally, an estimated 98 066 injuries were directly related to an action that was ruled illegal activity by a referee/official or disciplinary committee, giving an injury rate of 0.24 injuries per 1000 athletic competition-exposures. Boys' and girls' soccer had the highest rates of injuries related to illegal activity, and girls' volleyball, girls' softball, and boys' baseball had the lowest. Overall, 6.4% of all high school sports-related injuries were related to illegal activity, with the highest proportion in girls' basketball (14.0%), girls' soccer (11.9%), and boys' soccer (11.4%). A greater proportion of injuries related to illegal activity were to the head/face (32.3%) and were concussions (25.4%) than injuries not related to illegal activity (13.8% (injury proportion ratio 2.35; 95% CI 1.82 to 3.04; p<0.001) and 10.9% (injury proportion ratio 2.35; 95% CI 1.71 to 3.22; p<0.001), respectively). CONCLUSIONS: Illegal activity is an overlooked risk factor for sports-related injury. Reducing illegal activity through enhanced enforcement of sports' rules and targeted education about the dangers of illegal activity for players, coaches, and referees/officials may reduce sports-related injuries.

Torsion of an accessory spleen.

Torsion of an accessory spleen is extremely rare. We report a case of an acute torsion of an accessory spleen in a young patient who presented with acute left abdominal pain and discuss the computed tomographic findings of this exceptional condition. Awareness of this entity and familiarity with typical imaging findings are mandatory for preoperative diagnosis.

The fair sex? Foul play among female rugby players.

Rugby, a full contact sport, exposes participants to a high risk of injury. While several studies have explored injuries among male rugby players, few have investigated injuries among females. We conducted a cross-sectional study of United States of America (USA) female rugby players to assess the players' perception of foul play and the referee response to foul play and to evaluate the association between players' perception of foul play and injury. An anonymous, self-administered questionnaire reporting injury status, history of player perceived foul play and referee response was administered to 258 players recruited at a women's rugby tournament. The overall rate of injury was 4.4 injuries/100 matches, 0.2 injuries/100 practices and 1.4 injuries/100 total rugby exposures (matches and practices), with 107 (41.5%) players classified as injured. While 16.5% of players admitted to perpetrating foul play without an assessed penalty and 13.8% to being penalised for foul play, a smaller proportion reported being sent to the 'sin bin' (temporarily removed from play) or being ejected from a match (3.3% and 1.3% respectively). Of the 107 injured, 24.3% believed they had been injured as a result of foul play. Among all 258 players, self-perception of having been hurt due to unpenalised foul play was associated with study-defined injury (OR = 2.4, 95% CI = 1.0-5.9, p = 0.046). To make the sport safer, efforts should be made to minimise foul play. Suggested preventive methods include educating referees, coaches and players about the prevalence of foul play in women's rugby and the association between foul play and injury.

Computerized evaluation of mammographic lesions: what diagnostic role does the shape of the individual microcalcifications play compared with the geometry of the cluster?

OBJECTIVE: The objective of this study was to compare the diagnostic role of features reflecting the geometry of clusters with features reflecting the shape of the individual microcalcification in a mammographic computer-aided diagnosis system. MATERIALS AND METHODS: Three hundred twenty-four cases of clustered microcalcifications with biopsy-proven results were digitized at 42-microm resolution and analyzed on a computerized system. The shape factor and number of neighbors were computed for each microcalcification, and the eccentricity of the cluster was computed as well. The shape factor is related to the individual microcalcification; the average number of neighbors and the cluster eccentricity reflect the cluster geometry. Stepwise discriminant analysis was used to evaluate the contribution of the extracted features in predicting malignancy. The performance of a classifier based on the features selected by stepwise discriminant analysis was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: To obtain the best discrimination model, we used stepwise discriminant analysis to select the average number of neighbors and the shape of the individual microcalcification, but excluded cluster eccentricity. A classification scheme assigned the average number of neighbors a weighting factor, which was 1.49 times greater than that assigned to the shape factor of the individual microcalcification. A scheme based only on these two features yielded an ROC curve with an area under the curve (A(z)) of 0.87, indicating a positive predictive value of 61% for 98% sensitivity. CONCLUSION: Computerized analysis permitted calculations reflecting the shape of individual microcalcification and the geometry of clusters of microcalcifications. For the computerized classification scheme studied, the cluster geometry was more effective in differentiating benign from malignant clusters than was the shape of individual microcalcification.

A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer.

A multicentre, randomised study was carried out in Europe, South Africa and North America to compare the activity and tolerability of oral versus intravenous (i.v.) topotecan in patients with relapsed epithelial ovarian cancer. Patients who had failed first-line therapy after one platinum-based regimen, which could have included a taxane, were randomised to treatment with either oral (p.o.) topotecan, 2.3 mg/m(2)/day or i.v. topotecan 1.5 mg/m(2)/day for 5 days every 21 days. Patients were stratified by prior paclitaxel exposure, interval from previous platinum therapy and tumour diameter. 266 patients were randomised. Response rates were 13% orally (p.o.) and 20% (i.v.) with a complete response in 2 and 4 patients, respectively. The difference in the response rates was not statistically significant. Median survival was 51 weeks (p.o.) and 58 weeks (i.v.) with a risk ratio of death (p.o. to i.v. treatment) of 1.361 (95% confidence interval (CI): 1.001, 1.850). Median time to progression was 13 weeks (p.o.) and 17 weeks (i.v.). The principal toxicity was myelosuppression although grade 3/4 neutropenia occurred less frequently in those receiving oral topotecan. Toxicity was non-cumulative and infectious complications were relatively infrequent. Non-haematological toxicity was generally mild or moderate. The incidence of grade 3/4 gastrointestinal events was slightly higher for oral than i.v. topotecan. Oral topotecan shows activity in second-line ovarian cancer and neutropenia may be less frequent than with the i.v. formulation. A small, but statistically significant, difference in survival favoured the i.v. formulation, but the clinical significance of this needs to be interpreted in the context of second-line palliative treatment. Oral topotecan is convenient and well tolerated and further studies to clarify its role are ongoing.

Altered transcription in yeast expressing expanded polyglutamine.

Expanded polyglutamine tracts are responsible for at least eight fatal neurodegenerative diseases. In mouse models, proteins with expanded polyglutamine cause transcriptional dysregulation before onset of symptoms, suggesting that this dysregulation may be an early event in polyglutamine pathogenesis. Transcriptional dysregulation and cellular toxicity may be due to interaction between expanded polyglutamine and the histone acetyltransferase CREB-binding protein. To determine whether polyglutamine-mediated transcriptional dysregulation occurs in yeast, we expressed polyglutamine tracts in Saccharomyces cerevisiae. Gene expression profiles were determined for strains expressing either a cytoplasmic or nuclear protein with 23 or 75 glutamines, and these profiles were compared to existing profiles of mutant yeast strains. Transcriptional induction of genes encoding chaperones and heat-shock factors was caused by expression of expanded polyglutamine in either the nucleus or cytoplasm. Transcriptional repression was most prominent in yeast expressing nuclear expanded polyglutamine and was similar to profiles of yeast strains deleted for components of the histone acetyltransferase complex Spt/Ada/Gcn5 acetyltransferase (SAGA). The promoter from one affected gene (PHO84) was repressed by expanded polyglutamine in a reporter gene assay, and this effect was mitigated by the histone deacetylase inhibitor, Trichostatin A. Consistent with an effect on SAGA, nuclear expanded polyglutamine enhanced the toxicity of a deletion in the SAGA component SPT3. Thus, an early component of polyglutamine toxicity, transcriptional dysregulation, is conserved in yeast and is pharmacologically antagonized by a histone deacetylase inhibitor. These results suggest a therapeutic approach for treatment of polyglutamine diseases and provide the potential for yeast-based screens for agents that reverse polyglutamine toxicity.

A yeast sensor of ligand binding.

We describe a biosensor that reports the binding of small-molecule ligands to proteins as changes in growth of temperature-sensitive yeast. The yeast strains lack dihydrofolate reductase (DHFR) and are complemented by mouse DHFR containing a ligand-binding domain inserted in a flexible loop. Yeast strains expressing two ligand-binding domain fusions, FKBP12-DHFR and estrogen receptor-alpha (ERalpha)-DHFR, show increased growth in the presence of their corresponding ligands. We used this sensor to identify mutations in residues of ERalpha important for ligand binding, as well as mutations generally affecting protein activity or expression. We also tested the sensor against a chemical array to identify ligands that bind to FKBP12 or ERalpha. The ERalpha sensor was able to discriminate among estrogen analogs, showing different degrees of growth for the analogs that correlated with their relative binding affinities (RBAs). This growth assay provides a simple and inexpensive method to select novel ligands and ligand-binding domains.

Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age > or = 18 years, performance status < or = 2, and life expectancy > or = 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

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.

Preliminary results of combined therapy with topotecan and carboplatin in advanced non-small-cell lung cancer.

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.