Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.

In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.

Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. METHODS: In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461. FINDINGS: Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. INTERPRETATION: Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). FUNDING: ARIAD Pharmaceuticals.

Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients.

Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N=671) to determine the impact of ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average ponatinib dose intensity.

Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects.

Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open-label, nonrandomized, fixed-order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8-13, 15, and 16, and rifampin 600 mg with ponatinib on day 14. Rifampin decreased maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC0-t ) and from time zero to infinity (AUC0-∞ ) of ponatinib by 42%, 59%, and 63%, respectively, with no effect on time to Cmax . The limits of the 90% confidence intervals of the estimated geometric mean ratios of ponatinib Cmax , AUC0-t , and AUC0-∞ did not fall within the 80-125% margins for equivalence, suggesting a statistically significant interaction. Coadministration of ponatinib with strong CYP3A4 inducers should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure, because the safety of ponatinib dose increases has not been studied in this context.

Evaluation of the effect of multiple doses of lansoprazole on the pharmacokinetics and safety of ponatinib in healthy subjects.

BACKGROUND: In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. OBJECTIVES: The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. METHODS: This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. RESULTS: Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P < 0.001). A corresponding 25 % decrease in the geometric mean maximum plasma concentration (C max) of ponatinib was observed for ponatinib + lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUC∞ 1,153 ng·h/mL for lansoprazole + ponatinib vs. 1,222 ng·h/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. CONCLUSIONS: Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max, overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.

Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects.

PURPOSE: This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib. METHODS: Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose. RESULTS: Ponatinib maximum plasma concentrations (C max) were observed after 5-6 h in Child-Pugh A, Child-Pugh B, and healthy subjects, and after ~3 h in Child-Pugh C subjects. The estimated % geometric mean ratios for C max, area under the plasma concentration-time curves from time zero to last observation (AUC0-t ) and to infinity (AUC0-∞) suggested a slightly lower exposure in Child-Pugh B (61.4, 89.1, and 90.6%, respectively) and Child-Pugh C subjects (62.8, 77.1, and 79.4%) versus healthy subjects. Child-Pugh A subjects had similar estimated % geometric mean ratio for C max (106.7%), and slightly greater estimated % geometric mean ratios for AUC0-t (133.0%) and AUC0-∞ (122.8%), versus healthy subjects. Mean elimination half-life was extended in subjects with hepatic impairment (43-47 vs 36 h). Ponatinib was generally well tolerated. A single serious AE (pancreatitis) in the Child-Pugh C group resolved with treatment. DISCUSSION: As no major differences in ponatinib single-dose PK were observed in patients with hepatic impairment versus healthy subjects, a reduction of ponatinib starting dose in these patients is not necessary, but caution is recommended when administering ponatinib to these patients.

Effects of ketoconazole on the pharmacokinetics of ponatinib in healthy subjects.

Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia in patients resistant or intolerant to prior TKIs. In vitro studies suggested that metabolism of ponatinib is partially mediated by CYP3A4. The effects of CYP3A4 inhibition on the pharmacokinetics of ponatinib and its CYP3A4-mediated metabolite, AP24567, were evaluated in a single-center, randomized, two-period, two-sequence crossover study in healthy volunteers. Subjects (N = 22) received two single doses (orally) of ponatinib 15 mg, once given alone and once coadministered with daily (5 days) ketoconazole 400 mg, a CYP3A4 inhibitor. Ponatinib plus ketoconazole increased ponatinib maximum plasma concentration (C(max)) and area under the concentration-time curve (AUC) compared with ponatinib alone. The estimated mean ratios for AUC0-∞, AUC0-t, and C(max) indicated increased exposures to ponatinib of 78%, 70%, and 47%, respectively; exposure to AP24567 decreased by 71%. Exposure to AP24567 was marginal after ponatinib alone (no more than 4% of the exposure to ponatinib). These results suggest that caution should be exercised with the concurrent use of ponatinib and strong CYP3A4 inhibitors and that a ponatinib dose decrease to 30 mg daily, from the 45 mg daily starting dose, could be considered.

Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.

PURPOSE: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. METHODS: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. RESULTS: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. CONCLUSIONS: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.

Relationship between force and size in human single muscle fibres.

When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force').

A personality classification system for eating disorders: a longitudinal study.

BACKGROUND: Studies of eating disorders (EDs) suggest that empirically derived personality subtypes may explain heterogeneity in ED samples that is not captured by the current diagnostic system. Longitudinal outcomes for personality subtypes have not been examined. METHOD: In this study, personality pathology was assessed by clinical interview in 213 individuals with anorexia nervosa and bulimia nervosa at baseline. Interview data on EDs, comorbid diagnoses, global functioning, and treatment utilization were collected at baseline and at 6-month follow-up intervals over a median of 9 years. RESULTS: Q-factor analysis of the participants based on personality items produced a 5-prototype system, including high-functioning, behaviorally dysregulated, emotionally dysregulated, avoidant-insecure, and obsessional-sensitive types. Dimensional prototype scores were associated with baseline functioning and longitudinal outcome. Avoidant-Insecure scores showed consistent associations with poor functioning and outcome, including failure to show ED improvement, poor global functioning after 5 years, and high treatment utilization after 5 years. Behavioral dysregulation was associated with poor baseline functioning but did not show strong associations with ED or global outcome when histories of major depression and substance use disorder were covaried. Emotional dysregulation and obsessional-sensitivity were not associated with negative outcomes. High-functioning prototype scores were consistently associated with positive outcomes. CONCLUSIONS: Longitudinal results support the importance of personality subtypes to ED classification.

Interactions between eating disorders and drug abuse.

To examine the relationship between drug abuse and eating disorders in a longitudinal sample. In a prospective study, women diagnosed with either DSM-IV anorexia nervosa (n = 136) or bulimia nervosa (n = 110) were interviewed and assessed for research diagnostic criteria drug use disorder (DUD) every 6-12 months over 8.6 years. Contrary to expectation, DUD did not influence recovery from either eating disorder. Multivariate analyses indicated that alcohol use and suicide attempts over the course of the study, as well as hospitalization for an affective disorder before the study, predicted DUD in anorexia nervosa. For bulimia nervosa, multivariate predictors included the severity of alcohol use and the severity of bulimic symptoms over the course of the study, and a hospitalization before study entry for a nonaffective disorder. Drug abuse in women with eating disorders is an area of clinical concern and should be monitored routinely.

Diagnostic crossover in anorexia nervosa and bulimia nervosa: implications for DSM-V.

OBJECTIVE: The Diagnostic and Statistical Manual of Mental Disorders (DSM) is designed primarily as a clinical tool. Yet high rates of diagnostic "crossover" among the anorexia nervosa subtypes and bulimia nervosa may reflect problems with the validity of the current diagnostic schema, thereby limiting its clinical utility. This study was designed to examine diagnostic crossover longitudinally in anorexia nervosa and bulimia nervosa to inform the validity of the DSM-IV-TR eating disorders classification system. METHOD: A total of 216 women with a diagnosis of anorexia nervosa or bulimia nervosa were followed for 7 years; weekly eating disorder symptom data collected using the Eating Disorder Longitudinal Interval Follow-Up Examination allowed for diagnoses to be made throughout the follow-up period. RESULTS: Over 7 years, the majority of women with anorexia nervosa experienced diagnostic crossover: more than half crossed between the restricting and binge eating/purging anorexia nervosa subtypes over time; one-third crossed over to bulimia nervosa but were likely to relapse into anorexia nervosa. Women with bulimia nervosa were unlikely to cross over to anorexia nervosa. CONCLUSIONS: These findings support the longitudinal distinction of anorexia nervosa and bulimia nervosa but do not support the anorexia nervosa subtyping schema.

Should bulimia nervosa be subtyped by history of anorexia nervosa? A longitudinal validation.

OBJECTIVE: To determine whether a past diagnosis of anorexia nervosa (AN) predicts longitudinal course and outcome among women with bulimia nervosa (BN). METHOD: A subset (n = 176) of participants in the Longitudinal Study of Anorexia and Bulimia Nervosa who met DSM-IV criteria for BN either at study intake (n = 144) or during follow-up (n = 32; 4 had restricting AN at intake, 28 had binge/purge AN at intake) were included in this report. Over a median of 9 years, weekly eating disorder symptom data were collected from participants using the Longitudinal Interview Follow-up Examination, Eating Disorders Version. RESULTS: While there were no between-group differences in likelihood of partial recovery, women with BN who had a history of AN were more likely to have a protracted illness, relapsing into AN during follow-up, compared to those with no AN history who were more likely to move from partial to full recovery. CONCLUSION: Lifetime AN is an important prognostic indicator among women with BN and these longitudinal data would support the subtyping of BN on the basis of AN history.

Economic evaluation of interactive teledermatology compared with conventional care.

Teledermatology offers a means of providing specialist care to underserved patients. The objectives of this study were to compare the costs of interactive teledermatology with conventional care, and to evaluate from a healthcare provider perspective whether interactive teledermatology is economically viable in the northeastern region of the United States. We studied the interactive teledermatology practice at Nantucket Cottage Hospital on Nantucket Island and the ambulatory clinics at the Massachusetts General Hospital in Boston, Massachusetts. The cost-minimization analysis compared the costs of an interactive teledermatology practice with that of a face-to-face dermatology clinic. One-way sensitivity analyses examined the effect of varying the costs of technology, physician compensation, or clinic space on the overall cost of interactive teledermatology. We also assessed the economic viability of the interactive teledermatology practice by comparing the operating costs with reimbursements. The total hourly operating costs for the interactive teledermatology practice on Nantucket Island and the face-to-face clinic in Boston were $274 and $346, respectively. Three separate one-way sensitivity analyses showed that, for the cost of the teledermatology practice to equal that of the conventional clinic, the cost of teledermatology technology could increase by 9.3-fold, dermatologists working at the teledermatology practice could be compensated up to $197 an hour, or the cost of teledermatology clinic space could reach $57 an hour. Our analysis also showed that the hourly reimbursement for the teledermatology practice was $487, which exceeded its hourly operating cost of $274. The cost of operating an interactive teledermatology practice in a remote region may be less than that of a conventional clinic in a nearby urban center in the northeastern area of the United States. From a healthcare provider perspective, interactive teledermatology can be an economically viable means of providing dermatological care to remote regions.

Single skeletal muscle fiber elastic and contractile characteristics in young and older men.

The current investigation was designed to: (a) assess the impact of aging on elastic characteristics of single skeletal muscle fibers from young (N = 6) and older men (N = 6); and (b) correlate the potential changes, with the fiber contractile properties. Chemically skinned single muscle fibers (n = 235) from vastus lateralis muscle were maximally activated. Maximal force and cross-sectional area were measured, and specific force calculated. The slack test was used to measure maximal unloaded shortening velocity. A quick release of 0.15% of fiber length was applied to determine instantaneous stiffness. The myosin heavy chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aging induces changes in both fiber elasticity (i.e., increased instantaneous stiffness) and contractility (i.e., reduced specific force and unloaded shortening velocity) in type I and IIa fibers. However, the changes in fiber stiffness may not directly influence contractile characteristics alterations.

The educational impact of ACGME limits on resident and fellow duty hours: a pre-post survey study.

PURPOSE: To assess the educational impact of Accreditation Council for Graduate Medical Education resident work-hour limits implemented in July 2003. METHOD: All trainees in all 76 accredited programs at two large teaching hospitals were surveyed between May and June 2003 (before work-hour reductions) and then between May and June 2004 (after work-hour reductions) about hours, education, and fatigue. Based on changes in weekly duty hours, 13 programs experiencing substantial reduction in hours were classified into a reduced-hours group. Differences in assessments of educational endpoints before and after policy implementation by trainees in the reduced-hours group were compared with those in other programs to control for potential temporal trends, using two-way ANOVA with interaction. RESULTS: The number of respondents was 1,770 (60% response rate). The reduced-hours group reported a significant decrease in time spent directly caring for patients (from 48.5 to 42.3 mean h/wk, P = 0.03), but the volume of important clinical experiences, including procedures, was preserved, as was the sense of clinical preparedness. On 22 questions related to educational quality and adequacy, only three differences in differences were significant, with the reduced-hours group reporting a relative increase in opportunities for research, decrease in quality of faculty teaching, and decrease in educational satisfaction. The percentage of trainees reporting frequent negative effects of fatigue dropped more in the reduced-hours programs than in the other programs (P < 0.05). CONCLUSION: This study shows that it may be possible to reduce residents' hours--and the perceived adverse impact of fatigue--while generally preserving the self-assessed quality, quantity, and outcomes of graduate medical education.

Geometric determinants of functional tricuspid regurgitation: insights from 3-dimensional echocardiography.

BACKGROUND: Tricuspid regurgitation (TR) is an important predictor of morbidity and mortality in heart failure. We aimed to examine the 3D geometry of the tricuspid valve annulus (TVA) in patients with functional TR, comparing them with patients with normal tricuspid valve function and relating annular geometric changes to functional TR. METHODS AND RESULTS: TVA shape was examined by real-time 3D echocardiography in 75 patients: 35 with functional TR and 40 with normal tricuspid valve function (referent group). The 3D shape of the TVA was reconstructed from rotated 2D planes, and the annular plane was computed by least-squares fitting. Annular area and mediolateral, anteroposterior, and high (superior)-low (inferior) distances were calculated. TR was assessed by vena contracta width. The normal TVA has a bimodal pattern (high-low distance=7.23+/-1.05 mm). High points were located anteroposteriorly, and low points were located mediolaterally. With moderate or greater TR (vena contracta width 5.80+/-2.62 mm), the TVA became dilated (17.24+/-4.75 versus 9.83+/-2.18 cm2, P<0.0001, TR versus referent), more planar with decreased high-low distance (4.14+/-1.05 mm), and more circular with decreased ratio of mediolateral/anteroposterior (1.11+/-0.09 versus 1.32+/-0.09, P<0.0001, TR versus referent). CONCLUSIONS: The normal TVA has a bimodal shape with distinct high points located anteroposteriorly and low points located mediolaterally. With functional TR, the annulus becomes larger, more planar, and circular. These changes in annular shape with TR have potentially important mechanistic and therapeutic implications for tricuspid valve repair.

Predictors for the development of elevated anti-heparin/platelet factor 4 antibody titers in patients undergoing cardiac catheterization.

A substantial proportion of patients who undergo cardiac catheterization develop antibodies directed against the heparin/platelet factor 4 (PF4) complex after the procedure, which have been implicated in the pathogenesis of heparin-induced thrombocytopenia. This study attempted to identify factors that predicted the development of these antibodies in a prospective cohort study. Antiheparin/PF4 antibody titers were measured at baseline and again 5 +/- 2 days after cardiac catheterization by enzyme-linked immunosorbent assay. A total of 311 patients who underwent cardiac catheterization were included in the analysis. Of these, 25 (8.0%) developed positive antibody levels after catheterization. Patients who had positive antibody test results after catheterization had significantly greater baseline antiheparin/PF4 antibody titers compared with those whose titers remained low (optical density 0.227 vs 0.158, p < 0.001). In a logistic regression model, greater baseline antibody titers, a history of heparin exposure, and a lower platelet count at enrollment were the strongest predictors of conversion to positive antiheparin/PF4 antibody titers after cardiac catheterization. It is possible to identify patients at high risk for developing elevated titers of antiheparin/PF4 antibodies on the basis of their baseline clinical characteristics.

Single skeletal muscle fiber behavior after a quick stretch in young and older men: a possible explanation of the relative preservation of eccentric force in old age.

The origins of the smaller age-related decrease in eccentric force compared to isometric and concentric conditions in vivo remain unclear. Could this originate from contractile elements of muscle cells? The main intent of the current investigation was to assess the force behavior of muscle cells with aging, during lengthening. Chemically skinned single muscle fibers (n=235) from m. vastus lateralis of six young (mean age 31.6 years) and six older men (mean age 66.1 years) were maximally activated with pCa 4.5 at 15 degrees C. Maximal isometric force and cross-sectional area were measured allowing the calculation of the tension (T (0)). A quick stretch (2 nm per half-sarcomere length) was applied and caused an immediate increase in tension followed by a decrease and a secondary delayed and transient rise in tension (phase 3); finally, the tension recovered a steady state value (phase 4). The tension enhancements during phase 3 (DeltaT (3)) and phase 4 (DeltaT (4)) were evaluated. The myosin heavy-chain isoform composition of each single fiber was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. DeltaT (3) and DeltaT (4) were preserved in older men for both type I and IIa fibers despite a reduction in T (0). Therefore, the age-related preservation of the tension increments after a quick stretch in single muscle fibers could explain in part the smaller decrease in force during eccentric contractions compared to isometric and concentric conditions in vivo with aging usually observed.