Citations

AbstractA population pharmacokinetic (PK) model and exposure–response (E‐R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2 (20 mg/m2 in cycle 1 and, if tolerated, escalated to 56 mg/m2 on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E‐R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration–time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2. No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E‐R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2 as a 30‐minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E‐R analysis to support labeling dose recommendation in the absence of extensive clinical data.

AbstractWe present a case of JC polyomavirus (JCV)‐associated nephropathy (PyVAN) in an asymptomatic deceased‐donor kidney transplant recipient. Despite the presence of viral cytopathic effect in the kidney biopsy and positive BK polyomavirus (BKV) in situ hybridization (ISH), BKV real‐time polymerase chain reaction (PCR) results of plasma and urine were negative. JCV ISH was performed and was found to be positive. JCV real‐time PCR on urine, plasma, and the kidney biopsy tissue was positive. Reduction in immunosuppression resulted in resolution of JCV viremia. This case highlights that JC‐PyVAN is a distinct clinical entity and is likely to have a better clinical outcome than BK‐PyVAN. Concurrent infection with BKV and JCV may occur, but may be difficult to confirm due to the potential for cross‐reactivity between BKV and JCV ISH stains.

Perimesencephalic subarachnoid hemorrhage (PM‐SAH) refers to intracranial hemorrhage located in the perimesencephalic cistern. The etiology remains mainly unclear, although venous leakage or rupture has been postulated. We report an interesting case of a 57‐year‐old healthy man who presented initially with PM‐SAH with worsening of subcortical lesions on follow‐up neuroimaging. Histopathological examination demonstrated cerebral amyloid angiopathy with perivascular inflammation.

Purpose In-training evaluation reports (ITERs) constitute an integral component of medical student and postgraduate physician trainee (resident) assessment. ITER narrative comments have received less attention than the numeric scores. The authors sought both to determine what validity evidence informs the use of narrative comments from ITERs for assessing medical students and residents and to identify evidence gaps. Method Reviewers searched for relevant English-language studies in MEDLINE, EMBASE, Scopus, and ERIC (last search June 5, 2015), and in reference lists and author files. They included all original studies that evaluated ITERs for qualitative assessment of medical students and residents. Working in duplicate, they selected articles for inclusion, evaluated quality, and abstracted information on validity evidence using Kane’s framework (inferences of scoring, generalization, extrapolation, and implications). Results Of 777 potential articles, 22 met inclusion criteria. The scoring inference is supported by studies showing that rich narratives are possible, that changing the prompt can stimulate more robust narratives, and that comments vary by context. Generalization is supported by studies showing that narratives reach thematic saturation and that analysts make consistent judgments. Extrapolation is supported by favorable relationships between ITER narratives and numeric scores from ITERs and non-ITER performance measures, and by studies confirming that narratives reflect constructs deemed important in clinical work. Evidence supporting implications is scant. Conclusions The use of ITER narratives for trainee assessment is generally supported, except that evidence is lacking for implications and decisions. Future research should seek to confirm implicit assumptions and evaluate the impact of decisions.

Central (aortic) blood pressure, arterial stiffness, and sympathetic nerve activity increase with age in women. However, it is unknown if the age-related increase in sympathetic activity influences aortic hemodynamics and carotid-femoral pulse wave velocity (cfPWV), an index of central aortic stiffness. The goal of this study was to determine if aortic hemodynamics and cfPWV are directly influenced by sympathetic nerve activity by measuring aortic hemodynamics, cfPWV, and muscle sympathetic nerve activity (MSNA) in women before and during autonomic ganglionic blockade with trimethaphan camsylate. We studied 12 young premenopausal (23 ± 4 yr) and 12 older postmenopausal (57 ± 3 yr) women. These women did not differ in body mass index or mean arterial pressure ( P > 0.05 for both). At baseline, postmenopausal women had higher aortic pulse pressure, augmented pressure, augmentation index adjusted for a heart rate of 75 beats/min, wasted left ventricular pressure energy, and cfPWV than young women ( P < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women ( P < 0.05). Additionally, baseline MSNA was negatively correlated with the reductions in aortic pulse pressure, augmented pressure, and wasted left ventricular pressure energy during ganglionic blockade in postmenopausal women ( P < 0.05) but not young women. Baseline MSNA was not correlated with the changes in augmentation index adjusted for a heart rate of 75 beats/min or cfPWV in either group ( P > 0.05 for all). Our results suggest that some aortic hemodynamic parameters are influenced by sympathetic activity to a greater extent in older postmenopausal women than in young premenopausal women.NEW & NOTEWORTHY Autonomic ganglionic blockade results in significant decreases in multiple aortic pulse wave characteristics (e.g., augmented pressure) and central pulse wave velocity in older postmenopausal women but not in young premenopausal women. Certain aortic pulse wave parameters are negatively influenced by sympathetic activity to a greater extent in older postmenopausal women.