The effect of mirabegron on patient-related outcomes in patients with overactive bladder: the results of post hoc correlation and responder analyses using pooled data from three randomized Phase III trials

Purpose To understand how improvements in the symptoms of overactive bladder (OAB) seen with the b3-adrenoceptor agonist mirabegron 50 mg, correlate with patient experience as measured by validated and standard patient-reported outcomes (PROs), and to identify whether there is overall directional consistency in the responsiveness of PROs to treatment effect. Methods In a post hoc analysis of pooled data from three randomized, double-blind, placebo-controlled, 12-week Phase III trials of mirabegron 50 mg once daily, responder rates for incontinence frequency (C50 % reduction in incontinence episodes/24 h from baseline to final visit), micturition frequency (B8 micturitions/24 h at final visit), and PROs [minimally important differences in patient perception of bladder condition (PPBC) and subsets of the overactive bladder questionnaire (OAB-q) measuring total health-related quality of life (HRQoL), and symptom bother] were evaluated individually and in combination. Results Mirabegron 50 mg demonstrated greater improvement from baseline to final visit than placebo for each of the responder analyses, whether for individual objective and subjective outcomes or combinations thereof. These improvements versus placebo were statistically significant for all double and triple responder analyses and for all single responder analyses except PPBC. PRO measurements showed directional consistency and significant correlations, and there were also significant correlations between objective and subjective measures of efficacy. Conclusions The improvements in objective measures seen with mirabegron 50 mg translate into a meaningful clinical benefit as evident by the directional consistency seen in HRQoL measures of benefit

Myocardial Fibrosis in Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: Correlation With Echocardiographic Measurements, Sarcomeric Genotypes, and Pro-Left Ventricular Hypertrophy Polymorphisms Involving the Renin-Angiotensin-Aldosterone System

Introduction: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder of the cardiac sarcomere, resulting in myocyte hypertrophy and disarray, interstitial fibrosis, and cardiac dysfunction. Our aim was to determine whether the amount of fibrosis in HCM correlates with echocardiographic measures of diastolic dysfunction, presence of HCM-susceptibility mutations, or polymorphisms in the renin-angiotensin-aldosterone system (RAAS). Methods: Surgical specimens from patients with obstructive HCM undergoing septal myectomy at the Mayo Clinic (2001-2004) were examined and compared with autopsy-derived tissues from age- and sex-matched normal controls. Digital image analysis was used to quantitate the fibrosis in representative microscopic sections. Genotyping was performed for myofilament-HCM using polymerase chain reaction, high-performance liquid chromatography, and direct DNA sequencing. RAAS polymorphism status was similarly established. Results: The study included 59 HCM cases and 44 controls. Patients with HCM exhibited more fibrosis (mean 17%, range 3-45%) than controls (mean 8%, range 3-17%) (P\u3c.0001). A significant relationship existed between amount of fibrosis and maximum wall thickness (P=.02), left ventricular ejection fraction (P=.02), and peak early/late diastolic mitral annulus velocity (E/A ratio) (P=.002). Although there was no association between amount of fibrosis and myofilament-HCM genotype status or polymorphisms in the RAAS cascade, there was a trend toward more fibrosis in patients with ≥1 C-encoding allele in CYP11B2-encoded aldosterone synthase. Conclusions: Patients with HCM undergoing septal myectomy had significantly more myocardial interstitial fibrosis than controls. The amount of fibrosis in HCM patients correlated with degree of septal hypertrophy and left ventricular systolic and diastolic function. Notably, neither mutations in cardiac myofilament proteins or polymorphisms in RAAS exhibited strong associations with severity of myocardial fibrosis

Shoulder Pain, Function, and Ultrasound-determined Structure in Elite Wheelchair-using Para Athletes: An Observational Study.

PURPOSE: To determine the relationship between shoulder pain, physical examination, and tissue pathology in manual wheelchair users competing in elite sport. METHODS: Eighty elite para athletes who used a manual wheelchair for daily mobility were recruited from international track (n = 40), field (n = 19) and powerlifting (n = 21) competitions. Athletes were surveyed regarding shoulder pain history and symptoms (Wheelchair Users Shoulder Pain Index - WUSPI), while independent blind observers measured signs (Physical Examination of the Shoulder Scale - PESS) and tissue pathology (Ultrasound Shoulder Pathology Rating Scale - USPRS). Relationships between measures for the total cohort and for subgroups defined by sporting discipline were calculated. RESULTS: A large proportion of athletes reported a history of upper limb pain (39% dominant and 35% non-dominant). For the total cohort, WUSPI score was 22.3 ± 26.9, PESS 7.4 ± 6.7 and USPRS 5.2 ± 4.0. There were no USPRS score differences between athlete subgroups, however track athletes had lower WUSPI and PESS scores, especially compared to field athletes. The first principal component explained most of the variance in the WUSPI and PESS which were strongly correlated (r = 0.71), and the second orthogonal component explained the USPRS, which did not correlate with either the PESS (r = 0.21) or WUSPI (r = 0.20). Subgroup analysis showed track athletes had lower symptom scores for a given physical examination score. CONCLUSIONS: Elite para athletes who use manual wheelchairs for daily mobility have a high prevalence of shoulder symptoms, positive signs on physical exam and ultrasound-determined tissue pathology. Ultrasound-determined tissue pathology does not correlate with symptoms or signs. This information can help to guide clinicians in managing shoulder problems in this athlete population at high risk of injury

Evaluation of Bromocriptine in the Treatment of Acute Severe Peripartum Cardiomyopathy A Proof-of-Concept Pilot Study

Background-Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that occurs in previously healthy women. We identified prolactin, mainly its 16-kDa angiostatic and proapoptotic form, as a key factor in PPCM pathophysiology. Previous reports suggest that bromocriptine may have beneficial effects in women with acute onset of PPCM. Methods and Results-A prospective, single-center, randomized, open-label, proof-of-concept pilot study of women with newly diagnosed PPCM receiving standard care (PPCM-Std; n = 10) versus standard care plus bromocriptine for 8 weeks (PPCM-Br, n = 10) was conducted. Because mothers receiving bromocriptine could not breast-feed, the 6-month outcome of their children (n = 21) was studied as a secondary end point. Blinded clinical, hemodynamic, and echocardiographic assessments were performed at baseline and 6 months after diagnosis. Cardiac magnetic resonance imaging was performed 4 to 6 weeks after diagnosis in PPCM-Br patients. There were no significant differences in baseline characteristics, including serum 16-kDa prolactin levels and cathepsin D activity, between the 2 study groups. PPCM-Br patients displayed greater recovery of left ventricular ejection fraction (27% to 58%; P = 0.012) compared with PPCM-Std patients (27% to 36%) at 6 months. One patient in the PPCM-Br group died compared with 4 patients in the PPCM-Std group. Significantly fewer PPCM-Br patients (n = 1, 10%) experienced the composite end point of poor outcome defined as death, New York Heart Association functional class III/IV, or left ventricular ejection fraction < 35% at 6 months compared with the PPCM-Std patients (n = 8, 80%; P = 0.006). Cardiac magnetic resonance imaging revealed no intracavitary thrombi. Infants of mothers in both groups showed normal growth and survival. Conclusions-In this trial, the addition of bromocriptine to standard heart failure therapy appeared to improve left ventricular ejection fraction and a composite clinical outcome in women with acute severe PPCM, although the number of patients studied was small and the results cannot be considered definitive. Larger-scale multicenter and blinded studies are in progress to test this strategy more robustly. (Circulation. 2010;121:1465-1473.