The inherited bleeding disorder von Willebrand disease (VWD) is challenging to diagnose owing to disease heterogeneity, lack of a definitive laboratory test and variations in diagnostic criteria. We evaluated the impact of diagnosis and diagnostic delay on patient outcomes. The PharMetrics Plus Database was interrogated for medical claims for VWD (ICD-9 286.4) and bleeding events between 1 January 2006 and 30 June 2015. Longitudinal analysis was performed of patients newly diagnosed with VWD (≥9 months' continuous enrolment before first VWD claim) through 24 months following diagnosis. In total, 32 028 diagnosed, including 18 182 newly diagnosed, patients were identified. Most patients (72%) were female. Prediagnosis, bleeding symptoms were most commonly managed by a hospitalist/emergency room physician. Misrecognition of VWD was common, with 25% of patients visiting the same specialist type at least twice for an episodic bleed before diagnosis. Thirty-seven percentage of patients had no diagnostic laboratory test within 24 months of their initial diagnostic claim. Bleed claims reduced following diagnosis: 41% and 26% of female and male patients, respectively, had claims in the year prediagnosis, falling to 21% and 9% of patients at 1-2 years postdiagnosis. The proportion of patients with multiple bleed claims also decreased, from 17% to 6% (females) and 7% to 3% (males). Serially misrecognized patients continued to have more bleeding episodes than other patients, although bleed frequency was lower than before diagnosis. There is a need for improved patient management from bleeding presentation onward to reduce the time to VWD diagnosis and to enhance patient outcomes.

Mutations in mitochondrial kinase PINK1 cause Parkinson disease (PD), but the submitochondrial site(s) of PINK1 action remains unclear. Here, we report that three-dimensional structured illumination microscopy (3D-SIM) enables super-resolution imaging of protein submitochondrial localization. Dual-color 3D-SIM imaging analysis revealed that PINK1 resides in the cristae membrane and intracristae space but not on the outer mitochondrial membrane (OMM) of healthy mitochondria. Under normal physiological conditions, PINK1 colocalizes with its substrate TRAP1 in the cristae membrane and intracristae space. In response to mitochondrial depolarization, PINK1, but not TRAP1, translocates to the OMM. The PINK1 translocation to the OMM of depolarized mitochondria is independent of new protein synthesis and requires combined action of PINK1 transmembrane domain and C-terminal region. We found that mitochondrial depolarization-induced PINK1 OMM translocation is required for recruitment of parkin to the OMM of damaged mitochondria. Our findings suggest that differential submitochondrial localization of PINK1 serves as a molecular switch for mediating two distinct mitochondrial signalling pathways in maintenance of mitochondrial homeostasis. Furthermore, our study provides evidence for the involvement of deregulated PINK1 submitochondrial localization in PD pathogenesis.

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INTRODUCTION: Heavy menstrual bleeding (HMB) is common in women and adolescents post menarche, in some cases resulting in hysterectomy or uterine ablation. Based on retrospective studies 10-62% of women with HMB may have an underlying bleeding disorder (BD), such as von Willebrand Disease (VWD), the most common bleeding disorder. Despite public awareness campaigns, a diagnosis of a potential bleeding disorder is often missed or significantly delayed. Here we characterize the rates of hysterectomy/uterine ablation in a symptomatic undiagnosed (SUD) vs. symptomatic diagnosed VWD (SVWD) population. METHODS: We utilized the IMS Health Real-World Data Adjudicated Claims, looking at patients continuously enrolled for 2+ years (July 2013 ‒ July 2015) with 1+ severe bleed or 2+ bleed claims. These symptomatic patients were classified based on presence (SVWD; n=837) or absence (SUD; n=2,760) of a VWD diagnosis claim. RESULTS: The incidence of hysterectomies/uterine ablation was similar between the SUD vs. the SVWD patients (5.9% and 7.3% respectively). However, the mean age at the time of hysterectomy was significantly (P < 0.05) younger in SUD (35 years) versus the SVWD patients (42 years). 8% of the procedures performed in the SUD occurred in patients 18-25 years old versus 1% in the SVWD patients. CONCLUSION: Treatment options for HMB require an evaluation of the etiology, which may be, in many cases, an underlying BD. A timely diagnosis of VWD allows patients access to therapies specifically targeting VWD, including antifibrinolytics, DDAVP and factor replacement, potentially avoiding or delaying the need for more terminal therapies such as hysterectomy/uterine ablation.