Patient-relevant health outcomes for von Willebrand disease, platelet function disorders, and rare bleeding disorders:a Delphi study

Background: To assess patient value, it is essential to regularly measure health outcomes that matter to patients. It is currently unknown which health outcomes are important for patients with autosomal inherited bleeding disorders. Objectives: This study aimed to assess which health outcomes are important for patients with autosomal inherited bleeding disorders, consisting of von Willebrand disease, platelet function disorders, and rare bleeding disorders, as seen from the patients’, caregivers’, and healthcare professionals’ perspectives. Methods: Two panels, one consisting of patients and caregivers, and one consisting of healthcare professionals participated in a Delphi process. A list of 146 health outcomes was identified from the literature. During 3 rounds, both panels rated the importance of health outcomes on a 5-point Likert scale. A health outcome was considered important by a panel if it received a median score of 5 with an IQR of ≤1. Results: In total, 13 patients, 10 caregivers, and 19 healthcare professionals participated in the Delphi study. Both panels reached consensus on the importance of health outcomes related to bleeding episodes, life-threatening complications, and the intensity and impact of menstruation. Patients and caregivers additionally reached consensus on the importance of health outcomes related to menstruation and the impact of the bleeding disorder on their daily lives. Healthcare professionals reached consensus on the importance of health outcomes related to treatment, joint health, and pain. Conclusion: In this study, health outcomes were identified that should be considered when implementing value-based health care in the care of patients with autosomal inherited bleeding disorders.</p

KLC3 is involved in sperm tail midpiece formation and sperm function

AbstractKinesin light chain 3 (KLC3) is the only known kinesin light chain expressed in post-meiotic male germ cells. We have reported that in rat spermatids KLC3 associates with outer dense fibers and mitochondrial sheath. KLC3 is able to bind to mitochondria in vitro and in vivo employing the conserved tetratrico-peptide repeat kinesin light chain motif. The temporal expression and association of KLC3 with mitochondria coincides with the stage in spermatogenesis when mitochondria move from the spermatid cell periphery to the developing midpiece suggesting a role in midpiece formation. In fibroblasts, expression of KLC3 results in formation of large KLC3 aggregates close to the nucleus that contain mitochondria. However, the molecular basis of the aggregation of mitochondria by KLC3 and its role in sperm tail midpiece formation are not clear.Here we show that KLC3 expression from an inducible system causes mitochondrial aggregation within 6h in a microtubule dependent manner. We identified the mitochondrial outer membrane porin protein VDAC2 as a KLC3 binding partner. To analyze a role for KLC3 in spermatids we developed a transgenic mouse model in which a KLC3ΔHR mutant protein is specifically expressed in spermatids: this KLC3 mutant protein binds mitochondria and causes aggregate formation, but cannot bind outer dense fibers. Male transgenic mice display significantly reduced reproductive efficiency siring small sized litters. We observed defects in the mitochondrial sheath structure in a number of transgenic spermatids. Transgenic males have a significantly reduced sperm count and produce spermatozoa that exhibit abnormal motility parameters. Our results indicate that KLC3 plays a role during spermiogenesis in the development of the midpiece and in the normal function of spermatozoa