Hemophilia gene therapy knowledge and perceptions: Results of an international survey

Background Hemophilia gene therapy is a rapidly evolving therapeutic approach in which a number of programs are approaching clinical development completion. Objective The aim of this study was to evaluate knowledge and perceptions of a variety of health care practitioners and scientists about gene therapy for hemophilia. Methods This survey study was conducted February 1 to 18, 2019. Survey participants were members of the ISTH, European Hemophilia Consortium, European Hematology Association, or European Association for Hemophilia and Allied Disorders with valid email contacts. The online survey consisted of 36 questions covering demographic information, perceptions and knowledge of gene therapy for hemophilia, and educational preferences. Survey results were summarized using descriptive statistics. Results Of the 5117 survey recipients, 201 responded from 55 countries (4% response rate). Most respondents (66%) were physicians, and 59% were physicians directly involved in the care of people with hemophilia. Among physician respondents directly involved in hemophilia care, 35% lacked the ability to explain the science of adeno-associated viral gene therapy for hemophilia, and 40% indicated limited ability or lack of comfort answering patient questions about gene therapy for hemophilia based on clinical trial results to date. Overall, 75% of survey respondents answered 10 single-answer knowledge questions correctly, 13% incorrectly, and 12% were unsure of the correct answers. Conclusions This survey highlighted knowledge gaps and educational needs related to gene therapy for hemophilia and, along with other inputs, has informed the development of "Gene Therapy in Hemophilia: An ISTH Education Initiative.

First modulation of high-frequency polar mesospheric summer echoes by radio heating of the ionosphere

The first high-frequency (HF, 8 MHz) observations of the modulation of polar mesospheric summer echoes (PMSE) by artificial radio heating of the ionosphere are presented and compared to observations at 224 MHz and model predictions. The experiments were performed at the European Incoherent Scatter facility in northern Norway. It is shown that model results are in qualitative and partial quantitative agreement with the observations, supporting the prediction that with certain ranges of ice particle radii and concentration, PMSE at HF radar wavelengths can be enhanced by heating due to the dominance of dust charging over plasma diffusion

Bifurcations in annular electroconvection with an imposed shear

We report an experimental study of the primary bifurcation in electrically-driven convection in a freely suspended film. A weakly conducting, submicron thick smectic liquid crystal film was supported by concentric circular electrodes. It electroconvected when a sufficiently large voltage $V$ was applied between its inner and outer edges. The film could sustain rapid flows and yet remain strictly two-dimensional. By rotation of the inner electrode, a circular Couette shear could be independently imposed. The control parameters were a dimensionless number ${\cal R}$, analogous to the Rayleigh number, which is $\propto V^2$ and the Reynolds number ${\cal R}e$ of the azimuthal shear flow. The geometrical and material properties of the film were characterized by the radius ratio $\alpha$, and a Prandtl-like number ${\cal P}$. Using measurements of current-voltage characteristics of a large number of films, we examined the onset of electroconvection over a broad range of $\alpha$, ${\cal P}$ and ${\cal R}e$. We compared this data quantitatively to the results of linear stability theory. This could be done with essentially no adjustable parameters. The current-voltage data above onset were then used to infer the amplitude of electroconvection in the weakly nonlinear regime by fitting them to a steady-state amplitude equation of the Landau form. We show how the primary bifurcation can be tuned between supercritical and subcritical by changing $\alpha$ and ${\cal R}e$.Comment: 17 pages, 12 figures. Submitted to Phys. Rev. E. Minor changes after refereeing. See also http://mobydick.physics.utoronto.c

Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: Involvement of src family protein kinases

The increased production of amyloid beta -peptide (A beta) in Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain cortical cultures to A beta administration and found a marked increase in the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c (MAP2c). We also found that paired helical filaments of aggregated and hyperphosphorylated tau are tyrosine phosphorylated, indicating that changes in the phosphotyrosine content of cytoplasmic proteins in response to A beta are potentially an important process. Increased tyrosine phosphorylation of cytoskeletal and other neuronal proteins was specific to fibrillar A beta (25-35) and A beta (1-42). The tyrosine phosphorylation was blocked by addition of the Src family tyrosine kinase inhibitor 4-amino-5-( 4-chlorophenyl)- 7(t-butyl) pyrazol(3,4-D) pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family, from A beta (25-35)-treated neurons showed an increased association of Fyn with FAK. A beta treatment of cells also stimulated the sustained activation of extracellular regulated kinase-2, which was blocked by addition of PP2 and LY 294002, suggesting that FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein (MAP) kinase signaling in A beta -treated neurons. This cascade of signaling events contains the earliest biochemical changes in neurons to be described in response to A beta exposure and may be critical for subsequent neurodegenerative changes

Positive Youth Development Interventions Impacting the Sexual Health of Young Minority Adolescents: A Systematic Review

A systematic literature review was conducted to assess the utility of Positive Youth Development (PYD) concepts in promoting positive sexual health behaviors in young minority adolescents (n = 12 studies). Interventions reported significant associations between PYD-focused interventions and ever having sex, sexual partners in the last 30 days, using protection at the last sexual encounter, and decreased pregnancy rates. Outcomes were reviewed by age, gender, PYD constructs, cultural tailoring of interventions, and retention rates. Few interventions focused exclusively on young minority adolescents. PYD can be an effective tool in promoting sexual health in younger minority adolescents, but additional research is needed to determine beneficial strategies for this age group and timing of interventions. Recommendations for future studies include additional guidance on operationalization of PYD concepts, effective cultural tailoring methods, dosage of intervention components, and de-linking minority status from socioeconomic status (SES) and high-risk behaviors.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The design and development of a third generation OSEE instrument

Optically Stimulated Electron Emission (OSEE) has been used to quantify surface contamination in the aerospace community. As advances are made towards the understanding of OSEE, it is desirable to incorporate technological advances with succeeding generations of instrumentation, so that improvements in the practical application of OSEE may be disseminated among the user community. Several studies undertaken by Yost, Welch, Abedin and others have expanded the knowledge base related to the underlying principles of OSEE. The conclusions of these studies, together with inputs from the user community were the foundation upon which the development of a third generation OSEE instrument was based. This manuscript describes the significant improvements incorporated into a third generation OSEE instrument as well as the elements unique to its design

Syntaxin 16 is a master recruitment factor for cytokinesis

Recently it was shown that both recycling endosome and endosomal sorting complex required for transport (ESCRT) components are required for cytokinesis, in which they are believed to act in a sequential manner to bring about secondary ingression and abscission, respectively. However, it is not clear how either of these complexes is targeted to the midbody and whether their delivery is coordinated. The trafficking of membrane vesicles between different intracellular organelles involves the formation of soluble N-ethylmalei­mide–sensitive factor attachment protein receptor (SNARE) complexes. Although membrane traffic is known to play an important role in cytokinesis, the contribution and identity of intracellular SNAREs to cytokinesis remain unclear. Here we demonstrate that syntaxin 16 is a key regulator of cytokinesis, as it is required for recruitment of both recycling endosome–associated Exocyst and ESCRT machinery during late telophase, and therefore that these two distinct facets of cytokinesis are inextricably linked

Suitability of PSA-detected localised prostate cancers for focal therapy: Experience from the ProtecT study

This article is available through a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. Copyright @ 2011 Cancer Research UK.Background: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. Methods: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. Results: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38–66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. Conclusion: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.National Institute for Health Researc