Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: The A-SURE study

Introduction: Haemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8-12 hours typically administered every 2-3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use. Methods and analysis: A-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect. Ethics and dissemination: Study approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.This work was fully funded by Swedish Orphan Biovitrum AB (publ

Random close packing of granular matter

We propose an interpretation of the random close packing of granular materials as a phase transition, and discuss the possibility of experimental verification.Comment: 6 page

Failure of Standard Conservation Laws at a Classical Change of Signature

The Divergence Theorem as usually stated cannot be applied across a change of signature unless it is re-expressed to allow for a finite source term on the signature change surface. Consequently all conservation laws must also be `modified', and therefore insistence on conservation of matter across such a surface cannot be physically justified. The Darmois junction conditions normally ensure conservation of matter via Israel's identities for the jump in the energy-momentum density, but not when the signature changes. Modified identities are derived for this jump when a signature change occurs, and the resulting surface effects in the conservation laws are calculated. In general, physical vector fields experience a jump in at least one component, and a source term may therefore appear in the corresponding conservation law. Thus current is also not conserved. These surface effects are a consequence of the change in the character of physical law. The only way to recover standard conservation laws is to impose restrictions that no realistic cosmological model can satisfy.Comment: 15pp, figures available on request from Charles Hellaby at [email protected]

Initial loss to follow up among tuberculosis patients : the role of ward‑based outreach teams and short message service (SMS) technology (research proposal)

INTRODUCTION : Tuberculosis (TB) is a problem in South Africa. Initial loss to follow up (LTFU) among TB patients is high varying between 14.9 and 18%. Some of the reasons for this are: lack of proper communication between patient and staff on next steps after testing, not aware that results are ready; and other competing priorities. Receiving reminder messages that result is ready is an intervention that can be explored to reduce initial LTFU. This can be through either receiving a note from the Ward-Based Outreach Teams (WBOTs) or via short message service (SMS) advising the patient to collect test result at the facility. This proposal aims to assess the effectiveness of WBOTs or SMS technology in reducing TB initial LTFU. METHODS : This will be a mixed methods approach. In depth interviews with WBOT Managers and TB Program Managers will be conducted. Focus group discussions with WBOT members will also be conducted. Two interventions (enhanced WBOTs/SMS technology) will be tested using a 3 arm randomized controlled trial (standard of care, SMS technology or enhanced WBOTs). The WBOTs will deliver paper note reminders while SMS intervention will entail sending reminder SMS messages to patients as soon as TB results are ready.The Carnegie Corporation of New York, Sida, the DELTAS Africa Initiative and Deutscher Akademischer Austauschdienst. The DELTAS Africa Initiative is by the Wellcome Trust (UK) and the UK government.https://bmcresnotes.biomedcentral.comam2020Medical Microbiolog

The HTLV-1 Virological Synapse

Human T-lymphotropic virus-1 (HTLV-1) spreads efficiently between T-cells via a tight and highly organized cell-cell contact known as the virological synapse. It is now thought that many retroviruses and other viruses spread via a virological synapse, which may be defined as a virus-induced, specialized area of cell-to-cell contact that promotes the directed transmission of the virus between cells. We summarize here the mechanisms leading to the formation of the HTLV-1 virological synapse and the role played by HTLV-1 Tax protein. We propose a model of HTLV-1 transmission between T-cells based on the three-dimensional ultrastructure of the virological synapse. Finally, in the light of recent advances, we discuss the possible routes of HTLV-1 spread across the virological synapse

Sub-microsecond correlations in photoluminescence from InAs quantum dots

Photon correlation measurements reveal memory effects in the optical emission of single InAs quantum dots with timescales from 10 to 800 ns. With above-band optical excitation, a long-timescale negative correlation (antibunching) is observed, while with quasi-resonant excitation, a positive correlation (blinking) is observed. A simple model based on long-lived charged states is presented that approximately explains the observed behavior, providing insight into the excitation process. Such memory effects can limit the internal efficiency of light emitters based on single quantum dots, and could also be problematic for proposed quantum-computation schemes.Comment: 8 pages, 8 figure

Charmless Bs→PP,PV,VVB_s\to PP, PV, VV Decays Based on the six-quark Effective Hamiltonian with Strong Phase Effects II

We provide a systematic study of charmless $B_s \to PP, PV, VV$ decays ($P$ and $V$ denote pseudoscalar and vector mesons, respectively) based on an approximate six-quark operator effective Hamiltonian from QCD. The calculation of the relevant hard-scattering kernels is carried out, the resulting transition form factors are consistent with the results of QCD sum rule calculations. By taking into account important classes of power corrections involving "chirally-enhanced" terms and the vertex corrections as well as weak annihilation contributions with non-trivial strong phase, we present predictions for the branching ratios and CP asymmetries of $B_s$ decays into PP, PV and VV final states, and also for the corresponding polarization observables in VV final states. It is found that the weak annihilation contributions with non-trivial strong phase have remarkable effects on the observables in the color-suppressed and penguin-dominated decay modes. In addition, we discuss the SU(3) flavor symmetry and show that the symmetry relations are generally respected

Perinatal morbidity and health utilization among mothers of medically fragile infants

Objective: To determine the burden of perinatal morbidity among mothers of medically fragile infants. Study design: We conducted a retrospective cohort study of 6849 mothers who delivered liveborn infants at a quaternary care hospital during a two-year period. We compared mothers of well babies with mothers of infants admitted to the Neonatal Intensive Care Unit (NICU), and we used logistic regression to model predictors of postpartum acute care utilization among NICU mothers. Results: Rates of obstetric morbidity were highest for mothers of infants staying ≥72 h in the NICU; 54.2% underwent cesarean birth, 7.5% experienced severe maternal morbidity, and 6.6% required a blood transfusion. Factors independently associated with postpartum acute care use included gestational age 38 °C and receiving psychiatric medication during the birth hospitalization. Conclusion: Focused support for mothers of NICU infants has the potential to reduce maternal morbidity and improve health

Black Hole Spin via Continuum Fitting and the Role of Spin in Powering Transient Jets

The spins of ten stellar black holes have been measured using the continuum-fitting method. These black holes are located in two distinct classes of X-ray binary systems, one that is persistently X-ray bright and another that is transient. Both the persistent and transient black holes remain for long periods in a state where their spectra are dominated by a thermal accretion disk component. The spin of a black hole of known mass and distance can be measured by fitting this thermal continuum spectrum to the thin-disk model of Novikov and Thorne; the key fit parameter is the radius of the inner edge of the black hole's accretion disk. Strong observational and theoretical evidence links the inner-disk radius to the radius of the innermost stable circular orbit, which is trivially related to the dimensionless spin parameter a_* of the black hole (|a_*| < 1). The ten spins that have so far been measured by this continuum-fitting method range widely from a_* \approx 0 to a_* > 0.95. The robustness of the method is demonstrated by the dozens or hundreds of independent and consistent measurements of spin that have been obtained for several black holes, and through careful consideration of many sources of systematic error. Among the results discussed is a dichotomy between the transient and persistent black holes; the latter have higher spins and larger masses. Also discussed is recently discovered evidence in the transient sources for a correlation between the power of ballistic jets and black hole spin.Comment: 30 pages. Accepted for publication in Space Science Reviews. Also to appear in hard cover in the Space Sciences Series of ISSI "The Physics of Accretion onto Black Holes" (Springer Publisher). Changes to Sections 5.2, 6.1 and 7.4. Section 7.4 responds to Russell et al. 2013 (MNRAS, 431, 405) who find no evidence for a correlation between the power of ballistic jets and black hole spi

Challenges and key lessons from the design and implementation of an international haemophilia registry supported by a pharmaceutical company

Introduction: Real-world data are lacking regarding the relationship between prospectively collected patient-reported outcomes (PROs), clinical outcomes and treatment in people with haemophilia (PWH). The Expanding Communications on Hemophilia A Outcomes (ECHO) registry was designed to address this data gap, but a range of difficulties led to early study closure. Aim: To describe the challenges faced and lessons learned from implementing a multinational haemophilia registry. Methods: The Expanding Communications on Hemophilia A Outcomes was planned as a five-year observational cohort study to collect data from 2000 patients in nine countries. Based on direct observations, feedback from patients enrolled in ECHO, challenges of the study design and input from study-sponsor representatives, the ECHO Steering Committee systematically identified the challenges faced and developed recommendations for overcoming or avoiding them in future studies. Results: The study closed after two years because few countries were activated and patient recruitment was low. This was related to multiple challenges including delayed implementation, stringent pharmacovigilance requirements, objections of investigators and patients to the burden of multiple PROs, data collection issues, lack of resources at study sites, little engagement of patients and competing clinical trials, which further limited recruitment. At study closure, 269 patients had been enrolled in four of nine participating countries. Conclusions: Researchers planning studies similar to ECHO may want to consider the barriers identified in this global registry of PWH and suggestions to mitigate these limitations, such as greater patient involvement in design and analysis, clearer assessment and understanding of local infrastructure and potential changes to the administration of the study