Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants:Results from the phase III HOPE-B trial 2 years after gene therapy

Introduction:For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%. Aim: Assess how EDZ affects HRQoL in HOPE-B trial participants. Methods: HRQoL was evaluated using generic and disease-specific patient reported outcomes (PROs) including the EQ-5D-5L and the Hem-A-QoL questionnaires. Mean domain and total scores were compared 6 months pre- and the first 2 years post-EDZ administration using repeated measures linear mixed models. The percentage of participants with minimal clinically important improvements in HRQoL was also evaluated. Results: Two years post-EDZ, there were nominally significant increases in the least squares (LS) mean score for the EQ-5D-5L Index Value (.04; p =.0129), reflecting better HRQoL. Nominally significant decreases in the LS mean scores, reflecting better HRQoL, were also found for the Hem-A-QoL total score (−6.0; p &lt;.0001) and the Treatment (−13.94; p &lt;.0001), Feelings (−9.01; p &lt;.0001), Future (−6.45; p =.0004) and Work/School (−5.21; p =.0098) domains. The percentage of participants with ≥15-point improvement ranged from 45.83% (95% CI: 31.37%, 60.83%) for Treatment to 13.89% (95% CI: 4.67%, 29.50%) for Family Planning. Results were similar for Year 1. Conclusion:In conclusion, gene therapy with EDZ improved HRQoL in the first and second years in several Hem-A-QoL domains, including Treatment, Feelings, Work/School and Future domains, whereas improvement in other aspects of HRQoL were not demonstrated.</p

Tailoring the mechanical and degradation performance of Mg-2.0Zn-0.5Ca-0.4Mn alloy through microstructure design

A novel Mg-2.0Zn-0.5Ca-0.4Mn alloy has been formulated and processed through melt spinning and hot extrusion to enhance its mechanical and degradation properties. Microstructural characterization of rapidly solidified alloy ribbons consolidated by extrusion revealed a fine and fully recrystallized microstructure with average size of 4 µm. The conventionally extruded alloy consisted of several course second-phase strips as coarse as 100 µm, while the extrusion-consolidated ribbons were devoid of any second phases larger than 100 nm. Rapid solidification followed by extrusion processing resulted in significantly randomized texture where the majority of the basal planes were tilted toward transverse and extrusion directions. Such a weak texture resulted in higher activity of basal planes and thereby considerably improved the fracture elongation from 4% to 19%, while retaining relatively high tensile strength of 294 MPa. In addition to high strength and ductility due to the reduced activity of deformation twining during compression, the extrusion-consolidated alloy ribbons showed lower yielding asymmetric ratio than that measured for the conventionally extruded alloy (1.25 versus 1.61). Electrochemical measurements and immersion tests indicated that application of rapid solidification followed by extrusion remarkably reduced the corrosion rate from 2.49 mm/year to 0.37 mm/year due to recrystallization completion and suppression of coarse second-phase formation

Perioperative Outcomes of Patients with Bleeding Disorders Undergoing Major Surgery at an Academic Hemophilia Treatment Center

Persons with bleeding disorders (PwBD) are at high risk for bleeding with invasive procedures. However, the risk of bleeding in PwBD undergoing major surgery and outcomes of patients managed perioperatively at a hemophilia treatment center (HTC) are not well described. We performed a retrospective review of surgical outcomes among PwBD undergoing major surgery between January 1st, 2017 and December 31st, 2019 at the Cardeza Foundation Hemophilia and Thrombosis Center in Philadelphia, PA. The primary outcome was postoperative bleeding, assessed according to the ISTH-SSC\u27s 2010 definition. Secondary outcomes included use of unplanned postoperative hemostatic therapy, LOS, and 30-day readmission rate. Results were compared to non-PwBD population from a surgical database, matched for surgery, age, and sex. During the study period, 50 PwBD underwent 63 major surgeries. The most common diagnoses were VWD (64%) and hemophilia A (20.0%). The most common surgical procedure category was orthopedic (33.3%), predominantly arthroplasties. Postoperatively,4.8% of procedures were complicated by major bleeding and 1.6% by non-major bleeding. The mean LOS was 1.65 days, and 30-day readmission rate was 1.6%. In comparison to matched, non-PwBD patients in a national surgical database undergoing the same procedures, study patients had a similar rate of bleeding complications per procedure (5.0% vs 1.04

Towards revealing key factors in mechanical instability of bioabsorbable Zn-based alloys for intended vascular stenting

Zn-based alloys are recognized as promising bioabsorbable materials for cardiovascular stents, due to their biocompatibility and favorable degradability as compared to Mg. However, both low strength and intrinsic mechanical instability arising from a strong strain rate sensitivity and strain softening behavior make development of Zn alloys challenging for stent applications. In this study, we developed binary Zn-4.0Ag and ternary Zn-4.0Ag-xMn (where x = 0.2–0.6wt%) alloys. An experimental methodology was designed by cold working followed by a thermal treatment on extruded alloys, through which the effects of the grain size and precipitates could be thoroughly investigated. Microstructural observations revealed a significant grain refinement during wire drawing, leading to an ultrafine-grained (UFG) structure with a size of 700 nm and 200 nm for the Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. Mn showed a powerful grain refining effect, as it promoted the dynamic recrystallization. Furthermore, cold working resulted in dynamic precipitation of AgZn3 particles, distributing throughout the Zn matrix. Such precipitates triggered mechanical degradation through an activation of Zn/AgZn3 boundary sliding, reducing the tensile strength by 74% and 57% for Zn-4.0Ag and Zn-4.0Ag-0.6Mn, respectively. The observed precipitation softening caused a strong strain rate sensitivity in cold drawn alloys. Short-time annealing significantly mitigated the mechanical instability by reducing the AgZn3 fraction. The ternary alloy wire showed superior microstructural stability relative to its Mn-free counterpart due to the pinning effect of Mn-rich particles on the grain boundaries. Eventually, a shift of the corrosion regime from localized to more uniform was observed after the heat treatment, mainly due to the dissolution of AgZn3 precipitates. Statement of Significance Owing to its promising biodegradability, zinc has been recognized as a potential biodegradable material for stenting applications. However, Zn's poor strength alongside intrinsic mechanical instability have propelled researchers to search for Zn alloys with improved mechanical properties. Although extensive researches have been conducted to satisfy the mentioned concerns, no Zn-based alloys with stabilized mechanical properties have yet been reported. In this work, the mechanical properties and stability of the Zn-Ag-based alloys were systematically evaluated as a function of microstructural features. We found that the microstructure design in Zn alloys can be used to find an effective strategy to not only improve the strength and suppress the mechanical instability but also to minimize any damage by augmenting the corrosion uniformity

A viscoelastic deadly fluid in carnivorous pitcher plants

Background : The carnivorous plants of the genus Nepenthes, widely distributed in the Asian tropics, rely mostly on nutrients derived from arthropods trapped in their pitcher-shaped leaves and digested by their enzymatic fluid. The genus exhibits a great diversity of prey and pitcher forms and its mechanism of trapping has long intrigued scientists. The slippery inner surfaces of the pitchers, which can be waxy or highly wettable, have so far been considered as the key trapping devices. However, the occurrence of species lacking such epidermal specializations but still effective at trapping insects suggests the possible implication of other mechanisms. Methodology/Principal Findings : Using a combination of insect bioassays, high-speed video and rheological measurements, we show that the digestive fluid of Nepenthes rafflesiana is highly viscoelastic and that this physical property is crucial for the retention of insects in its traps. Trapping efficiency is shown to remain strong even when the fluid is highly diluted by water, as long as the elastic relaxation time of the fluid is higher than the typical time scale of insect movements. Conclusions/Significance : This finding challenges the common classification of Nepenthes pitchers as simple passive traps and is of great adaptive significance for these tropical plants, which are often submitted to high rainfalls and variations in fluid concentration. The viscoelastic trap constitutes a cryptic but potentially widespread adaptation of Nepenthes species and could be a homologous trait shared through common ancestry with the sundew (Drosera) flypaper plants. Such large production of a highly viscoelastic biopolymer fluid in permanent pools is nevertheless unique in the plant kingdom and suggests novel applications for pest control

On the early and developed stages of surface condensation: competition mechanism between interfacial and condensate bulk thermal resistances

Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged.We use molecular dynamics simulation to investigate the early and developed stages of surface condensation. We find that the liquid-vapor and solid-liquid interfacial thermal resistances depend on the properties of solid and fluid, which are time-independent, while the condensate bulk thermal resistance depends on the condensate thickness, which is time-dependent. There exists intrinsic competition between the interfacial and condensate bulk thermal resistances in timeline and the resultant total thermal resistance determines the condensation intensity for a given vapor-solid temperature difference. We reveal the competition mechanism that the interfacial thermal resistance dominates at the onset of condensation and holds afterwards while the condensate bulk thermal resistance gradually takes over with condensate thickness growing. The weaker the solid-liquid bonding, the later the takeover occurs. This competition mechanism suggests that only when the condensate bulk thermal resistance is reduced after it takes over the domination can the condensation be effectively intensified. We propose a unified theoretical model for the thermal resistance analysis by making dropwise condensation equivalent to filmwise condensation. We further find that near a critical point (contact angle being ca. 153°) the bulk thermal resistance has the least opportunity to take over the domination while away from it the probability increases.Financial supports from the National Natural Science Foundation of China (51406205), the Beijing Natural Science Foundation (3142021) and the Engineering and Physics Science Research Council (EPSRC) of the UK (EP/L001233/1) are acknowledged

Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection

Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)