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Introduction Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. Aim Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. Methods Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. Results Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. Conclusions Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Background: Recurrent overt or occult gastrointestinal (GI) bleeding is a serious complication of von Willebrand Disease (VWD) and is the most common cause of hospitalization for patients with VWD. Data from the VWD Prophylaxis Network (VPN) emphasized the importance of prophylaxis in minimizing bleeding episodes in VWD; however, the management of GI bleeding in these patients remains challenging. Despite the availability of von Willebrand factor (VWF) replacement therapy, GI bleeding may be refractory and require the use of multiple treatment approaches. Currently, there are limited published data and no consensus regarding the most effective treatment for GI bleeding in patients with VWD. Aims: To describe the natural history of treatment and management of GI bleeds in patients with VWD, stratified by those patients who have a history of GI bleeding that precedes this chart review versus patients who experienced their first GI bleed within the 5 years of this chart review. Outcomes following the use of VWF replacement products and adjuvant therapy, including recombinant VWF were collected. Methods: This ongoing retrospective, multicenter, observational chart review (abstraction initiated 2019) will include up to 20 patients from 6 US centers with confirmed congenital VWD with ≥1 GI bleed within the last 5 years. Demographics and clinical information, including potential etiology, treatment regimens, will be gathered from patient records on all recorded GI bleeds within the last 5 years. Clinical effectiveness will be defined by treatment response, change in duration of treatment, or time to bleed resolution across treatment cohorts (e.g., prophylaxis vs on-demand; recombinant VWF [rVWF] vs plasma-derived VWF [pdVWF]), at the time of a GI bleed and for any subsequent period of prophylactic treatment to prevent GI bleed recurrence. Data will be analyzed descriptively. Results: To date, data on 37 bleeds in 13 patients with Type 1 (23%), Type 2 (46%) or Type 3 (31%) VWD have been abstracted; 54% were female, mean (±SD) age was 53.9 (22.0) years, 85% had ≥1 recorded GI-specific morbidity, 6 patients (46%) had no history of prior GI bleeding. Three patients (23%) were on regular prophylaxis using pdVWF-factor VIII (FVIII) concentrates at initial GI bleed presentation. All were receiving Humate-P; dose was not recorded for 2 patients and 1 patient received 50 IU/kg. Out of 37 bleeding episodes, 9 (24%) occurred in patients during VWF prophylaxis, of which 7 occurred in 1 patient. Among the 7 patients with a previous history of GI bleeding, 1 was on a prophylactic regimen prior to the initial GI bleeding episode. None of the patients without a history of GI bleeding were on a prophylactic regimen at the initiation of the chart review; 1 patient was receiving prophylaxis at the time the fourth bleed was documented. On-demand treatment for GI bleeding included aminocaproic acid, tranexamic acid, pdVWF-FVIII concentrates, rFVIII, rVWF, corticosteroids, polypectomy, and thalidomide. After resolution of the GI bleeding episode, in 17/37 bleeding events, prophylactic treatment continued (either as part of the final treatment regimen to resolve the bleed and sustained prophylaxis, or after the final treatment regimen purely as prophylaxis). At the conclusion of data collection for the current patients, 4 out of 6 without a GI bleeding history, and 1 out of 7 with a GI bleeding history, were receiving prophylaxis. Conclusions: Data from this retrospective chart review are the first to describe prophylactic regimens prior to and after GI bleeding, in VWD patients with and without a GI bleeding history. More patients with congenital VWD and a history of GI bleeding were treated with prophylaxis following GI bleeds, compared to patients without a history of GI bleeds. These data describe the role of prophylaxis in management of GI bleeding and add to existing data from the VPN describing a modest reduction of GI bleeding in some patients on prophylaxis. These data underscore the continuing unmet need of the successful management of GI bleeding in VWD. Further data will be collected, and additional analyses performed to determine if this trend persists in a larger sample of patients with VWD. Disclosures Roberts: uniQure:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau;Pfizer:Consultancy;Novo Nordisk:Consultancy, Speakers Bureau;Sanofi:Consultancy, Speakers Bureau;Octapharma:Consultancy, Speakers Bureau.Escobar:National Hemophilia Foundation:Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novo Nordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees.Acharya:Novonordisk, BPL:Membership on an entity's Board of Directors or advisory committees.Hwang:Takeda:Honoraria;Shire:Honoraria.Wang:Bioverativ Inc:Honoraria;CSL Behring:Honoraria;Biomarin:Honoraria;Genentech:Honoraria;Takeda:Honoraria;Bayer:Honoraria.Hale:Takeda Pharmaceutical Company Limited:Current Employment.Oladapo:Takeda:Current Employment, Current equity holder in publicly-traded company.Asghar:HCD Economics:Current Employment.

Introduction: Among the most challenging complications of hemophilia A is inhibitor formation. A T-cell dependent B-cell response to exogenous factor VIII (FVIII), inhibitors result in a high burden of disease, with poorly controlled bleeding, twice the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of non-inhibitor patients. Thus, a major goal of hemophilia management is to prevent and eradicate inhibitors. With the availability of novel therapies, including eloctate, a recombinant Fc-fusion protein (rFVIII-Fc) which induces regulatory T cells to promote FVIII tolerance, and emicizumab, a bispecific monoclonal FVIII mimetic, we designed the INHIBIT Clinical Trials Platform (X01HL143024), Fig.1. The platform is composed of two linked randomized phase III trials, the Inhibitor Prevention Trial (NCT04303559), comparing rFVIII-Fc vs emicizumab prophylaxis to prevent inhibitors, and the Inhibitor Eradication Trial (NCT04303572), comparing rFVIII-Fc immune tolerance induction (ITI) plus emicizumab vs rFVIII-Fc ITI alone to eradicate inhibitors. The platform uses adaptive design to incorporate historical data (Bayesian priors) on inhibitor formation to increase power and promote efficient use of rare data. Yet, there is equipoise regarding the optimal approach to inhibitor prevention and eradication, and, as clinical practice is changing, we aimed to test the feasibility of the INHIBIT trial design. Methods: To establish design feasibility, we conducted interviews with 30 hemophilia treatment center (HTC) physicians participating in the INHIBIT trials, to determine prophylaxis and tolerance regimens they prescribe and perceived barriers to the INHIBIT trials design. A 4-question survey was subsequently emailed to these physicians to ascertain the initial prophylaxis regimens they prescribe in previously untreated patients (PUPs) with severe hemophilia A, and the initial immune tolerance induction (ITI) they prescribe in high-responding inhibitor patients with severe hemophilia A; if new inhibitors had been observed during emicizumab prophylaxis, and willingness to participate in post-trial surveillance. Results: In interviews, HTC physicians indicated the issues that influenced choice of prophylaxis/ ITI regimen were patient preference, family history of inhibitors, infusion frequency, IV access, port requirement, and family fatigue. In the absence of clinical trials data in PUPs, there was general agreement that emicizumab prophylaxis, with it simpler subcutaneous (SQ) administration, might delay or potentially prevent inhibitors. Survey findings in Table 1 indicated 75% of physicians prescribe extended half-life (EHL) FVIII in a once-weekly prophylaxis regimen, as planned in the Prevention Trial, despite the persistent 27% inhibitor rate (ALong PUPs Trial, Königs et al, ISTH 2020) and potential risks with port use. There was support for the 1:3 preferential randomization to emicizumab in the Prevention Trial due to the simpler SQ route, despite concern it might delay rather than prevent inhibitor formation, although no inhibitors were reported by physician survey with emicizumab use alone. There was also concern that breakthrough bleeds requiring FVIII during emicizumab prophylaxis, might lead to immune activation and inhibitor formation. There was strong agreement, however, in 29 (97%) of physicians to participate in post-trial surveillance for long-term inhibitor outcomes. FVIII ITI was considered essential to eradicate inhibitors, despite the intensity of the infusion regimen. Notably, 60% prescribe emicizumab with FVIII ITI, as planned in the Eradicate Trial, although the every-other-day infusion was considered a potential barrier to participation. Omitting FVIII ITI was not favored due to the risk of inhibitor anamnesis if FVIII treatment was subsequently required for surgery or acute hemorrhages. Despite these concerns, there was agreement to participate in the trials. Discussion: Physician interviews and surveys confirm there is heterogeneity in current hemophilia clinical practice, specifically in initial prophylaxis regimens and in initial immune tolerance regimens, including agent choice and duration. However, there is physician consensus with the INHIBIT trial aims and with the proposed INHIBIT trial regimens to prevent and eradicate inhibitors. Disclosures Ragni: Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam/Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; ATHN: Research Funding; Sangamo: Research Funding. Seaman:Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Takeda: Consultancy. Acharya:Novonordisk: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding. Wheeler:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Tarango:Takeda/Shire: Honoraria, Other; Bayer: Consultancy, Other; Sanofi: Honoraria, Other. Dunn:ATHN: Research Funding; Spire: Honoraria; Medscape: Honoraria; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy; Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding. Chitlur:Takeda: Honoraria; Biovertiv: Honoraria; Agios Pharmaceuticals: Research Funding; Pfizer: Honoraria; Novo Nordisk: Consultancy, Honoraria. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Malec:Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy; Takeda: Consultancy; Bayer: Consultancy; SOBI: Consultancy. Leissinger:Bayer: Consultancy; Kedrion: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Spark: Consultancy. Carpenter:Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding. Knoll:NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Wang:Bioverativ Inc: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Takeda: Honoraria. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Thornburg:Genentech: Speakers Bureau; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; American Thrombosis and Hemostasis Network: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lucas:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hwang:Shire: Honoraria; Takeda: Honoraria.

The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Iron oxide nanocrystals are of great scientific and technological interest. In this work, these materials are the starting point for producing a reactive nanoparticle whose surface resembles that of natural green rusts. Treatment of iron oxide nanoparticles with cysteamine leads to the reduction of iron and the formation of a brilliant green aqueous solution of nanocrystals rich in iron(II). These materials remained crystalline with magnetic and structural features of the original iron oxide. However, new low-angle X-ray diffraction peaks as well as vibrational features characteristic of cysteamine were found in the nanocrystalline product. X-ray absorption spectroscopy (XAS), X-ray photoemission (XPS) and Mossbauer spectroscopies indicated the presence of an iron(II)-rich phase with high sulfur content analogous to the iron–oxygen structures found in natural green rusts. Electron microscopy found that these structural components remained associated with the nonreduced iron oxide cores. These sulfur-rich ...

Exposure to smoke from the use of solid fuels and inefficient stoves for cooking and heating is responsible for approximately 4 million premature deaths yearly. As increasing investments are made to tackle this important public health issue, there is a need for identifying and providing guidance on best practices for exposure and stove performance monitoring, particularly for public health research and evaluation studies. This paper, which builds upon the discussion at an expert consultation on exposure assessment convened by the Global Alliance for Clean Cookstoves, the Centers for Disease Control and Prevention, and PATH in late 2012, aims to provide general guidance on what to monitor, who and where to monitor, and how to monitor household air pollution exposures. In addition, we summarize information about commercially available monitoring equipment and the technical properties of these monitors most important for household air pollution exposure assessment. The target audience includes epidemiologists conducting health studies and program evaluators aiming to quantify changes in exposures to estimate the potential health benefits of cookstoves intervention projects.

Background Increased concern for potential health and environmental impacts of chemicals, including nanomaterials, in consumer products is driving demand for greater transparency regarding potential risks. Chemical hazard assessment is a powerful tool to inform product design, development and procurement and has been integrated into alternative assessment frameworks. The extent to which assessment methods originally designed for conventionally-sized materials can be used for nanomaterials, which have size-dependent physical and chemical properties, have not been well established. We contracted with a certified GreenScreen profiler to conduct three GreenScreen hazard assessments, for conventional silver and two forms of nanosilver. The contractor summarized publicly available literature, and used defined GreenScreen hazard criteria and expert judgment to assign and report hazard classification levels, along with indications of confidence in those assignments. Where data were not available, a data gap (DG) was assigned. Using the individual endpoint scores, an aggregated benchmark score (BM) was applied. Results Conventional silver and low-soluble nanosilver were assigned the highest possible hazard score and a silica-silver nanocomposite called AGS-20 could not be scored due to data gaps. AGS-20 is approved for use as antimicrobials by the US Environmental Protection Agency. Conclusions An existing method for chemical hazard assessment and communication can be used – with minor adaptations– to compare hazards across conventional and nano forms of a substance. The differences in data gaps and in hazard profiles support the argument that each silver form should be considered unique and subjected to hazard assessment to inform regulatory decisions and decisions about product design and development. A critical limitation of hazard assessments for nanomaterials is the lack of nano-specific hazard data – where data are available, we demonstrate that existing hazard assessment systems can work. The work is relevant for risk assessors and regulators. We recommend that regulatory agencies and others require more robust data sets on each novel nanomaterial before granting market approval. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0188-y) contains supplementary material, which is available to authorized users.

Background: Non-severe hemophilia A and B account for 50% of patients with hemophilia, in which factor level does not consistently correlate with bleeding phenotype. Clinical decision-making in regards to timely prophylaxis initiation and tailored surgical management could be informed by a biomarker that is more predictive of bleeding phenotype. We hypothesized that a global method to assess clotting potential, such as thrombin generation (TG), is more predictive of bleeding phenotype than factor level. Objectives: Determine the ability of TG, as compared to standard baseline factor activity, to differentiate bleeding phenotype severity in patients with non-severe hemophilia. Methods: Subjects were recruited from two hemophilia treatment centers (HTCs): Rady Children's Hospital San Diego (RCHSD) and Center for Inherited Blood Disorders (CIBD). Subjects were eligible for enrollment if they were at least one year of age and had a diagnosis of non-severe congenital hemophilia A or B, or were genetically confirmed or suspected female carriers. All enrolled patients or their parents completed the standardized, self-administered pediatric bleeding questionnaire (Self-PBQ) or bleeding assessment tool (Self-BAT). Clinical and laboratory information were extracted from the medical chart, including age at diagnosis, bleeding event history, past surgical history, treatment history and factor VIII or IX gene analysis. Validation of self-reported bleeding symptoms was performed using chart-derived data. Bleeding phenotype was assessed using standard calculation of the bleeding score, as defined by the respective validated self-reported tools. For the purpose of this analysis, we defined a high bleeding score as 13 or more, while a low bleeding score was defined as 12 or less. After a washout period of 5x the standard half-life of the administered factor product, blood samples were collected at time of enrollment. Platelet poor plasma was obtained according to a strict protocol to minimize pre-analytical variables. TG was measured by means of the calibrated automated thrombogram, with three different reagents: low (1 pM of tissue factor [TF]), regular (5 pM of TF) and High (20 pM of TF). The following TG parameters were evaluated: Peak TG (Peak), estimated thrombin potential (ETP) and velocity index (VI). Results: Eighty-one subjects were enrolled. The median age of our cohort was 15.6 years (IQR 21.2, range 4.9 - 59.8), with a slight female predominance (51%) due to inclusion of female carriers. The median follow-up period at the HTC was 5.3 years (IQR 7.5 years), with the majority having follow-up for at least three years. Enrolled patients had the following diagnoses: mild hemophilia A (70%), mild hemophilia B (3%), moderate hemophilia A (13%), moderate hemophilia B (3%), hemophilia A carriers with normal factor VIII levels (10%) and hemophilia B carriers with normal factor IX levels (1%). Median age at diagnosis was 8 years (IQR 26.3, range 0.1 - 56.1), which strongly correlated lower baseline factor activity (r=0.573, p-value < 0.0001). The median baseline factor activity was 21% (IQR 26, range 2 - 249). Factor exposure occurred in 46% of patients (n=37), of which 5 patients were on prophylaxis at time of enrollment. Chronic arthropathy was present in 2 patients (one with mild hemophilia A and one with moderate hemophilia A) and none of the patients had a history of an inhibitor. The majority of patients had a low bleeding score (74% vs. 26%). Baseline factor level and TG values obtained with regular reagent (5 pM of TF) showed significant correlation with bleeding score (r = -0.229 to -0.237, p-value < 0.05), while values obtained with other reagents did not show a significant correlation. Sensitivity/specificity analysis revealed the following optimal cutoff values for differentiating between bleeding severities, as obtained from TG with regular reagent: ETP ( Conclusion: Even though both TG and baseline factor level had comparable correlation with bleeding severity, all TG values with 5 pM TF showed a much higher sensitivity outcome and greater ability to differentiate between bleeding severities in this population. This approach shows potential for predicting bleeding severity in patients with non-severe hemophilia and should be validated in long-term prospective studies. Disclosures Nossair: Novo Nordisk: Other: Conference - Haemophilia Acadamy; Novo Nordisk: Research Funding. Hwang:BPI: Consultancy; Bayer: Consultancy; Hema Biologics: Consultancy; Shire: Consultancy; Bioverativ: Other: PI in clinical research study. Thornburg:ATHN: Research Funding; Bayer Pharmaceuticals: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Bioverativ: Consultancy; Genentech: Speakers Bureau; Octapharma: Research Funding; NovoNordisk: Research Funding; Shire: Research Funding; Johns Hopkins All Children's Hospital: Research Funding; Bluebird Bio: Consultancy.

Introduction: Immune tolerance induction (ITI) is the standard of care for eradication of inhibitors in subjects with severe hemophilia A. ITI is not always effective and can require a lengthy and burdensome treatment regimen. Those who have previously failed ITI are more likely to fail subsequent ITI. The successful use of recombinant factor VIII Fc fusion protein (rFVIIIFc) for ITI was described in our initial retrospective review of 19 high-risk subjects, including first-time and rescue ITI subjects (Carcao et al, Haemophilia, 2018). These findings indicated that time to tolerization appears to be faster with rFVIIIFc, despite a high-risk profile. It has been postulated that the Fc domain of rFVIIIFc may promote tolerization due to immunomodulatory properties. We report characteristics and ITI outcomes of 6 newly identified subjects, as well as follow-up data from 12 of the 19 subjects included in the original analysis. Methods: A follow-up of subjects enrolled in the original retrospective chart review and clinical outcomes of newly identified males with severe hemophilia A and historical high-titer inhibitors (≥5 BU) treated with rFVIIIFc for ITI is reported from 12 sites in the US and Canada. De-identified data were collected via electronic surveys. This interim analysis was performed on aggregated data collected through July 6, 2018. Data collection is ongoing, with 29 subject charts (19 original subjects and an additional 10) expected by October. Results: Of 25 charts reviewed to date, 9 were first-time ITI and 16 were rescue ITI subjects. Of 9 first-time ITI charts, 7 subjects were from the original study (4 had follow-up data), and 2 subjects were newly identified. Of 16 rescue ITI charts, 12 subjects were from the original study (8 with follow-up data), and 4 subjects were newly identified. All but 1 subject in the first-time ITI group had ≥1 high-risk feature. The median (range) age (n=9) at initiation of rFVIIIFc ITI was 1.4 (0.8-4.3) years and the median (range) time from inhibitor detection to initiation of rFVIIIFc ITI was 1.5 (0-9.4) months (Table 1). The median (range) inhibitor titer at rFVIIIFc ITI initiation was 32 (3-1126) BU/mL, and the dosing regimen of rFVIIIFc ranged from 50 IU/kg 3 times per week (TIW) to 200 IU/kg daily. All 16 rescue ITI subjects had high-risk features. The median (range) age at rFVIIIFc ITI initiation was 7.8 (1.6-48.9) years, with a median (range) time from inhibitor detection to initiation of rFVIIIFc ITI of 7.1 (0.6-43) years (Table 1). The median (range) number of prior ITI courses was 2.5 (1-7). The median (range) inhibitor titer at rFVIIIFc ITI start was 24.2 (0.6-237) BU/mL, and the dosing regimen of rFVIIIFc ranged from 43 IU/kg TIW to 200 IU/kg daily. Eight of 9 first-time ITI subjects achieved a negative Bethesda titer in a median (range) time of 27.2 (3-64.1) weeks and mean (standard deviation [SD]) time of 25.9 (20.7) weeks. All 8 were subsequently tolerized with a median (range) time to tolerization of 29.7 (3-64.1) weeks and a mean (SD) time to tolerization of 33.4 (20.4) weeks (Table 2). One of the 8 subjects, although he achieved a negative Bethesda titer and ultimately was tolerized (time to tolerization: 59 weeks), did so after a complicated course of ITI: he was initially on rFVIIIFc ITI for 15 weeks then was switched to plasma-derived FVIII ITI for 12 weeks. Owing to lack of reduction in inhibitor titer, the subject was switched back to rFVIIIFc ITI. Fourteen weeks later he became Bethesda titer‒negative and achieved tolerance 18 weeks after that. The 9th subject had a reduced titer and continues on rFVIIIFc ITI. Eight of 16 rescue ITI subjects reached negative Bethesda titer in a median (range) time of 29.6 (3-70) weeks (Table 2) and a mean (SD) of 34.9 (25.6) weeks. Of these, 2 subjects were tolerized at 23.1 and 35 weeks, respectively; both have transitioned to rFVIIIFc prophylaxis. Eight subjects continue on rFVIIIFc ITI and 6 transitioned to other ITI treatment regimens. Conclusions: A rapid time to tolerization was achieved in high-risk first-time ITI subjects in a real-world setting. ITI with rFVIIIFc led to rapid negative inhibitor titer in most first-time ITI subjects and many rescue ITI subjects. Faster time to tolerization is expected to improve subject's quality of life, joint health, and healthcare utilization. Findings from this study are being tested in 2 prospective trials using rFVIIIFc for ITI in subjects with hemophilia A with inhibitors (first time and rescue). Disclosures Carcao: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Octapharma: Research Funding; Daiichi Sankyo: Research Funding; OPKO: Research Funding; Kedrion Biopharma: Consultancy, Research Funding. Hwang:Bioverativ: Other: PI in clinical research study; Shire: Consultancy; Hema Biologics: Consultancy; Bayer: Consultancy; BPI: Consultancy. Pipe:Catalyst Biosciences: Consultancy; Shire: Consultancy, Research Funding; Spark Therapeutics: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; Apcintex: Consultancy; Ainylam: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; CSL Behring: Consultancy; Bioverativ: Consultancy; Nove Nordisk: Consultancy; Siemens: Research Funding; HEMA Biologics: Consultancy; R2 Diagnostics: Research Funding. Ahuja:Shire: Honoraria, Speakers Bureau; Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau. Staber:uniQure: Honoraria; Bayer: Honoraria; NovoNordisk: Consultancy. Sun:Octapharma: Research Funding; Novo Nordisk: Consultancy. Ding:Bioverativ: Other: Site PI for clinical research study. Wang:Bayer: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; CSL Behring: Consultancy; Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy. Steele:Baxter/SHIRE: Other: Travel, Hotel; Bayer: Honoraria; Roche: Honoraria. Tsao:Bioverativ: Employment. Feng:Bioverativ: Employment. Al-Khateeb:Bioverativ: Other: Consultancy (via Trinity Partners, LLC). Dumont:Bioverativ: Employment. Jain:Bioverativ: Employment.

The U.S. Environmental Protection Agency’s (EPA) Water Laboratory Alliance relies on the Centers for Disease Control and Prevention’s ultrafiltration-based Water Processing Procedure (WPP) for concentration of biosafety level 3 (BSL-3) agents from 10 L to 100 L of drinking water. The WPP requires comprehensive training and practice to maintain proficiency, resulting in a critical need for quality control (QC) criteria. The aim of this study was to develop criteria using male-specific (MS2) coliphage (BSL-2 agent) to minimize safety hazards associated with BSL-3 agents and to use the criteria to evaluate analytical proficiency during a demonstration exercise. EPA Method 1602 with EasyPhage was used during the study to develop QC criteria for 100-mL, and 40–100 L samples. The demonstration exercise indicated that the MS2 criteria would allow laboratories to demonstrate proficiency using the WPP with 40–100 L samples. In addition, the QC criteria developed for 100-mL samples has broad applicability at laboratories that are using MS2 for other types of analyses, such as assessment of water treatment devices. The development of MS2 QC criteria allows laboratories to develop and confirm ongoing proficiency using the WPP.

The U.S. Environmental Protection Agency's (EPA) Water Laboratory Alliance (WLA) currently uses ultrafiltration (UF) for concentration of biosafety level 3 (BSL-3) agents from large volumes (up to 100-L) of drinking water prior to analysis. Most UF procedures require comprehensive training and practice to achieve and maintain proficiency. As a result, there was a critical need to develop quality control (QC) criteria. Because select agents are difficult to work with and pose a significant safety hazard, QC criteria were developed using surrogates, including Enterococcus faecalis and Bacillus atrophaeus. This article presents the results from the QC criteria development study and results from a subsequent demonstration exercise in which E. faecalis was used to evaluate proficiency using UF to concentrate large volume drinking water samples. Based on preliminary testing EPA Method 1600 and Standard Methods 9218, for E. faecalis and B. atrophaeus respectively, were selected for use during the QC criteria development study. The QC criteria established for Method 1600 were used to assess laboratory performance during the demonstration exercise. Based on the results of the QC criteria study E. faecalis and B. atrophaeus can be used effectively to demonstrate and maintain proficiency using ultrafiltration.