Genetic variant detection in a South African haemophilia B population.

BACKGROUND: Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. METHODS: Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. RESULTS AND DISCUSSION: A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. CONCLUSION: The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Unresolved hemostasis issues in haemophilia.

Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half-life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas.

Fix low dose venetoclax-azacitidine treatment of unfit acute myeloid leukemia patients.

The prognosis of elderly AML patients had not even been improved by using hypomethylating agents; however, synergistic effect of combining azacitidin with venetoclax had resulted in a remarkable therapeutic advance. Our goal was to study the latter treatment with a new dosing regimen in a retrospective/observational study. In our department, we analyzed the data of AML patients who were unfit for curative high-dose treatment and accepted the medication with a fixed-dose of azacitidin and venetoclax combination (AZA-VEN, 100 mg sc for 7 days-100 mg per os continuously). The primary end point was the overall survival. In total, 55 AML patients received the treatment between OCT/2019-DEC/2022. Mean age was 69.4-year (48-84), median overall survival was 17.2-month (95% CI, 14.3-20.10) Composite CR: (CR + CRi) 62%. Side effect CTCAE 3 or higher: neutropenia with fever: 36.4%, anemia: 29.1%, thrombocytopenia: 16.4% and nausea 20%. AZA-VEN combination treatment of our unfit AML patients was found to be a good therapeutic option. The results achieved with significantly lower doses of the fixed dose of AZA-VEN are comparable to the conclusions of the VIALE-A study, and the less severe side effects we have observed are explained by the milder neutropenia of the newly introduced regimen.

Easy-fix attentional focus manipulation boosts the intuitive and deliberate use of base-rate information.

In addressing human reasoning biases, "easy-fix" attentional focus interventions have shown that we can prompt reasoners to align responses with logico-mathematical principles. The current study aimed to test the impact of such interventions on both intuitive and deliberate responses on base-rate items. Using a two-response paradigm, participants provided initial intuitive responses under time constraints and cognitive load, followed by deliberate responses. During the intervention, we used attentional focus manipulations with base-rate items that aimed to redirect participants' attention toward the "logical" base-rate cue (i.e., the logical intervention) or toward the "heuristic" descriptive cue (i.e., the heuristic intervention). The results indicate that the logical intervention led to improved alignment with logico-mathematical principles in both intuitive and deliberate responses, albeit with a modest effect size. Conversely, the heuristic intervention had no discernible impact on accuracy. This indicates that our attentional focus manipulation is more effective at getting reasoners to respect rather than to override base-rates.

Autonomous Lunar Rover Localization while Fully Scanning a Bounded Obstacle-Rich Workspace.

This article addresses the scanning path plan strategy of a rover team composed of three rovers, such that the team explores unknown dark outer space environments. This research considers a dark outer space, where a rover needs to turn on its light and camera simultaneously to measure a limited space in front of the rover. The rover team is deployed from a symmetric base station, and the rover team's mission is to scan a bounded obstacle-rich workspace, such that there exists no remaining detection hole. In the team, only one rover, the hauler, can locate itself utilizing stereo cameras and Inertial Measurement Unit (IMU). Every other rover follows the hauler, while not locating itself. Since Global Navigation Satellite System (GNSS) is not available in outer space, the localization error of the hauler increases as time goes on. For rover's location estimate fix, one occasionally makes the rover home to the base station, whose shape and global position are known in advance. Once a rover is near the station, it uses its Lidar to measure the relative position of the base station. In this way, the rover fixes its localization error whenever it homes to the base station. In this research, one makes the rover team fully scan a bounded obstacle-rich workspace without detection holes, such that a rover's localization error is bounded by letting the rover home to the base station occasionally. To the best of our knowledge, this article is novel in addressing the scanning path plan strategy, so that a rover team fully scans a bounded obstacle-rich workspace without detection holes, while fixing the accumulated localization error occasionally. The efficacy of the proposed scanning and localization strategy is demonstrated utilizing MATLAB-based simulations.

Concurrent plate fixation and pedicled flap coverage for open fractures complicated by soft tissue loss of the tibia in pediatric cohort: a clinical series.

BACKGROUND: The optimal treatment of open fractures complicated by soft tissue loss of pediatric tibial fractures remains inconclusive. The author described a protocol of concurrent plate fixation and pedicled flap coverage and retrospectively reviewed the outcomes of such injuries. METHODS: A total of 25 pediatric cases with Gustilo lllB open tibial fracture were treated by single-stage plate fixation and pedicled flap reconstruction. The reviewed information consisted of time to fix and flap, type of plate, type of pedicled flap, fracture union time, postoperative complication and the clinical outcomes by objective scoring system. RESULTS: Fix and flap was undergone between 7 and 12 days after injury with the average time of 8.2 days. Regarding the type of plate, narrow LCP was applied in 8, 3.5 mm precontoured LCP in 10, 5.0 mm precontoured in 2 and double LCP in 5. According to soft tissue reconstruction, the medial gastrocnemius flap was selected in 6 cases, myocutaneous medial gastrocnemius flap in 2, soleus flap in 3, hemisoleus flap in 5, reverse sural flap in 6 and combined medial gastrocnemius and hemisoleus flaps in 3. No flap-related complication was demonstrated. All cases established fracture union in between 12 and 24 weeks with an average time to union of 17.7 weeks. According to postoperative complications, infected plate occurred in 2 cases and implant irritation in 5. According to Puno functional score, excellent results were presented in 7 cases and good results in 18 cases. CONCLUSION: Single-stage plate fixation and pedicled flap coverage are a reliable regimen for pediatric open fractures complicated by soft tissue loss of the tibia.

A comparison of multiband and multiband multiecho gradient-echo EPI for task fMRI at 3 T.

A multiband (MB) echo-planar imaging (EPI) sequence is compared to a multiband multiecho (MBME) EPI protocol to investigate differences in sensitivity for task functional magnetic resonance imaging (fMRI) at 3 T. Multiecho sampling improves sensitivity in areas where single-echo-EPI suffers from dropouts. However, It requires in-plane acceleration to reduce the echo train length, limiting the slice acceleration factor and the temporal and spatial resolution Data were acquired for both protocols in two sessions 24 h apart using an adapted color-word interference Stroop task. Besides protocol comparison statistically, we performed test-retest reliability across sessions for different protocols and denoising methods. We evaluated the sensitivity of two different echo-combination strategies for MBME-EPI. We examined the performance of three different data denoising approaches: "Standard," "AROMA," and "FIX" for MB and MBME, and assessed whether a specific method is preferable. We consider using an appropriate autoregressive model order within the general linear model framework to correct TR differences between the protocols. The comparison between protocols and denoising methods showed at group level significantly higher mean z-scores and the number of active voxels for MBME in the motor, subcortical and medial frontal cortices. When comparing different echo combinations, our results suggest that a contrast-to-noise ratio weighted echo combination improves sensitivity in MBME compared to simple echo-summation. This study indicates that MBME can be a preferred protocol in task fMRI at spatial resolution (≥2 mm), primarily in medial prefrontal and subcortical areas.

IDEAL study: A real-world assessment of pattern of use and clinical outcomes with recombinant coagulation factor IX albumin fusion protein (rIX-FP) in patients with haemophilia B in Italy.

INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.

Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: A review of the literature.

INTRODUCTION: People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life. AIM: To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making. METHODS: A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life. RESULTS: Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n = 609) and 29% (n = 668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n = 599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health. CONCLUSION: There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype.

Management of a broken guiding catheter tip: Cut and fix technique.

A 49-year-old male presented with class III exertional angina, 1 year after angioplasty of the left anterior descending artery (LAD) and right coronary artery. Coronary angiogram revealed 90% in-stent restenosis (ISR) in mid-LAD with angiographic impression of stent fracture. Optical coherence tomographic evaluation of mid-LAD ISR showed a distinct 3 mm long "eclipse sign" indicating embolized, broken guiding catheter tip as a cause of ISR, which was confirmed on reviewing 1-year-old angiographic images. This was managed with "cut and fix technique" using cutting balloon and another drug-eluting stent. Optical coherence tomographic at 9 months showed well endothelialized stent with a thin layer of neo-intimal hyperplasia over the sandwiched broken guiding tip.

Predicting kill sites of an apex predator from GPS data in different multiprey systems.

Kill rates are a central parameter to assess the impact of predation on prey species. An accurate estimation of kill rates requires a correct identification of kill sites, often achieved by field-checking GPS location clusters (GLCs). However, there are potential sources of error included in kill-site identification, such as failing to detect GLCs that are kill sites, and misclassifying the generated GLCs (e.g., kill for nonkill) that were not field checked. Here, we address these two sources of error using a large GPS dataset of collared Eurasian lynx (Lynx lynx), an apex predator of conservation concern in Europe, in three multiprey systems, with different combinations of wild, semidomestic, and domestic prey. We first used a subsampling approach to investigate how different GPS-fix schedules affected the detection of GLC-indicated kill sites. Then, we evaluated the potential of the random forest algorithm to classify GLCs as nonkills, small prey kills, and ungulate kills. We show that the number of fixes can be reduced from seven to three fixes per night without missing more than 5% of the ungulate kills, in a system composed of wild prey. Reducing the number of fixes per 24 h decreased the probability of detecting GLCs connected with kill sites, particularly those of semidomestic or domestic prey, and small prey. Random forest successfully predicted between 73%-90% of ungulate kills, but failed to classify most small prey in all systems, with sensitivity (true positive rate) lower than 65%. Additionally, removing domestic prey improved the algorithm's overall accuracy. We provide a set of recommendations for studies focusing on kill-site detection that can be considered for other large carnivore species in addition to the Eurasian lynx. We recommend caution when working in systems including domestic prey, as the odds of underestimating kill rates are higher.

The assessment of effectiveness, tolerance, and patient satisfaction with the use of a new fixed-dose combination product, containing salmeterol and fluticasone propionate, Salflumix Easyhaler® in the treatment of asthma in the daily clinical practice.

BACKGROUND: The effectiveness of a fix-dose salmeterol/fluticasone combination therapy in asthma was previously shown for the original product. The study aim was to evaluate the clinical effectiveness and safety of a second entry DPI - dry powder inhaler (Salflumix Easyhaler) in patients with asthma in everyday clinical practice. PATIENTS AND METHODS: This multicenter Investigator-Initiated Study that enrolled 2,037 adult outpatients with asthma treated with Salflumix Easyhaler, was conducted by 220 pulmonologists across Poland. Asthma control was assessed during 3 visits with 6 ± 2 weeks intervals based on the Asthma Control Test (ACT). In addition, patient Satisfaction with Asthma Treatment Questionnaire (SATQ) and adherence and adverse events (AEs) were monitored. RESULTS: During the observation (86 ± 30 days) the percentage of patients with controlled asthma (ACT 20-25 pts) increased from 35.5% at the first visit to 86.5% at the third visit (p < 0.001). In the subgroup analysis, there were more patients not obtaining asthma control among patients that switched from the treatment with other devices than in naive ones. Global SATQ scores increased from 5.8 ± 0.7 to 6.2 ± 0.6 during the observation. Patients' satisfaction with the use of the Salflumix Easyhaler was high. Adherence exceeded 95%. Eight AEs were reported. CONCLUSIONS: Salflumix Easyhaler is highly effective and well-tolerated by naïve patients with asthma and those switching from another device. In general, patients show good compliance with medical product and are satisfied with the use of this new device, and not reporting difficulties and errors related to its' use. Their physicians' overall perception of Salflumix Easyhaler use is very positive.

Simultaneous internal fixation and latissimus dorsi pedicle flap coverage: A reliable regimen for open fractures with accompanying sizable soft tissue loss of the upper extremities.

BACKGROUND: The optimal treatment protocol for open fractures with accompanying sizable soft tissue defect of the upper extremities has not been specifically delineated. The authors described the concurrent use of internal fixation and latissimus dorsi (LD) pedicle flap coverage in managing such complex fractures. METHODS: Twenty patients with open fractures accompanied by large soft tissue defect of the upper extremities (8 clavicle fractures and 12 humeral fractures) were treated by fix & LD pedicle flap. The dimension of the defect, time to fix & flap, post-operative complications, time to union and clinical measurements were recorded. RESULTS: The mean size of the defect was 132.45 cm2 (range 6-12 x 2-20 cm2). The average time to fix & flap was 9.9 days (range 7-14). Fractures union was achieved in all patients with an average duration of 18.5 weeks (range 14-28). Regarding post-operative complications, distal flap necrosis occurred in 3 patients, retained seroma in 3 and heterotopic ossification in 1. By the Mayo Elbow Performance (MEP) score, 3 cases were considered to be excellent, 6 were good, 7 were fair and 4 were poor. By the University of California-Los Angeles (UCLA) shoulder score, 2 cases were considered to be excellent, 7 were good, 7 were fair and 4 were poor. The average Disabilities of Arm, Shoulder and Hand (DASH) score was 31.29 (range 12.5-58.3). CONCLUSION: Fix & LD pedicle flap is a reliable regimen for open fractures with sizable soft tissue defect of the clavicle and humerus.

CRISPR-Mediated In Situ Introduction or Integration of F9-Padua in Human iPSCs for Gene Therapy of Hemophilia B.

Hemophilia B (HB) is an X-linked recessive disease caused by F9 gene mutation and functional coagulation factor IX (FIX) deficiency. Patients suffer from chronic arthritis and death threats owing to excessive bleeding. Compared with traditional treatments, gene therapy for HB has obvious advantages, especially when the hyperactive FIX mutant (FIX-Padua) is used. However, the mechanism by which FIX-Padua works remains ambiguous due to a lack of research models. Here, in situ introduction of F9-Padua mutation was performed in human induced pluripotent stem cells (hiPSCs) via CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs). The hyperactivity of FIX-Padua was confirmed to be 364% of the normal level in edited hiPSCs-derived hepatocytes, providing a reliable model for exploring the mechanism of the hyperactivity of FIX-Padua. Moreover, the F9 cDNA containing F9-Padua was integrated before the F9 initiation codon by CRISPR/Cas9 in iPSCs from an HB patient (HB-hiPSCs). Integrated HB-hiPSCs after off-target screening were differentiated into hepatocytes. The FIX activity in the supernatant of integrated hepatocytes showed a 4.2-fold increase and reached 63.64% of the normal level, suggesting a universal treatment for HB patients with various mutations in F9 exons. Overall, our study provides new approaches for the exploration and development of cell-based gene therapy for HB.

[Sumatriptan-naproxen sodium fix-dose combination for acute migraine treatment, a review]. / Szumatriptán­naproxén-nátrium fix dózisú kombinációja a migrén akut kezelésében ­ irodalmi áttekintés.

Migraine as a common primary headache disorder has a significant negative effect on quality of life of the patients. Its pharmacotreatment includes acute and preventative therapies. Based on the shared therapeutic guideline of the European Headache Federation and the European Academy of Neurology for acute migraine treatment a combination of triptans and non-steroidal anti-inflammatory drugs is recommended for acute migraine treatment in triptan-nonresponders. In this short review we summarized the results of the randomized controlled clinical trials evaluating the effectiveness and safety of sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination. It was revealed that the fix-dose combination was better than placebo for the primary outcomes of exemption of pain and headache relief at 2 hours. Furthermore the combination showed beneficial effect on accompanying symptoms of migraine attack (i.e. nausea, photo- and phonophobia). Adverse events were mild or moderate in severity and rarely led to withdrawal of the drug.
It can be concluded that sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination is effective, safe and well-tolerated in the acute treatment of migraine. 

Acute versus delayed total hip arthroplasty after acetabular fracture fixation: a systematic review and meta-analysis.

BACKGROUND: Post-traumatic osteoarthritis (PTOA) is a disabling complication of open reduction and internal fixation (ORIF) for acetabular fractures. There is a trend towards acute total hip arthroplasty (THA), 'fix-and-replace', in patients considered to have a poor prognosis and likelihood of PTOA. Controversy remains between early fix-and-replace, versus delayed THA as required after initial ORIF. This systematic review included studies comparing functional and clinical outcomes between acute versus delayed THA after displaced acetabular fractures. METHODS: Comprehensive searches following the PRISMA guideline were performed on six databases for articles in English published anytime up to 29 March 2021. Two authors screened articles and discrepancies were resolved by consensus. Patient demographics, fracture classification, functional and clinical outcomes were compiled and analysed. RESULTS: The search yielded 2770 unique studies, of which five retrospective studies were identified with a total of 255 patients. Of them, 138 (54.1%) were treated with acute and 117 (45.9%) treated with delayed THA. Delayed THA group represented a younger cohort compared to the acute group (mean age, 64.3 vs 73.3). The mean follow-up time for the acute and delayed group was 23 and 50 months, respectively. There was no difference in functional outcomes between the two study groups. Complication and mortality rates were comparable. Delayed THA had a higher revision rate compared to the acute group (17.1 vs 4.3%; p = 0.002). CONCLUSION: Fix-and-replace had functional outcomes and complication rates similar to ORIF and delayed THA, but lower revision rates. Although the quality of studies was mixed, sufficient equipoise now exists to justify randomised studies in this area. PROSPERO registration: CRD42021235730.

Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies.

Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance.

The important impact of dental care on haemostatic treatment burden in patients with mild haemophilia.

BACKGROUND: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. OBJECTIVES: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. METHODS: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint-Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18-81 years). RESULTS: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. CONCLUSION: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Eradication of FIX inhibitor in haemophilia B children using low-dose immune tolerance induction with rituximab-based immunosuppressive agent(s) in China.

INTRODUCTION: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. AIM: To characterize clinical features and outcome of ITI on HBI. METHODS: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-times-weekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. RESULTS: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months). CONCLUSIONS: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications.