Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

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 < .0001) and the Treatment (-13.94; p < .0001), Feelings (-9.01; p < .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.

Observational cohort study of long-term outcomes of liver transplantation in haemophilia.

INTRODUCTION: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality-of-life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX- men in the ATHNdataset to compare post-OLTX factor VIII and IX on quality of life (QoL) by Haem-A-QoL and PROMIS-29. METHODS: OLTX- were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post-transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem-A-Qol and PROMIS-29 were compared in OLTX+ and OLTX- by student's t-test and univariate regression models. RESULTS: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX- were identified. OLTX+ and OLTX- had a similar frequency of target joint disease (p = .806), HA genotypes, null versus non-null (p = .696), and HIV infection (p = .316). At a median 9.2 years post-OLTX, median FVIII, .63 IU/mL [IQR 0.52-0.97] and FIX, .91 IU/mL [IQR .63-1.32], Haem-A-QoL, PROMIS-29, and HOT scores were comparable. Severe HA/HB had lower post-OLTX 'dealing with haemophilia' scores (p = .022) and higher 'sports and leisure' (p = .010) and 'view of yourself' scores (p = .024) than OLTX+ non-severe participants. Non-caucasian OLTX+ had significantly lower scores in sports and leisure (p = .042), future expectations (p = .021) and total score (p = .010). CONCLUSION: Nine years after OLTX, QoL is comparable to OLTX-, but significantly better in OLTX+ with severe than non-severe disease and in caucasians than non-caucasians.

Prophylaxis with recombinant factor IX Fc fusion protein reduces the risk of bleeding and delays time to first spontaneous bleed event in previously untreated patients with haemophilia B: A post hoc analysis of the PUPs B-LONG study.

OBJECTIVES: Haemophilia B (HB), characterised by deficient factor IX (FIX), leads to spontaneous bleeds. Severe cases require prophylactic FIX replacement. This post hoc analysis assessed the first spontaneous bleeds among previously untreated patients (PUPs) with HB treated with recombinant FIX Fc fusion protein (rFIXFc) (NCT02234310) to identify factors influencing bleeds. METHODS: Subjects included paediatric PUPs with HB (≤2 IU/dL endogenous FIX). Analyses described treatment patterns (on demand [OD] vs. prophylaxis) and prophylaxis type (started on vs. switched to prophylaxis). Kaplan-Meier analyses assessed the time to first spontaneous bleed, including median time to event and fitting models with predictors for treatment regimen and/or baseline age. RESULTS: PUPs B-LONG enrolled 33 subjects. Baseline age did not influence the time to first spontaneous bleed for any rFIXFc regimen. Those who started on prophylaxis with rFIXFc (n = 11), compared with those treated OD (n = 22), had an extended time to first spontaneous bleed. Starting prophylaxis afforded a 93% reduced risk of first spontaneous bleed versus starting OD (hazard ratio [95% confidence interval]: 0.071 [0.009-0.592]) (p = .015). CONCLUSION: rFIXFc prophylaxis, particularly starting early, reduced the risk of bleeding and delayed time to first spontaneous bleed compared with rFIXFc OD. Hence, initial treatment regimens impact bleed patterns in paediatric PUPs.

Deep Learning Reconstruction Enables Prospectively Accelerated Clinical Knee MRI.

Background MRI is a powerful diagnostic tool with a long acquisition time. Recently, deep learning (DL) methods have provided accelerated high-quality image reconstructions from undersampled data, but it is unclear if DL image reconstruction can be reliably translated to everyday clinical practice. Purpose To determine the diagnostic equivalence of prospectively accelerated DL-reconstructed knee MRI compared with conventional accelerated MRI for evaluating internal derangement of the knee in a clinical setting. Materials and Methods A DL reconstruction model was trained with images from 298 clinical 3-T knee examinations. In a prospective analysis, patients clinically referred for knee MRI underwent a conventional accelerated knee MRI protocol at 3 T followed by an accelerated DL protocol between January 2020 and February 2021. The equivalence of the DL reconstruction of the images relative to the conventional images for the detection of an abnormality was assessed in terms of interchangeability. Each examination was reviewed by six musculoskeletal radiologists. Analyses pertaining to the detection of meniscal or ligament tears and bone marrow or cartilage abnormalities were based on four-point ordinal scores for the likelihood of an abnormality. Additionally, the protocols were compared with use of four-point ordinal scores for each aspect of image quality: overall image quality, presence of artifacts, sharpness, and signal-to-noise ratio. Results A total of 170 participants (mean age ± SD, 45 years ± 16; 76 men) were evaluated. The DL-reconstructed images were determined to be of diagnostic equivalence with the conventional images for detection of abnormalities. The overall image quality score, averaged over six readers, was significantly better (P < .001) for the DL than for the conventional images. Conclusion In a clinical setting, deep learning reconstruction enabled a nearly twofold reduction in scan time for a knee MRI and was diagnostically equivalent with the conventional protocol. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Roemer in this issue.

Designing Clinical MRI for Enhanced Workflow and Value.

MRI is an expensive and traditionally time-intensive modality in imaging. With the paradigm shift toward value-based healthcare, radiology departments must examine the entire MRI process cycle to identify opportunities to optimize efficiency and enhance value for patients. Digital tools such as "frictionless scheduling" prioritize patient preference and convenience, thereby delivering patient-centered care. Recent advances in conventional and deep learning-based accelerated image reconstruction methods have reduced image acquisition time to such a degree that so-called nongradient time now constitutes a major percentage of total room time. For this reason, architectural design strategies that reconfigure patient preparation processes and decrease the turnaround time between scans can substantially impact overall throughput while also improving patient comfort and privacy. Real-time informatics tools that provide an enterprise-wide overview of MRI workflow and Picture Archiving and Communication System (PACS)-integrated instant messaging can complement these efforts by offering transparent, situational data and facilitating communication between radiology team members. Finally, long-term investment in training, recruiting, and retaining a highly skilled technologist workforce is essential for building a pipeline and team of technologists committed to excellence. Here, we highlight various opportunities for optimizing MRI workflow and enhancing value by offering many of our own on-the-ground experiences and conclude by anticipating some of the future directions for process improvement and innovation in clinical MR imaging. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 1.

Patient-centered radiology: a roadmap for outpatient imaging.

Creating a patient-centered experience is becoming increasingly important for radiology departments around the world. The goal of patient-centered radiology is to ensure that radiology services are sensitive to patients' needs and desires. This article provides a framework for addressing the patient's experience by dividing their imaging journey into three distinct time periods: pre-exam, day of exam, and post-exam. Each time period has aspects that can contribute to patient anxiety. Although there are components of the patient journey that are common in all regions of the world, there are also unique features that vary by location. This paper highlights innovative solutions from different parts of the world that have been introduced in each of these time periods to create a more patient-centered experience. CLINICAL RELEVANCE STATEMENT: Adopting innovative solutions that help patients understand their imaging journey and decrease their anxiety about undergoing an imaging examination are important steps in creating a patient centered imaging experience. KEY POINTS: • Patients often experience anxiety during their imaging journey and decreasing this anxiety is an important component of patient centered imaging. • The patient imaging journey can be divided into three distinct time periods: pre-exam, day of exam, and post-exam. • Although components of the imaging journey are common, there are local differences in different regions of the world that need to be considered when constructing a patient centered experience.

Hopping as an Indicator of Chemotoxicity: Gait Analysis in Patients With Leukemia and Lymphoma.

BACKGROUND: Survivors of acute lymphoblastic leukemia (ALL) can experience chemotherapy-related changes in neuromuscular function, which can persist and impact the quality of life. Clinically, neuromuscular changes are assessed by observing gait. The primary aims of this study were to compare observational gait/functional movement analysis to matched electronic gait analysis in children with ALL and lymphoblastic lymphoma at specific time points during and after treatment. PATIENTS AND METHODS: Participants 2 to 27 years old diagnosed with ALL/lymphoblastic lymphoma who were on or off therapy within 10 years were eligible. Participants underwent electronic gait assessment using GAITRite, observational gait, and functional movement analysis and completed quality of life questionnaires. Parents also completed quality-of-life assessments. RESULTS: Electronic gait parameters were not different in this cohort compared with controls. Mean overall scores on observational gait and functional movement analysis improved over time. Hopping was the most frequent and walking was the least frequent noted deficit. Participants had a lower patient and parent-reported QoL scores compared with the general population. CONCLUSION: Observational gait and functional movement analysis identified more deficits than the electronic gait assessment. Future studies are warranted to determine whether hopping deficits are an early clinical indicator of toxicity and signal for intervention.

Fast and Frictionless: A Novel Approach to Radiology Appointment Scheduling Using a Mobile App and Recommendation Engine.

Many outpatient radiology orders are never scheduled, which can result in adverse outcomes. Digital appointment self-scheduling provides convenience, but utilization has been low. The purpose of this study was to develop a "frictionless" scheduling tool and evaluate the impact on utilization. The existing institutional radiology scheduling app was configured to accommodate a frictionless workflow. A recommendation engine used patient residence, past and future appointment data to generate three optimal appointment suggestions. For eligible frictionless orders, recommendations were sent in a text message. Other orders received either a text message for the non-frictionless app scheduling approach or a call-to-schedule text. Scheduling rates by type of text message and scheduling workflow were analyzed. Baseline data for a 3-month period prior to the launch of frictionless scheduling showed that 17% of orders that received an order notification text were scheduled using the app. In an 11-month period after the launch of frictionless scheduling, the rate of app scheduling was greater for orders that received a text message with recommendations (frictionless approach) versus app schedulable orders that received a text without recommendations (29% vs. 14%, p < 0.01). Thirty-nine percent of the orders that received a frictionless text and scheduled using the app used a recommendation. The most common recommendation rules chosen for scheduling included location preference of prior appointments (52%). Among appointments that were scheduled using a day or time preference, 64% were based on a rule using the time of the day. This study showed that frictionless scheduling was associated with an increased rate of app scheduling.

Building the blueprint: Formulating a community-generated national plan for future research in inherited bleeding disorders.

INTRODUCTION: Decades of inherited bleeding disorders (BD) research transformed severe haemophilia from a childhood killer to a disorder managed across a full lifespan for many in economically developed countries. Health equity, a life unimpaired by disease complications, however, remains unimaginable for most people with an inherited BD (PWIBD). AIM: The National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network (ATHN) undertook the development of a community-driven United States (US) National Blueprint for Inherited Bleeding Disorders Research to transform the experience of all PWIBD and those who care for them. METHODS: Extensive community consultations were conducted to identify the issues most important to PWIBD and those who love and care for them. Expert multidisciplinary teams distilled these key areas of need into prioritised research questions, and identified the resources and infrastructure required to pursue them. A summit was held to gather feedback and inform the detailed blueprint. RESULTS: Community-prioritised research areas fell into three broad categories: issues common across inherited BDs, those specific to individual disorders, and issues of infrastructure and capacity. NHF State of the Science Research Summit discussions of the research questions derived from the community priorities by six working groups provided important input for the drafting of the research blueprint for the coming decades. CONCLUSION: The inherited BD community came together to develop the US National Blueprint for Inherited Bleeding Disorders Research dedicated to transforming the lives of all PWIBD including innovating solutions for the rarest disorders and under-represented populations.

Big picture initiatives in bleeding disorders.

INTRODUCTION: The inherited bleeding disorders (IBD) community has witnessed significant therapeutic advances recently, yet important gaps persist, particularly for those with rare disorders and historically underserved populations. AIMS: -To create a national research blueprint agenda, led by the National Hemophilia Foundation (NHF), enhancing patient-centric principles, accelerate research progress and address important gaps in care. -To review critical gaps that remain to be addressed in women with IBDs, who face specific bleeding challenges. METHODS: The NHF research blueprint research agenda was defined by input from across the community, including caregivers and patients who are considered subject matter experts of their IBD, research leaders, allied health professionals and specialists, and representatives of the biopharmaceutical industry. In addition, two medical experts in the field of IBDs performed a comprehensive review to address the knowledge gaps in women with IBDs. RESULTS: Two foundational principles of the NHF blueprint are: (1) it must deliver on key issues that significantly impact the lives of those affected by IBDs, and (2) the priorities defined are relevant and actionable aimed to achieve health equity among all those affected by IBDs. A multidisciplinary approach is necessary for an optimal management of puberty, transition to adulthood and pregnancy. Even if strict guidelines are followed, recent studies show that women with IBDs are still facing a high burden. CONCLUSION: NHF blueprint will be issued in 2022. A specific research agenda is needed in women with IBDs to further improve their management and quality of life.

The GOAL-Hem journey: Shared decision making and patient-centred outcomes.

INTRODUCTION: GOAL-Hem is a novel, haemophilia-specific, patient-centred outcome measure (PCOM) based on goal attainment scaling, allowing people with haemophilia (PwH) to set and monitor the attainment of individualized goals for treatment. AIM: To provide a thorough overview of the creation, validation, and development of GOAL-Hem. METHODS: Clinician workshops were held to develop a haemophilia-specific goal menu. Qualitative data from semistructured interviews with PwH and their caregivers guided further revisions to the goal menu (i.e., goal domains and descriptors). A feasibility study was performed including a 12-week, prospective, noninterventional evaluation involving clinicians and PwH at four US haemophilia treatment centres. Finally, the Patient Voice Study gathered feedback from PwH and their caregivers via an online survey, interviews, and a focus group. RESULTS: The feasibility study validated GOAL-Hem with successful outcomes in construct/content validity and responsiveness, including a large effect in patient- and clinician-rated goal attainments. The Patient Voice Study led to significant refinement of GOAL-Hem goals and descriptors, resulting in a more straightforward and relatable menu for PwH and their caregivers. Overall, GOAL-Hem captured qualitative data in areas important to PwH and employed quantitative methods to evaluate meaningful changes in those areas. The individualized tool was well equipped to handle the complex and chronic nature of haemophilia and was endorsed by PwH, their caregivers, and clinicians. CONCLUSION: The GOAL-Hem development journey may serve as a roadmap for other PCOMs in a variety of settings, including clinical studies, haemophilia treatment centres for care planning, and as a tool to gather real-world evidence.

Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors.

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 µg/kg eptacog beta followed by 75 µg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS: Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 µg/kg initial dose regimen (IDR) and 60% in the 225 µg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 µg/kg IDR and 98% for the 225 µg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION: Both 75 and 225 µg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Video Radiology Reports: A Valuable Tool to Improve Patient-Centered Radiology.

BACKGROUND. Improved communication between radiologists and patients is a key component of patient-centered radiology. OBJECTIVE. The purpose of this study was to create patient-centered video radiology reports using simple-to-understand language and annotated images and to assess the effect of these reports on patients' experience and understanding of their imaging results. METHODS. During a 4-month study period, faculty radiologists created video radiology reports using a tool integrated within the diagnostic viewer that allows both image and voice capture. To aid patients' understanding of cross-sectional images, cinematically rendered images were automatically created and made immediately available to radiologists at the workstation, allowing their incorporation into video radiology reports. Video radiology reports were made available to patients via the institutional health portal along with the written radiology report and the examination images. Patient views of the video report were recorded, and descriptive analyses were performed on radiologist and examination characteristics as well as patient demographics. A survey was sent to patients to obtain feedback on their experience. RESULTS. During the study period, 105 of 227 faculty radiologists created 3763 video radiology reports (mean number of reports per radiologist, 36 ± 27 [SD] reports). Mean time to create a video report was 238 ± 141 seconds. Patients viewed 864 unique video reports. The mean overall video radiology report experience rating based on 101 patient surveys was 4.7 of 5. The mean rating for how well the video report helped patients understand their findings was also 4.7 of 5. Of the patients who responded to the survey, 91% preferred having both written and video reports together over having written reports alone. CONCLUSION. Patient-centered video radiology reports are a useful tool to help improve patient understanding of imaging results. The mechanism of creating the video reports and delivering them to patients can be integrated into existing informatics infrastructure. CLINICAL IMPACT. Video radiology reports can play an important role in patient-centered radiology, increasing patient understanding of imaging results, and they may improve the visibility of radiologists to patients and highlight the radiologist's important role in patient care.

Artificial intelligence in musculoskeletal imaging: a perspective on value propositions, clinical use, and obstacles.

Artificial intelligence and deep learning (DL) offer musculoskeletal radiology exciting possibilities in multiple areas, including image reconstruction and transformation, tissue segmentation, workflow support, and disease detection. Novel DL-based image reconstruction algorithms correcting aliasing artifacts, signal loss, and noise amplification with previously unobtainable effectiveness are prime examples of how DL algorithms deliver promised value propositions in musculoskeletal radiology. The speed of DL-based tissue segmentation promises great efficiency gains that may permit the inclusion of tissue compositional-based information routinely into radiology reports. Similarly, DL algorithms give rise to a myriad of opportunities for workflow improvements, including intelligent and adaptive hanging protocols, speech recognition, report generation, scheduling, precertification, and billing. The value propositions of disease-detecting DL algorithms include reduced error rates and increased productivity. However, more studies using authentic clinical workflow settings are necessary to fully understand the value of DL algorithms for disease detection in clinical practice. Successful workflow integration and management of multiple algorithms are critical for translating the value propositions of DL algorithms into clinical practice but represent a major roadblock for which solutions are critically needed. While there is no consensus about the most sustainable business model, radiology departments will need to carefully weigh the benefits and disadvantages of each commercially available DL algorithm. Although more studies are needed to understand the value and impact of DL algorithms on clinical practice, DL technology will likely play an important role in the future of musculoskeletal imaging.

The critical need for postmarketing surveillance in gene therapy for haemophilia.

INTRODUCTION: The goal of gene therapy for haemophilia is to alter the clinical phenotype to a milder form or even cure, by increasing endogenous coagulation factor levels through transfer of a functional gene encoding the respective deficient coagulation factor and subsequent transgene expression. Over the past decade, there has been tremendous progress in gene therapy, particularly in use of liver-directed adeno-associated viral vectors, such that several programmes for both haemophilia A and B are in phase 3 trials. With regulatory approval of the first gene therapy product expected as early as mid-2020, there is an urgent need for a mechanism to collect long-term data on safety and variability and durability of efficacy. There will be elements required by regulators for postmarketing surveillance and additional data needed to enhance our understanding of gene therapy outcomes and their impact on the lives of people with haemophilia. AIM: The aim of this manuscript was to describe efforts underway by the American Thrombosis and Hemostasis Network and the World Federation of Hemophilia to collect long-term harmonized data and considerations of the European and US regulatory agencies, which will inform ongoing data collection. METHODS: The status of data collection around gene therapy in haemophilia and important outcome measures were obtained by literature review. Each author described elements relevant to the activities of their organization. CONCLUSION: Support of all stakeholders in gene therapy, providers, patients, industry and regulators, augers successful capture of uniform long-term safety and efficacy data to ensure optimal treatment of people with haemophilia.

Biomarkers of bone disease in persons with haemophilia.

INTRODUCTION: Persons with haemophilia (PwH) have abnormally low bone density and increased risk of fractures. We previously demonstrated decreased skeletal health in factor VIII (FVIII)-deficient mice. Thus, we hypothesized factor deficiency is an independent risk factor for decreased skeletal health. AIM: We seek to identify differences in bone-related cytokine expression among PwH and healthy controls. METHODS: We evaluated plasma samples from 79 participants with severe FVIII deficiency and 51 age-matched healthy controls. Plasma samples were assessed for RANKL and OPG, cytokines that regulate bone metabolism, and CTX-1, a biomarker for bone resorption, as well as 10 bone-related cytokines. RESULTS: CTX-1 is higher among samples from FVIII-deficient participants compared to controls (P < .01) but not among participants with recent factor use (within 24 hours of sample collection) (P = .21). Among PwH greater than 16 years of age (PwH ≥ 16), OPG is increased with recent factor use (P < .01) but not without (P = .34). Lower levels of TNF-α (P < .01), interleukin (IL)-12 (P < .01) and IL-10 (P < .001) were found among samples from PwH. Controlling for subject age, IL-12 and IL-10 levels are lower in PwH ≥ 16 (P < .01, P < .001) but not PwH under 16 (PwH < 16) (P > .05). Levels of TNF-α were lower among PwH < 16 only (P < .05). These differences are not observed in participants with recent factor use. CONCLUSIONS: In PwH, markers of bone metabolism and circulating cytokine levels are abnormal. Recent factor use reverses many of these differences suggesting FVIII replacement ameliorates this pathology. This study suggests bone disease present in PwH is intrinsic to FVIII deficiency.

Impact of haemophilia on patients with mild-to-moderate disease: Results from the P-FiQ and B-HERO-S studies.

INTRODUCTION: Epidemiologic studies suggest that joint bleeding occurs in patients with mild-to-moderate haemophilia, including women and girls. However, most previous studies on the impacts of haemophilia focus on men with severe disease. AIM: To identify unmet needs in men and women with mild-to-moderate haemophilia. METHODS: The Pain, Functional Impairment, and Quality of Life (P-FiQ) study assessed the impact of pain on functional impairment and health-related quality of life in men with haemophilia A or B of any severity. The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) study evaluated the psychosocial needs of adults and children with haemophilia B of any severity, including women and girls. Both studies employed patient-reported outcome measures. RESULTS: In the P-FiQ study, 16% (62/381) of participants had mild and 13% (50/381) had moderate haemophilia. In the B-HERO-S study, 29% (86/299) of adult participants were female, 25% (74/299) had mild haemophilia, and 63% (189/299) had moderate haemophilia. In addition, 63% (46/74) of patients with mild and 86% (162/189) of patients with moderate haemophilia routinely infused factor products to prevent bleeding. Patients reported difficulty gaining access to factor products (54%; 142/263) and a haemophilia treatment centre (17%; 44/263). During the P-FiQ study, 78% (48/62) of patients with mild and 87% (44/50) with moderate haemophilia described problems with pain on the Brief Pain Inventory. Patients also reported issues with anxiety, depression and relationships. CONCLUSIONS: Mild-to-moderate haemophilia has physical and psychosocial impacts on patients. We offer some solutions to help alleviate these impacts and resolve unmet needs.

Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment.

INTRODUCTION: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. AIM: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. METHODS: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. RESULTS: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). CONCLUSION: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.